Anti-FGFR2 antibodies in combination with chemotherapy agents in cancer treatment

Abstract

To provide a method of treating gastric cancer in a subject.SOLUTION: The method comprises administering, to a subject having gastric cancer, a therapeutically effective amount of an anti-fibroblast growth factor receptor 2 IIIb (anti-FGFR2-IIIb) antibody and modified FOLFOX6 (mFOLFOX6) chemotherapy (oxaliplatin, leucovorin, 5-fluorouracil).SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 507,053, filed May 16, 2017, and U.S. Provisional Patent Application No. 62 / 581,992, filed November 6, 2017, which are incorporated by reference in their entireties.

[0002] The present application relates to the use of antibodies against fibroblast growth factor receptor 2 (FGFR2), such as antibodies against FGFR2 isoform FGFR2-IIIb (also known as FGFR2b), in the treatment of certain cancers in combination with mFOLFOX6 chemotherapy. [Background technology]

[0003] Fibroblast growth factor (FGF) family members bind to the four known tyrosine kinase receptors fibroblast growth factor receptors 1-4 (FGFR1-4) and their isoforms, and individual FGFs bind to different FGFRs to different degrees (Zhang et al., J. Biol. Chem. 281:15694, 2006). The protein sequence of human FGFR2 is provided, for example, in GenBank Locus AF487553. Each FGFR consists of an extracellular domain (ECD) containing three immunoglobulin (Ig)-like domains (D1, D2, and D3), a single transmembrane helix, and an intracellular catalytic kinase domain (Mohammadi et al., Cytokine Growth Factor Revs, 16:107, 2005). FGFs bind to the receptors primarily through the D2 and D3 regions of the receptor. The linker between D1 and D2 contains a region of consecutive acidic amino acids called the "acid box" (AB). The region containing D1 and AB is thought to be involved in autoinhibition of the receptor, which is relieved by binding to a ligand.

[0004] FGFRs are characterized by multiple alternative splicing of their mRNAs, resulting in various isoforms (Ornitz et al., J. Biol. Chem. 271:15292, 1996; for the sequence of FGFR2 and its isoforms, see also Swiss-Prot P21802 and isoforms P21802-1 to P21802-20). In particular, there are forms that contain all three Ig domains (α isoforms) or only two Ig domains, D2 and D3 domains but not D1 (β isoforms). In FGFR1, FGFR2 and FGFR3, all forms contain the first half of D3, designated IIIa, but for the second half of D3 two alternative exons can be used, resulting in forms IIIb and IIIc. For FGFR2, these forms are designated FGFR2-IIIb and FGFR2-IIIc (or simply FGFR2b and FGFR2c), respectively, and the corresponding beta forms are designated FGFR2(beta)IIIb and FGFR2(beta)IIIc. The FGFR2-IIIb form of FGFR2 (also designated K-sam-II) is a high affinity receptor for both FGF1 and KGF family members (FGF7, FGF10, and FGF22), whereas FGFR2-IIIc (also designated K-sam-I) binds well to both FGF1 and FGF2, but does not bind to KGF family members (Miki et al., Proc. Natl. Acad. Sci. USA 89:246, 1992). In fact, FGFR2-IIIb is the only receptor for KGF family members (Ornitz et al., 1996, op.cit.), and is therefore also designated KGFR.

[0005] FGFRs and their isoforms are differentially expressed in various tissues. FGFR2-IIIb (as well as the IIIb forms of FGFR1 and FGFR3) are expressed in epithelial tissues, whereas FGFR2-IIIc is expressed in mesenchymal tissues (Duan et al., J. Biol. Chem. 267:16076, 1992; Ornitz et al., 1996, op.cit.). Some of the FGF ligands of these receptors have opposite expression patterns. Thus, KGF subfamily members including FGF7 (KGF), FGF10 and FGF22 bind only to FGFR2-IIIb (Zhang et al., op.cit.) and are expressed in mesenchymal tissues, and therefore may be paracrine effectors of epithelial cells (Ornitz et al., 1996, op.cit.). In contrast, FGF4 subfamily members FGF4-6 bind to FGFR2-IIIc and are expressed in both epithelial and mesenchymal systems, and may therefore have either autocrine or paracrine functions. The expression patterns of FGFR2 isoforms and their ligands implicate FGFR2 in epithelial-mesenchymal interactions (Finch et al., Dev. Dyn. 203:223, 1995), so it is not surprising that knockout of FGFR2-IIIb in mice results in embryonic abnormalities and lethality (De Moerlooze et al., Development 127:483, 2000).

[0006] KGF (FGF7) and KGFR (FGFR2-IIIb) are overexpressed in many pancreatic cancers (Ishiwata et al., Am. J. Pathol. 153:213, 1998), and their coexpression correlates with poor prognosis (Cho et al., Am. J. Pathol. 170:1964, 2007). Somatic mutations in the FGFR2 gene were found in 12% of a large panel of endometrial (uterine) cancers and were required for tumor cell survival in some tested cases (Dutt et al., Proc. Natl. Acad. Sci. USA 105:8713, 2008). In the two tumors, the FGFR2 mutation was found to be the same S252W substitution associated with Apert syndrome. Amplification and overexpression of FGFR2 are associated with undifferentiated diffuse gastric cancer, which has a particularly poor prognosis, and inhibition of FGFR2 activity with small molecule compounds strongly inhibited the proliferation of such cancer cells (Kunii et al., Cancer Res. 68:2340, 2008; Nakamura et al., Gastroenterol. 131:1530, 2006).

[0007] Inhibition of FGFR signaling has been reported to improve anti-tumor immunity and reduce metastasis of breast cancer (see, e.g., T. Ye et al., Breast Cancer Res. Treat. 143:435-446 (2014)). Anti-FGFR2 antibodies have also been tested, for example, in models of gastric cancer. Specific anti-FGFR2 antibodies are described, for example, in U.S. Pat. No. 8,101,723 B2, including monoclonal antibodies that bind to human FGFR2-IIIb but poorly or not to FGFR2-IIIc, and vice versa. U.S. Patent Application Publication No. 2015-0050273 A1 describes certain afucosylated antibodies that bind to FGFR2-IIIb. Summary of the Invention

[0008] The present disclosure includes a method of treating a gastrointestinal cancer, such as, for example, gastric cancer, in a subject, comprising administering to the subject a therapeutically effective amount of anti-fibroblast growth factor receptor 2 (anti-FGFR2) and modified FOLFOX6 (mFOLFOX6) chemotherapy. In some embodiments, the anti-FGFR2 antibody is an anti-FGFR2-IIIb antibody. In some embodiments, the anti-FGFR2-IIIb antibody has one or more of the following properties: binds to FGFR2-IIIb with greater affinity than to FGFR2-IIIc or does not detectably bind to FGFR2-IIIc, inhibits binding of FGF2 to human FGFR2, inhibits binding of FGF7 to human FGFR2, inhibits human tumor growth in a mouse tumor model, induces ADCC activity, has enhanced ADCC activity, is afucosylated, and is capable of increasing the number of one or more of PD-L1 positive cells, NK cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, and macrophages in tumor tissue in a mouse tumor model compared to a control.

[0009] In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises a heavy chain hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 6, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8, and the light chain variable region comprises a light chain hypervariable region L1 (HVR-L1) comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain variable domain of the anti-FGFR2-IIIb antibody comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the light chain variable domain of the anti-FGFR2-IIIb antibody comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the heavy chain variable domain of the anti-FGFR2-IIIb antibody comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the light chain variable domain of the anti-FGFR2-IIIb antibody comprises the amino acid sequence of SEQ ID NO:5. In some embodiments, the heavy chain of the anti-FGFR2-IIIb antibody comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-FGFR2-IIIb antibody comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:3. In some embodiments, the heavy chain of the anti-FGFR2-IIIb antibody comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, the light chain of the anti-FGFR2-IIIb antibody comprises the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-FGFR2-IIIb antibody is a chimeric antibody, a humanized antibody, or a human antibody. In some embodiments, the anti-FGFR2-IIIb antibody is selected from Fab, Fv, scFv, Fab', and (Fab')2.

[0010] In some embodiments of the methods herein, the anti-FGFR2-IIIb antibody has one or more of the following properties: it lacks fucose at position Asn297, it comprises a kappa light chain constant region, it comprises an IgG1 heavy chain constant region, it has enhanced ADCC activity in vitro compared to an antibody having the same amino acid sequence in which position Asn297 is fucosylated, it has enhanced affinity for Fc gamma RIIIA compared to an antibody having the same amino acid sequence in which position Asn297 is fucosylated, and it is capable of increasing the number of one or more of PD-L1 positive cells, NK cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, and macrophages in tumor tissue in a mouse tumor model compared to a control.

[0011] In some embodiments of the methods herein, the subject has gastric cancer that is locally advanced, unresectable or metastatic. In some embodiments, the gastric cancer is gastroesophageal cancer.

[0012] In some embodiments of the methods herein, the anti-FGFR2-IIIb antibody is administered at a dose of 6-15 mg / kg, 10-15 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg. In some embodiments, the anti-FGFR2-IIIb antibody is administered once every 10-21 days, once every 10-15 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, or once every 21 days. In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dose of 6 mg / kg, 10 mg / kg or 15 mg / kg, and the anti-FGFR2-IIIb antibody is administered once every 14 days.

[0013] In some embodiments, the anti-FGFR2-IIIb antibody is administered in the following dosing regimen: (a) anti-FGFR2-IIIb antibody is administered at a dose of 6 to 15 mg / kg once every 14 days; (b) anti-FGFR2-IIIb antibody is administered at a dose of 6 mg / kg once every 14 days; (c) anti-FGFR2-IIIb antibody is administered at a dose of 10 mg / kg once every 14 days; or (d) anti-FGFR2-IIIb antibody is administered at a dose of 15 mg / kg once every 14 days. In some embodiments, (a) the anti-FGFR2-IIIb antibody is administered at a dose of 6-15 mg / kg, 10-15 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg once every 11-17 days, once every 12-16 days, once every 13-15 days, or once every 14 days; and (b) at least one intermediate dose of 3-8 mg / kg, 5-8 mg / kg, 7-8 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, or 8 mg / kg is administered between two administrations of (a), wherein the dose of (b) is less than the dose of (a).In some embodiments, (i) the dose of (a) is 10-15 mg / kg every 13-15 days, (ii) the dose of (a) is 15 mg / kg every 13-15 days, (iii) the dose of (b) is 5-8 mg / kg and is administered 6-8 days after at least one administration of (a) and 6-8 days before any subsequent administration of (a), and (iv) the dose of (a) is 10-15 mg / kg every 13-15 days and the dose of (b) is 7-8 mg / kg and is administered 6-8 days after at least one administration of (a) and 6-8 days before any subsequent administration of (a). (v) the dose of (a) is 15 mg / kg every 14 days and the dose of (b) is 7-8 mg / kg, administered 7 days after at least one administration of (a) and 7 days before the subsequent administration of (a); (vi) the dose of (a) is 15 mg / kg every 14 days and the dose of (b) is 7.5 mg / kg, administered 7 days after at least one administration of (a) and 7 days before the subsequent administration of (a); and / or (vii) the dose of (b) is administered after the first administration of any of the doses of (a) of (i)-(vi). In some embodiments, the anti-FGFR2-IIIb antibody is administered once every 14 days at a dose of 15 mg / kg, and the anti-FGFR2-IIIb antibody is further administered at a dose of 7.5 mg / kg 6-8 days after the first administration of the anti-FGFR2-IIIb antibody. In some such embodiments, the anti-FGFR2-IIIb antibody is administered at a dose of 15 mg / kg once every 14 days, and 7 days after the first administration of the anti-FGFR2-IIIb antibody, the anti-FGFR2-IIIb antibody is administered at a dose of 7.5 mg / kg. In some such embodiments, the 7.5 mg / kg dose is administered only once, i.e., between the first and second administrations of 15 mg / kg.

[0014] In some embodiments of the methods herein, mFOLFOX6 is administered at a dose of 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin, and 400 mg / m 2In some embodiments, mFOLFOX6 is administered at 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-fluorouracil (5-FU) administered by intravenous (IV) infusion or IV bolus at 2,400 mg / m for 44 to 48 hours. 2 In some embodiments, mFOLFOX6 is administered once every 10-21 days, once every 10-15 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, or once every 21 days. In some embodiments, mFOLFOX6 is administered once every 14 days. In some embodiments, mFOLFOX6 is administered at a dose of 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-fluorouracil (5-FU) administered by intravenous (IV) infusion or IV bolus at 2,400 mg / m for 44 to 48 hours. 2 of 5-FU administered by IV infusion, and mFOLFOX6 administered once every 14 days.

[0015] In some embodiments of the methods herein, the anti-FGFR2-IIIb antibody and mFOLFOX6 are administered simultaneously or sequentially. In some embodiments, one or more doses of mFOLFOX6 are administered prior to administration of the anti-FGFR2-IIIb antibody. In some embodiments, two doses of mFOLFOX6 are administered prior to administration of the anti-FGFR2-IIIb antibody. In some embodiments, the anti-FGFR2-IIIB antibody is administered on the same day as mFOLFOX6 and prior to administration of mFOLFOX6.

[0016] In some embodiments, the gastric cancer is predetermined to overexpress FGFR2-IIIb and / or the gastric cancer is predetermined to have FGFR2 gene amplification. In some embodiments, the method further comprises determining whether the gastric cancer overexpresses FGFR2-IIIb and / or determining whether the gastric cancer has FGFR2 gene amplification. In some embodiments, FGFR2-IIIb overexpression is determined at the protein level by immunohistochemical staining (IHC). In some embodiments, overexpression is predetermined or determined by an IHC signal of 3+ in at least 10%, 20%, 30%, 40%, or 50% of the tumor cells. In some embodiments, FGFR2 gene amplification is predetermined or determined by obtaining a ratio of FGFR2 to chromosome 10 centromere (CEN10) using fluorescent in situ hybridization (FISH), where the FGFR2 gene is considered to be amplified when the FGFR2 / CEN10 ratio determined by FISH is 2 or more. In some embodiments, FGFR2 amplification has been previously detected or is detected in circulating tumor DNA (ctDNA).

[0017] Some embodiments of the present disclosure provide a method of treating locally advanced, unresectable, or metastatic gastric cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-fibroblast growth factor receptor 2 IIIb (anti-FGFR2-IIIb) antibody and modified FOLFOX6 (mFOLFOX6) chemotherapy, wherein the anti-FGFR2-IIIb antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, The light chain variable region is (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11,

[0018] Anti-FGFR2-IIIb antibodies were administered intravenously at a dose of 10-15 mg / kg, followed by 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin, and 400 mg / m 2 of 5-fluorouracil (5-FU) administered by IV infusion or IV bolus at 2400 mg / m for 44 to 48 hours. 2 mFOLFOX6 is administered comprising 100 mg of 5-FU administered by IV infusion, and anti-FGFR2-IIIb and mFOLFOX6 are administered every 2 weeks. Some embodiments of the present disclosure include a method of treating locally advanced, unresectable or metastatic gastric cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-fibroblast growth factor receptor 2 IIIb (anti-FGFR2-IIIb) antibody and modified FOLFOX6 (mFOLFOX6) chemotherapy, wherein the anti-FGFR2-IIIb antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, The light chain variable region is (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11, The anti-FGFR2-IIIb antibody and mFOLFOX6 are administered every 13 to 15 days, and optionally, a single dose of 3 to 8 mg / kg of anti-FGFR2-IIIb antibody is administered 6 to 8 days after a first dose of 6 to 15 mg / kg of anti-FGFR2-IIIb antibody and 6 to 8 days before a second dose of 6 to 15 mg / kg of anti-FGFR2-IIIb antibody. In some such embodiments, (a) anti-FGFR2-IIIb antibody is administered intravenously at a dose of 15 mg / kg, (b) anti-FGFR2-IIIb antibody and mFOLFOX6 are administered on the same day every 14 days, and (c) a single dose of 7.5 mg / kg anti-FGFR2-IIIb antibody is administered 7 days after a first dose of 15 mg / kg anti-FGFR2-IIIb antibody and 7 days before a second dose of 15 mg / kg anti-FGFR2-IIIb antibody.

[0019] In some embodiments herein, the gastric cancer is pre-determined to overexpress FGFR2-IIIb, as indicated by an IHC signal of 3+ in at least 10% of tumor cells, and / or the gastric cancer is pre-determined to have FGFR2 gene amplification in ctDNA. In some such embodiments, the subject has received two doses of mFOLFOX6 prior to the first dose of anti-FGFR2-IIIb antibody.

[0020] The present disclosure also encompasses compositions comprising an anti-FGFR2-IIIb antibody as described herein and each of oxaliplatin, leucovorin and 5-FU for use in treating a patient for gastrointestinal cancer, such as gastric cancer, for example, according to any of the above methods. In some embodiments, the composition comprises a combination of an anti-FGFR2-IIIb antibody as described herein and at least one of oxaliplatin, leucovorin and 5-FU. In some embodiments, the anti-FGFR2-IIIb antibody and at least one of oxaliplatin, leucovorin and 5-FU are in separate containers or compartments. In some such embodiments, the composition comprises a combination of the antibody and each of oxaliplatin, leucovorin and 5-FU in separate containers or compartments. In some embodiments, the composition further comprises instructions for use in treating gastrointestinal cancer, such as gastric cancer.

[0021] In some embodiments of the methods or compositions herein, the anti-FGFR2-IIIb antibody has the amino acid sequences of the heavy and light chain hypervariable regions (HVRs) H1, H2, H3, L1, L2, and L3 of the monoclonal antibody GAL-FR21, GAL-FR22, or GAL-FR23 described in U.S. Patent No. 8,101,723B2. In some embodiments, the heavy chain variable region of the anti-FGFR2-IIIb antibody comprises (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, and the light chain variable region comprises (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11.

[0022] In some embodiments, the anti-FGFR2-IIIb antibody has a heavy chain variable domain that is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 4, or that includes the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-FGFR2-IIIb antibody has a light chain variable domain that is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 5, or that includes the amino acid sequence of SEQ ID NO: 5. In some embodiments, the heavy chain variable domain is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 4, or that includes the amino acid sequence of SEQ ID NO: 4, and the light chain variable domain is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 5, or that includes the amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-FGFR2-IIIb antibody has a heavy chain that is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 2, or includes the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-FGFR2-IIIb antibody has a light chain that is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 3, or includes the amino acid sequence of SEQ ID NO: 3. In some embodiments, the heavy chain is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 2, or includes the amino acid sequence of SEQ ID NO: 2, and the light chain is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 3, or includes the amino acid sequence of SEQ ID NO: 3.

[0023] In some embodiments, the heavy chain variable region of the anti-FGFR2-IIIb antibody comprises (i) a CDR1 comprising the amino acid sequence of SEQ ID NO: 16, (ii) a CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and (iii) a CDR3 comprising the amino acid sequence of SEQ ID NO: 18, and the light chain variable region comprises (iv) a CDR1 comprising the amino acid sequence of SEQ ID NO: 20, (v) a CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and (vi) a CDR3 comprising the amino acid sequence of SEQ ID NO: 22.

[0024] In some embodiments, the anti-FGFR2-IIIb antibody has a heavy chain variable domain that is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 15, or that includes the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-FGFR2-IIIb antibody has a light chain variable domain that is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 19, or that includes the amino acid sequence of SEQ ID NO: 19. In some embodiments, the heavy chain variable domain is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 15, or that includes the amino acid sequence of SEQ ID NO: 15, and the light chain variable domain is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 19, or that includes the amino acid sequence of SEQ ID NO: 19.

[0025] In some embodiments, the anti-FGFR2-IIIb antibody is afucosylated. In some embodiments, the antibody lacks fucose at Asn297. In some embodiments, the anti-FGFR2-IIIb antibody comprises a kappa light chain constant region. In some embodiments, the antibody comprises an IgG1 heavy chain constant region. In some embodiments, the afucosylated antibody has enhanced ADCC (antibody-dependent cell-mediated cytotoxicity) activity in vitro and / or in vivo compared to an antibody with the same amino acid sequence in which Asn297 is fucosylated. In some embodiments, the afucosylated antibody has enhanced affinity for Fc gamma RIIIA compared to an antibody with the same amino acid sequence in which Asn297 is fucosylated. In some embodiments, the afucosylated antibody is capable of increasing the number of one or more of PD-L1 positive cells, NK cells, CD3+ T cells, CD4+ T cells, CD8+ T cells and macrophages in tumor tissue compared to a control (e.g., compared to a control antibody that does not target FGFR2) in mouse xenograft and / or allograft tumor models.

[0026] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of the claims. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All references cited herein, including patent applications and patent publications, are hereby incorporated by reference in their entirety for all purposes. [Brief description of the drawings]

[0027] [Figure 1] The dosing schedule for dose escalation Part I of the clinical trial described in Example 1 below is shown. The initial cohort is at dose level 1, and additional enrollments will be at dose levels 1, 2, or -1 as indicated in the figure, following an analysis for the presence of dose-limiting toxicities (DLTs) as described in Table 2 below. [Diagram 2]1 is a flow chart illustrating patient evaluations performed for Part I of the clinical trial described in Example 1 below. [Diagram 3] 1 shows the dosing schedule for dose escalation (Phase 1) of the clinical trial described in Example 2. The initial cohorts are Cohorts 1 and 2, with Cohort 3 optionally initiated, and Cohort 4 (not shown) optionally initiated. Further details are described in Example 2 below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] definition Unless otherwise defined, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0029] Exemplary techniques used in connection with recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection), enzymatic reactions, and purification techniques are known in the art. Many of such techniques and procedures are described, for example, in Sambrook et al. Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989)) and elsewhere. In addition, exemplary techniques for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients are also known in the art.

[0030] In this application, the use of "or" means "and / or" unless otherwise indicated. In the context of multiple dependent claims, the use of "or" refers to two or more preceding independent or dependent claims in the alternative. Also, terms such as "element" or "component" include both elements and components comprising a single unit and elements and components comprising two or more subunits, unless otherwise specified.

[0031] As used in accordance with the present disclosure, the following terms, unless otherwise specified, shall be understood to have the following meanings:

[0032] The terms "nucleic acid molecule" and "polynucleotide" may be used interchangeably and refer to a polymeric compound of nucleotides. Such polymeric compounds of nucleotides may contain natural and / or non-natural nucleotides, including, but not limited to, DNA, RNA, and PNA. A "nucleic acid sequence" refers to the linear sequence of nucleotides that comprises a nucleic acid molecule or polynucleotide.

[0033] The terms "polypeptide" and "protein" are used interchangeably herein to refer to polymeric compounds of amino acid residues, and are not limited to a minimum length. Such polymeric compounds of amino acid residues may contain natural or non-natural amino acid residues, including, but not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by this definition. The term also includes post-expression modifications of the polypeptide, such as glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present invention, "polypeptide" refers to a protein that contains modifications such as deletions, additions, and substitutions (generally conservative substitutions in nature) relative to the native sequence, so long as the protein retains the desired activity. These modifications may be intentional, such as site-directed mutagenesis, or may be accidental, such as mutations by the host producing the protein or errors due to PCR amplification.

[0034] "FGFR2" refers to human fibroblast growth factor receptor 2, including any of its alternative splice forms, such as IIIa, IIIb, and IIIc splice forms. The term FGFR2 encompasses wild-type FGFR2 and naturally occurring mutants, such as FGFR2-S252W, which is found in some cancer cells, and other FGFR2 activating mutants. "FGFR2-IIIb" or "FGFR2b" are used interchangeably herein to refer to the human fibroblast growth factor receptor 2 IIIb splice form. An exemplary human FGFR2-IIIb sequence is shown in GenBank Accession No. NP_075259.4, dated July 7, 2013. A non-limiting exemplary mature human FGFR2-IIIb amino acid sequence is shown in SEQ ID NO: 1. "FGFR2-IIIc" or "FGFR2c" are used interchangeably herein to refer to the human fibroblast growth factor receptor 2 IIIc splice form. An exemplary human FGFR2-IIIc sequence is set forth in GenBank Accession No. NP_000132.3, dated July 7, 2013. A non-limiting exemplary mature FGFR2-IIIc amino acid sequence is set forth in SEQ ID NO:12.

[0035] "FGFR2 extracellular domain" or "FGFR2 ECD" refers to the extracellular domain of human FGFR2, including naturally occurring and engineered variants thereof. An example of an FGFR2 ECD is set forth in SEQ ID NO:13.

[0036] The term "antibody" as used herein refers to a molecule that contains at least hypervariable regions (HVRs) H1, H2, and H3 of the heavy chain and L1, L2, and L3 of the light chain, and is capable of binding to an antigen. The term antibody includes, but is not limited to, fragments capable of binding to an antigen, such as Fv, single chain Fv (scFv), Fab, Fab', and (Fab')2. The term antibody also includes, but is not limited to, chimeric antibodies, humanized antibodies, human antibodies, and antibodies of various species, such as mouse, human, and cynomolgus monkey. It also includes antibodies conjugated to other molecules, such as small molecule pharmaceuticals, bispecific antibodies, and multispecific antibodies.

[0037] An "anti-FGFR2" antibody refers to an antibody that specifically binds to FGFR2. An "anti-FGFR2-IIIb" antibody or an "anti-FGFR2b" antibody refers to an antibody that specifically binds to FGFR2-IIIb (also known as FGFR2b). Such an antibody has a higher affinity for FGFR2-IIIb than for other isoforms of FGFR2, such as FGFR2-IIIc. In some embodiments, the antibody cannot detectably bind to FGFR2-IIIc. The terms "anti-FGFR2 antibody", "anti-FGFR2-IIIb antibody" and "anti-FGFR2b antibody" specifically include afucosylated forms of such antibodies.

[0038] The term "heavy chain variable region" refers to a region comprising heavy chain HVR1, framework (FR) 2, HVR2, FR3, and HVR3. In some embodiments, the heavy chain variable region also comprises at least a portion of FR1 and / or at least a portion of FR4.

[0039] The term "heavy chain constant region" refers to at least three heavy chain constant domains, H 1. C H 2 and C HThe term "heavy chain constant region" refers to a region that includes the 3 constant regions. Non-limiting exemplary heavy chain constant regions include gamma, delta, and alpha. Non-limiting exemplary heavy chain constant regions also include epsilon and mu. Each heavy chain constant region corresponds to an antibody isotype. For example, an antibody that includes a gamma constant region is an IgG antibody, an antibody that includes a delta constant region is an IgD antibody, and an antibody that includes an alpha constant region is an IgA antibody. Furthermore, an antibody that includes a mu constant region is an IgM antibody, and an antibody that includes an epsilon constant region is an IgE antibody. A particular isotype can be further divided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (containing a gamma 1 constant region), IgG2 (containing a gamma 2 constant region), IgG3 (containing a gamma 3 constant region) and IgG4 (containing a gamma 4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (containing an alpha 1 constant region) and IgA2 (containing an alpha 2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2.

[0040] The term "heavy chain" refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain also comprises at least a portion of a heavy chain constant region. The term "full-length heavy chain" refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0041] The term "light chain variable region" refers to a region comprising light chain HVR1, framework (FR) 2, HVR2, FR3, and HVR3. In some embodiments, the light chain variable region also comprises FR1 and / or FR4.

[0042] The term "light chain constant region" refers to a light chain constant domain C L Non-limiting exemplary light chain constant regions include lambda and kappa.

[0043] The term "light chain" refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain also comprises at least a portion of a light chain constant region. The term "full-length light chain" refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0044] The term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops ("hypervariable loops"). Generally, naturally occurring four-chain antibodies have a V H 3 (H1, H2, H3) and V L The antibody contains six HVRs, three at the top (L1, L2, L3). HVRs generally contain amino acid residues from the hypervariable loops and / or "complementarity determining regions" (CDRs), the latter of which are of greatest sequence variability and / or involved in antigen recognition. Exemplary hypervariable loops are located at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) are located at amino acid residues 24-34 of L1, 50-56 of L2, 89-97 of L3, 31-35B of H1, 50-65 of H2, and 95-102 of H3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)). The terms hypervariable region (HVR) and complementarity determining region (CDR) both refer to the portions of the variable regions that form the antigen binding region.

[0045] "Affinity" or "binding affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). In some embodiments, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K d ) can be expressed as

[0046] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcR) present on certain cytotoxic cells (e.g., NK cells, neutrophils, and macrophages), thereby enabling these cytotoxic effector cells to specifically bind to antigen-bearing target cells and subsequently kill the target cells with cytotoxins. NK cells, the primary cells mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess the ADCC activity of a molecule of interest, an in vitro ADCC assay can be performed, such as those described in U.S. Pat. Nos. 5,500,362 or 5,821,337 or U.S. Pat. No. 6,737,056 (Presta). Useful effector cells for such assays include PBMCs and NK cells. Alternatively or additionally, the ADCC activity of a molecule of interest may be assessed in vivo, for example in an animal model as disclosed in Clynes et al. Proc. Natl. Acad. Sci. (USA) 95:652-656 (1998). Further antibodies with modified amino acid sequences in the Fc region and with enhanced or decreased ADCC activity are described, for example, in U.S. Pat. Nos. 7,923,538 and 7,994,290.

[0047] An antibody with "enhanced ADCC activity" refers to an antibody that is more effective at mediating ADCC in vitro or in vivo compared to a parent antibody, where the antibody and parent antibody differ in at least one structural feature, and the amounts of the antibody and parent antibody used in the assay are essentially the same. In some embodiments, the antibody and parent antibody have the same amino acid sequence, but the antibody is afucosylated, whereas the parent antibody is fucosylated. In some embodiments, the ADCC activity is determined using an in vitro ADCC assay, such as that disclosed in US Patent Publication No. 2015-0050273-A1, although other assays or methods for determining ADCC activity, such as in animal models, are also contemplated. In some embodiments, an antibody with enhanced ADCC activity also has enhanced affinity for Fc gamma RIIIA. In some embodiments, an antibody with enhanced ADCC activity has enhanced affinity for Fc gamma RIIIA(V158). In some embodiments, the antibody with enhanced ADCC activity has enhanced affinity for Fc gamma RIIIA (F158).

[0048] "Enhanced affinity for Fc gamma RIIIA" refers to an antibody that has greater affinity for Fc gamma RIIIA (sometimes referred to as CD16a) than a parent antibody, where the antibody and the parent antibody differ in at least one structural feature. In some embodiments, the antibody and the parent antibody have the same amino acid sequence, but the antibody is afucosylated, whereas the parent antibody is fucosylated. Any suitable method for determining affinity for Fc gamma RIIIA may be used. In some embodiments, affinity for Fc gamma RIIIA is determined by the method described in US Patent Application Publication No. 2015-0050273-A1. In some embodiments, an antibody with enhanced affinity for Fc gamma RIIIA also has enhanced ADCC activity. In some embodiments, an antibody with enhanced affinity for Fc gamma RIIIA has enhanced affinity for Fc gamma RIIIA(V158). In some embodiments, the antibody with enhanced affinity for Fc gamma RIIIA has enhanced affinity for Fc gamma RIIIA(F158).

[0049] As used herein, a "chimeric antibody" refers to an antibody that comprises at least one variable region derived from a first species (e.g., mouse, rat, cynomolgus monkey, etc.) and at least one constant region derived from a second species (e.g., human, cynomolgus monkey, etc.). In some embodiments, a chimeric antibody comprises at least one mouse variable region and at least one human constant region. In some embodiments, a chimeric antibody comprises at least one cynomolgus monkey variable region and at least one human constant region. In some embodiments, a chimeric antibody comprises at least one rat variable region and at least one mouse constant region. In some embodiments, all of the variable regions of a chimeric antibody are derived from a first species and all of the constant regions of a chimeric antibody are derived from a second species.

[0050] As used herein, a "humanized antibody" refers to an antibody in which at least one amino acid in the framework region of a non-human variable region is replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or a fragment thereof. In some embodiments, a humanized antibody is a Fab, scFv, (Fab')2, etc.

[0051] As used herein, "human antibody" refers to antibodies produced in humans, antibodies produced in non-human animals that contain human immunoglobulin genes, such as the XenoMouse®, and antibodies selected using in vitro methods such as phage display, where the antibody repertoire is based on human immunoglobulin sequences.

[0052] An "afucosylated" or "fucose-devoid" antibody refers to an IgG1 or IgG3 isotype antibody lacking fucose in the glycosylation of its constant region. Glycosylation of human IgG1 or IgG3 occurs at Asn297 (N297), as is core fucosylated biantennary complex type oligosaccharide glycosylation with up to 2 Gal residues at the terminus. In some embodiments, an afucosylated antibody lacks fucose at Asn297. These structures are designated G0, G1 (α1,6 or α1,3) or G2 glycan residues, depending on the amount of terminal Gal residues. See, e.g., Raju, TS, BioProcess Int. 1:44-53 (2003). CHO-type glycosylation of antibody Fc is described, e.g., in Routier, FH, Glycoconjugate J. 14:201-207 (1997). Within a population of antibodies, an antibody is considered to be afucosylated if less than 5% of the antibodies in the population contain fucose at Asn297.

[0053] "Effector function" refers to a biological activity attributable to the Fc region of an antibody and varies with the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptor), and activation of B cells.

[0054] With respect to anti-FGFR2 antibodies, the term "blocking binding" or "inhibiting binding" of a ligand refers to the ability to inhibit the interaction between FGFR2 and an FGFR2 ligand, such as human fibroblast growth factor 1 (FGF1) or FGF2. Such inhibition can occur through any mechanism, including, for example, direct interference with ligand binding, e.g., by overlapping of binding sites on FGFR2, and / or antibody-induced conformational changes in FGFR2 that alter ligand affinity, or, for example, in the case of FGFR2 ECD or FGFR2 ECD fusion molecules, by competition for binding to the FGFR2 ligand.

[0055] The term "isolated" as used herein refers to a molecule that is separated from at least some of the components that are typically found in nature. For example, a polypeptide is said to be "isolated" if it is separated from at least some of the components of the cell in which it is produced. In the case of a polypeptide that is secreted by a cell after expression, physically separating the supernatant containing the polypeptide from the cell that produces the polypeptide is considered to "isolate" the polypeptide. Similarly, a polynucleotide is said to be "isolated" if it is not part of a larger polynucleotide that is typically found in nature (e.g., in the case of a DNA polynucleotide, genomic DNA or mitochondrial DNA, etc.) or, in the case of an RNA polynucleotide, for example, if the polynucleotide is separated from at least some of the components of the cell in which it is produced. Thus, a DNA polynucleotide contained in a vector within a host cell can also be said to be "isolated" as long as the polynucleotide is not found in the vector in nature.

[0056] The term "high level" means that the protein level is higher in a particular tissue of a subject compared to the same tissue of a control, such as an individual(s) not suffering from cancer or other conditions described herein. High levels can be the result of any mechanism, such as increased expression of the protein, increased stability, decreased degradation, increased secretion, decreased clearance, etc.

[0057] The terms "reduce" or "reduce" or "increase" or "increase" with respect to a protein or cell type means that the level of the protein or cell type in a particular tissue of a subject, such as a tumor, is changed by at least 10%. In some embodiments, an agent such as an anti-FGFR2 antibody increases or decreases the level of the protein or cell type in a particular tissue of a subject, such as a tumor, by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to the level before contact with the antibody.

[0058] The terms "subject" and "patient" are used interchangeably herein to refer to humans. In some embodiments, methods of treating other mammals are also provided, including, but not limited to, rodents, monkeys, cats, dogs, horses, cows, pigs, sheep, goats, laboratory mammals, farm mammals, sport mammals, and pet mammals.

[0059] The term "sample," as used herein, refers to a composition taken from or derived from a subject, containing cellular and / or other molecular entities that are to be characterized, quantified, and / or identified, e.g., based on physical, biochemical, chemical, and / or physiological characteristics. An exemplary sample is a tissue sample.

[0060] The term "cancer" refers to a malignant proliferative disease associated with uncontrolled cell proliferation, unrestrained cell growth, and decreased cell death via apoptosis. The term "gastrointestinal cancer" or "GI cancer" refers to cancer of the digestive tract, such as gastric cancer, colon cancer, or pancreatic adenocarcinoma. In some embodiments, gastrointestinal cancer is "gastric cancer" or "GC," as used herein, including gastroesophageal cancer.

[0061] In some embodiments, the cancer comprises an FGFR2 gene amplification, while in some embodiments, the cancer does not comprise an FGFR2 amplification. In some embodiments, where amplification occurs, the FGFR2 amplification has an FGFR2:CEN10 (chromosome 10 centromere) ratio of >3. In some embodiments, the FGFR2 amplification has an FGFR2:CEN10 ratio of >= 2. However, in other embodiments, the FGFR2 level has an FGFR2:CEN10 ratio between 1 and 2, indicating no proliferation of FGFR2. In some embodiments, a mutation or translocation may be responsible for the FGFR2 gene amplification.

[0062] FGFR2 gene amplification can be determined, for example, using a fluorescent in situ hybridization assay (FISH). FGFR2 gene amplification can also be detected by blood-based assays or "liquid biopsies". In some embodiments of blood-based assays, FGFR2 gene amplification can be detected in DNA from circulating tumor cells or "CTCs". Methods for the detection and molecular characterization of CTCs are described, for example, in Alix-Panabieres (2013) Clinical Chemistry 59:1 110-118. In some embodiments of blood-based assays, FGFR2 gene amplification is detected in ctDNA. The term "ctDNA" refers to "circulating tumor DNA", which is fragmented DNA from tumors in the bloodstream that is not associated with cells. Methods for detection and molecular characterization of ctDNA are described, for example, in Han et al. (2017) Genomics, Proteomics & Bioinformatics 15:2 59-72, and include PCR-based methods and next generation sequencing (NGS).

[0063] In some embodiments, the cancer overexpresses FGFR2-IIIb. In some embodiments, the cancer overexpresses FGFR2-IIIb more than FGFR2-IIIc. In some embodiments, the cancer expresses FGFR2-IIIb at a normalized level that is 2-fold, 3-fold, 5-fold, or 10-fold higher than the normalized FGFR2-IIIc expression level. In some embodiments, the cancer overexpresses FGFR2-IIIb but does not contain FGFR2 gene amplification, and in other embodiments, the cancer contains FGFR2 gene amplification and also overexpresses FGFR2-IIIb. Expression of FGFR2-IIIb can be determined at the protein level, for example, by immunohistochemical staining (IHC) of tumor samples from patients compared to normal tissue. The terms "overexpression of FGFR2-IIIb protein" and "overexpression of FGFR2-IIIb" and the like refer to elevated levels of FGFR2-IIIb protein, regardless of the cause of such elevated levels (i.e., whether the elevated levels are the result of increased protein translation and / or decreased degradation, other mechanisms, or a combination of mechanisms). In some embodiments, overexpression of FGFR2-IIIb can be detected at the mRNA level compared to non-cancerous tissue, for example, using techniques such as reverse transcriptase polymerase chain reaction (RT-PCR) analysis.

[0064] The expression level of FGFR2 or FGFR2-IIIb by IHC may be determined by giving the tumor sample an IHC score on a scale of 0 to 3. Herein, a score of "0" is given if no reactivity is observed or if less than 10% of the tumor cells have cell membrane reactivity. A score of "1+" is given if at least 10% of the tumor cells have slight or barely discernible cell membrane reactivity or if the cells are reactive on only a portion of their cell membrane. A score of "2+" is given if at least 10% of the tumor cells have weak to moderate complete basal or lateral cell membrane reactivity. A score of "3+" is given if at least 10% of the tumor cells have strong complete basal or lateral cell membrane reactivity. In some embodiments, 1+, 2+ or 3+ staining of tumor cells by IHC indicates overexpression of FGFR2-IIIb. In some embodiments, 2+ or 3+ staining of tumor cells by IHC indicates overexpression of FGFR2-IIIb. In some embodiments, 3+ staining of tumor cells by IHC indicates overexpression of FGFR2-IIIb.

[0065] A "modified FOLFOX6" or "mFOLFOX6" chemotherapy regimen, as provided in various embodiments described herein, refers to a regimen in which a combination of oxaliplatin (e.g., Eloxatin®), leucovorin (e.g., leucovorin calcium or folinic acid), and 5-fluorouracil (5-FU) are administered to a human patient by IV infusion or IV bolus, respectively, over about 2-8 hours, followed by a further infusion of 5-FU administered by IV infusion over about 2 days.

[0066] "Treatment" as used herein refers to therapeutic treatment, e.g., the purpose is to reduce the severity or slow the progression of the targeted pathological condition or disorder, and, e.g., the purpose is to inhibit the recurrence of the condition or disorder. In certain embodiments, the term "treatment" encompasses any administration or application of a therapeutic drug for a patient's disease, including inhibiting or slowing the disease or disease progression, alleviating the disease, partially or completely, e.g., by causing remission or restoring or repairing lost, impaired or defective functions, stimulating an inefficient process, or reducing the severity of a disease that has reached a plateau. The term "treatment" also includes reducing the severity of any phenotypic characteristic and / or reducing the occurrence, extent or likelihood of said characteristic. Those in need of treatment include those who already have the disorder, as well as those at risk of recurrence of the disorder or those in need of preventing or delaying the recurrence of the disorder.

[0067] The term "effective amount" or "therapeutically effective amount" refers to an amount of drug effective to treat a disease or disorder of interest. In certain embodiments, an effective amount refers to an amount effective at the dosage and duration necessary to achieve a desired therapeutic or prophylactic result. The therapeutically effective amount of the anti-FGFR2 antibody and chemotherapy regimen of the present invention may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the antibody(ies) to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which the therapeutic beneficial effects outweigh any toxic or harmful effects of the antibody(ies). In some embodiments, the term "effective amount" refers to an amount of antibody that is effective in treating cancer.

[0068] Administration "in combination with" one or more further therapeutic agents, such as a chemotherapeutic regimen, includes simultaneous (concurrent) and sequential (sequential) administration, in any order.

[0069] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid excipient, diluent, encapsulating material, formulation aid, or carrier conventionally used in the art for use in therapeutic agents that comprise a "pharmaceutical composition" together for administration to a subject. A pharmaceutically acceptable carrier is one that is non-toxic to a recipient at the dosage and concentration employed and is compatible with other components of the formulation. A pharmaceutically acceptable carrier is one that is suitable for the formulation employed. For example, if the therapeutic agent is administered orally, the carrier may be a gel capsule. If the therapeutic agent is administered subcutaneously, the carrier is ideally one that is non-irritating to the skin and does not cause injection site reactions.

[0070] Further definitions can be found in the following sections.

[0071] Exemplary Anti-FGFR2 Antibodies Exemplary anti-FGFR2 antibodies include antibodies that specifically bind to FGFR2-IIIb, i.e., anti-FGFR2-IIIb antibodies. In some embodiments, anti-FGFR2-IIIb antibodies bind to FGFR2-IIIc with lower affinity than they bind to FGFR2-IIIb. In some embodiments, anti-FGFR2-IIIb antibodies do not bind to FGFR2-IIIc at detectable levels.

[0072] An exemplary anti-FGFR2-IIIb antibody used in the embodiments herein is the HuGAL-FR21 antibody described in U.S. Pat. No. 8,101,723B2, issued Jan. 24, 2012, and expressly incorporated herein by reference. Figures 13 and 14 of U.S. Pat. No. 8,101,723B2 show the amino acid sequences of the variable region and full-length mature antibody chain of HuGAL-FR21, and are hereby incorporated by reference. The heavy chain variable region sequence of antibody HuGAL-FR21 is underlined in Figure 13 of U.S. Pat. No. 8,101,723B2, and is hereby expressly incorporated by reference. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297. Further antibodies that may be used in embodiments of the present specification include those described in U.S. Patent Application Publication No. 2015-0050273-A1, which describes certain afucosylated anti-FGFR2-IIIb antibodies, and is incorporated herein by reference.

[0073] In some embodiments, the anti-FGFR2-IIIb antibody comprises at least one, two, three, four, five, or six hypervariable regions (HVRs; e.g., CDRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0074] In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain variable region and a light chain variable region. In some embodiments, the anti-FGFR2-IIIb antibody comprises at least one heavy chain comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and at least one light chain comprising a light chain variable region and at least a portion of a light chain constant region. In some embodiments, the anti-FGFR2-IIIb antibody comprises two heavy chains and two light chains, each heavy chain comprising at least a portion of a heavy chain variable region and a heavy chain constant region, and each light chain comprising at least a portion of a light chain variable region and a light chain constant region. In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5. In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2 and a light chain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody that lacks fucose at Asn297.

[0075] In some embodiments, the anti-FGFR2-IIIb antibody comprises six HVRs, including (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the anti-FGFR2-IIIb antibody comprises the six HVRs described above and binds to FGFR2-IIIb. In some embodiments, the anti-FGFR-IIIb antibody does not bind to FGFR2-IIIc. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0076] In one aspect, the anti-FGFR2-IIIb antibody competes with an anti-FGFR2-IIIb antibody comprising six HVRs, including: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0077] In some embodiments, the anti-FGFR2-IIIb antibody comprises at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0078] In some embodiments, the anti-FGFR2-IIIb antibody comprises at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0079] In some embodiments, the anti-FGFR2-IIIb antibody comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 6; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; and (iii) HVR-H3 comprising the amino acid sequence selected from SEQ ID NO: 8; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0080] In some embodiments, anti-FGFR2-IIIb antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 4. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions compared to the reference sequence, but the anti-FGFR2-IIIb antibody comprising such sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, such anti-FGFR2-IIIb antibody retains the ability to selectively bind to FGFR2-IIIb without binding to FGFR2-IIIc at a detectable level. In certain embodiments, a total of 1-10 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 4. In certain embodiments, the substitutions, insertions or deletions are in a region other than the HVR (i.e., the FR). Optionally, the anti-FGFR2-IIIb antibody comprises a VH sequence of SEQ ID NO: 5, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 6, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0081] In some embodiments, anti-FGFR2-IIIb antibody comprises a light chain variable domain (VL) with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5. In certain embodiments, the VL sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions compared to the reference sequence, but the anti-FGFR2-IIIb antibody comprising said sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, anti-FGFR2-IIIb antibody retains the ability to selectively bind to FGFR2-IIIb without binding to FGFR2-IIIc. In certain embodiments, a total of 1-10 amino acids are substituted, inserted and / or deleted in SEQ ID NO:5. In certain embodiments, the substitutions, insertions or deletions are in a region other than the HVR (i.e., the FR). Optionally, the anti-FGFR2-IIIb antibody comprises a VL sequence of SEQ ID NO:4, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0082] In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:4, and a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:5. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, and a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-FGFR2-IIIb antibody comprising such a sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, such an anti-FGFR2-IIIb antibody retains the ability to selectively bind to FGFR2-IIIb without binding to FGFR2-IIIc. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 4. In certain embodiments, a total of 1-10 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 5. In certain embodiments, the substitutions, insertions or deletions are in a region other than the HVR (i.e., the FR). Optionally, the anti-FGFR2-IIIb antibody comprises a VH sequence of SEQ ID NO: 4 and a VL sequence of SEQ ID NO: 5, including post-translational modifications of one or both sequences.In certain embodiments, the VH comprises one, two or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, and the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0083] In some embodiments, the VH of the anti-FGFR2-IIIb antibody is as in any of the embodiments provided above, and the VL is as in any of the embodiments provided above. In one embodiment, the antibody comprises the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 5, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0084] In some embodiments, anti-FGFR2-IIIb antibody comprises a heavy chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 2. In certain embodiments, a heavy chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity contains substitutions (e.g., conservative substitutions), insertions or deletions compared to the reference sequence, but the anti-FGFR2-IIIb antibody comprising such sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, such anti-FGFR2-IIIb antibody retains the ability to selectively bind to FGFR2-IIIb without detectably binding to FGFR2-IIIc. In certain embodiments, a total of 1-10 amino acids are substituted, inserted and / or deleted in SEQ ID NO:2. In certain embodiments, the substitutions, insertions or deletions are in a region other than the HVRs (i.e., the FRs). Optionally, the heavy chain of the anti-FGFR2-IIIb antibody comprises the VH sequence of SEQ ID NO:2, including post-translational modifications of that sequence. In certain embodiments, the heavy chain comprises one, two or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0085] In some embodiments, the anti-FGFR2-IIIb antibody comprises a light chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the light chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-FGFR2-IIIb antibody comprising the sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, such an anti-FGFR2-IIIb antibody retains the ability to selectively bind to FGFR2-IIIb without detectably binding to FGFR2-IIIc. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 3. In certain embodiments, the substitutions, insertions or deletions are in regions other than the HVRs (i.e., FRs). Optionally, the light chain of the anti-FGFR2-IIIb antibody comprises the VL sequence of SEQ ID NO: 3, including post-translational modifications of that sequence. In certain embodiments, the light chain comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0086] In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 2, and a light chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the heavy chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-FGFR2-IIIb antibody comprising the sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, such anti-FGFR2-IIIb antibodies retain the ability to selectively bind to FGFR2-IIIb without detectably binding to FGFR2-IIIc. In certain embodiments, a light chain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-FGFR2-IIIb antibody comprising such a sequence retains the ability to bind to FGFR2-IIIb. In certain embodiments, such an FGFR2-IIIb antibody retains the ability to selectively bind to FGFR2-IIIb without detectably binding to FGFR2-IIIc. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 3. In certain embodiments, the substitutions, insertions or deletions are in regions other than the HVR (i.e., FR). Optionally, the heavy chain of the anti-FGFR2-IIIb antibody comprises the VH sequence of SEQ ID NO: 2, including post-translational modifications of that sequence, and the light chain of the anti-FGFR2-IIIb antibody comprises the VL sequence of SEQ ID NO: 3, including post-translational modifications of that sequence.In certain embodiments, the heavy chain comprises one, two or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:7, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, and the light chain comprises one, two or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody is afucosylated. In some embodiments, the antibody is an IgG1 or IgG3 antibody lacking fucose at Asn297.

[0087] Further exemplary anti-FGFR2 antibodies are the GAL-FR22 and GAL-FR23 antibodies described in U.S. Pat. No. 8,101,723B2, which is incorporated herein by reference. The light and heavy chain variable regions of GAL-FR22 are provided, for example, in SEQ ID NOs: 7 and 8 of U.S. Pat. No. 8,101,723B2, and the Kabat CDRs and light and heavy chain variable regions are provided in FIG. 16 of the patent, which is incorporated herein by reference. Hybridomas producing GAL-FR21, GAL-FR22 and GAL-FR23 have been deposited at the American Type Culture Collection (PO Box 1549, Manassas VA, USA, 20108) under ATCC numbers 9586, 9587 and 9408 on Nov. 6, 2008, Nov. 6 and Aug. 12, 2008, respectively. Thus, in some embodiments, the FGFR2 antibody is an antibody that comprises the amino acid sequence of an antibody obtained from one of these three hybridoma lines.

[0088] The heavy and light chain variable regions of GAL-FR22 are also shown in SEQ ID NOs: 39 and 43 of the patent, and the Kabat CDRs are shown in SEQ ID NOs: 40 to 42 and 44 to 46 of the patent. Thus, in some embodiments, the heavy chain variable region of the anti-FGFR2-IIIb antibody comprises (i) a CDR1 comprising the amino acid sequence of SEQ ID NO: 40, (ii) a CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and (iii) a CDR3 comprising the amino acid sequence of SEQ ID NO: 42, and the light chain variable region comprises (iv) a CDR1 comprising the amino acid sequence of SEQ ID NO: 44, (v) a CDR2 comprising the amino acid sequence of SEQ ID NO: 45, and (vi) a CDR3 comprising the amino acid sequence of SEQ ID NO: 46.

[0089] In some embodiments, the anti-FGFR2 antibody comprises an anti-FGFR2-IIIb antibody, the heavy chain variable domain of which is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to, or comprises, the amino acid sequence of SEQ ID NO: 39. In some embodiments, the anti-FGFR2 antibody comprises an anti-FGFR2-IIIb antibody, the light chain variable domain of which is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to, or comprises, the amino acid sequence of SEQ ID NO: 43. In some embodiments, the heavy chain variable domain of which is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to, or comprises, the amino acid sequence of SEQ ID NO: 39, and the light chain variable domain of which is at least 95%, e.g., at least 97%, at least 98%, or at least 99% identical to, or comprises, the amino acid sequence of SEQ ID NO: 43. In some embodiments, the antibody is an IgG1 or IgG3 antibody that lacks fucose at Asn297.

[0090] In any of the methods described herein, the anti-FGFR2 antibody may be a humanized antibody, a chimeric antibody or a human antibody. In any of the compositions or methods described herein, the anti-FGFR2 antibody may be selected from Fab, Fv, scFv, Fab', and (Fab')2. In any of the compositions or methods described herein, the anti-FGFR2 antibody may be selected from IgA, IgG, and IgD. In any of the compositions or methods described herein, the anti-FGFR2 antibody may be IgG. In any of the methods described herein, the antibody may be IgG1 or IgG3.

[0091] Exemplary Properties of Antibodies In some embodiments, the anti-FGFR2-IIIb antibody binds to FGFR2-IIIb with higher affinity than to FGFR2-IIIc, or does not detectably bind to FGFR2-IIIc, inhibits the binding of FGF2 to human FGFR2, and / or inhibits the binding of FGF7 to human FGFR2. The binding of the antibody to FGFR2 and the inhibition of the binding between FGFR2 and FGF can be assessed by, for example, an ELISA assay as described in U.S. Pat. No. 8,101,723, or a chip-based assay as described in, for example, Example 2 of WO2015 / -17600. In some embodiments, the antibody induces ADCC activity, and in some embodiments has enhanced ADCC activity, for example, as described in WO2015 / -17600. ADCC activity can be determined, for example, as described in Example 3 of WO2015 / -17600. In some embodiments, the antibody may inhibit the growth of human tumors in a mouse model, e.g., as shown in Example 1 of International Application No. PCT / US2016 / 063332. In some embodiments, the anti-FGFR2-IIIb antibody may increase the number of one or more of PD-L1 positive cells, NK cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, and macrophages in tumor tissue compared to a control in a mouse tumor model, e.g., as described in Example 2 of International Application No. PCT / US2016 / 063332.

[0092] Afucosylated anti-FGFR2 antibody In some embodiments, the anti-FGFR2 antibody, such as the anti-FGFR2-IIIb antibody described above, has a carbohydrate structure that lacks fucose attached (directly or indirectly) to the Fc region (i.e., an afucosylated antibody), i.e., the antibody is afucosylated. In some embodiments, the afucosylated antibody is an IgG1 or IgG3 antibody that lacks fucose at Asn297.

[0093] As used herein, an antibody is considered to be afucosylated if a plurality of such antibodies comprises at least 95% afucosylated antibody. The amount of fucose can be determined by calculating the average amount of fucose in the glycan of Asn297 relative to the sum of all glycan structures (e.g., complex, mixed and high mannose structures) attached to Asn297. Non-limiting exemplary methods for detecting fucose in antibodies include MALDI-TOF mass spectrometry (see, e.g., WO 2008 / 077546), HPLC measurement of released fluorescently labeled oligosaccharides (see, e.g., Schneider et al., “N-Glycan analysis of monoclonal antibodies and other glycoproteins using UHPLC with fluorescence detection,” Agilent Technologies, Inc. (2012); Lines, J. Pharm. Biomed. Analysis, 14:601-608 (1996); Takahasi, J. Chrom., 720:217-225 (1996)), capillary electrophoresis measurement of released fluorescently labeled oligosaccharides (see, e.g., Ma et al., Anal. Chem., 71:5185-5192 (1999)), and HPLC with pulsed amperometric detection to measure monosaccharide composition (see, e.g., Hardy, et al., Analytical Chemistry, 1999, 11:111-112 (1999)). Biochem., 170:54-62 (1988).

[0094] Asn297 refers to an asparagine residue located near position 297 in the Fc region (Fc region residues in EU numbering), although in a given antibody sequence, Asn297 may be located approximately ±3 amino acids upstream or downstream from position 297, i.e., between positions 294 and 300, due to minor sequence variations in the antibody. In the anti-FGFR2-IIIb antibodies described herein, Asn297 is located at the sequence [ka] (positions 292-296 of SEQ ID NO:2) and is shown in bold and underlined in SEQ ID NO:2 of the sequence listing below.

[0095] Fucosylation variants may have improved ADCC function. See, e.g., US Patent Application Publication No. 2003 / 0157108 (Presta, L.); US2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "afucosylated" or "fucose-deficient" antibodies include US2003 / 0157108; WO2000 / 61739; WO2001 / 29246; US2003 / 0115614; US2002 / 0164328; US2004 / 0093621; US2004 / 0132140; US2004 / 0110704; US2004 / 0110282; US2004 / 0109865; WO2003 / 085119; WO2003 / 084570; WO2005 / 035586; WO2005 / 035778; WO2005 / 053742; WO2002 / 031140; Okazaki et al. al. J. Mol. Biol. 336:1239-1249(2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614(2004). Examples of cell lines capable of producing afucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application Publication No. US 2003 / 0157108 A1 (Presta, L); and WO 2004 / 056312 A1 (Adams et al., especially Example 11) and cell lines lacking a functional alpha-1,6-fucosyltransferase gene FUT8, e.g. knockout cell lines such as knockout CHO cells (e.g. Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al. al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003 / 085107).

[0096] The anti-FGFR2 antibodies herein may have bisected oligosaccharides, e.g., biantennary oligosaccharides attached to the Fc region of the antibody are bisected by GlcNAc. Such antibodies may have reduced fucosylation and / or improved ADCC function. Examples of such antibodies are described, for example, in WO2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US2005 / 0123546 (Umana et al.). In some embodiments, the anti-FGFR2 antibodies have at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibodies may have improved CDC function. Such antibodies are described, for example, in WO1997 / 30087 (Patel et al.); WO1998 / 58964 (Raju, S.); and WO1999 / 22764 (Raju, S.).

[0097] In some embodiments of the present invention, the afucosylated anti-FGFR2 antibody mediates ADCC in the presence of human effector cells more effectively than an antibody having the same amino acid sequence containing fucose. Generally, ADCC activity can be determined using the in vitro ADCC assay disclosed in US Patent Publication No. 2015-0050273A1, although other assays or methods for determining ADCC activity, such as in animal models, are also contemplated.

[0098] In some embodiments, the anti-FGFR2 antibody comprises the heavy and light chain sequences of SEQ ID NOs: 2 and 3. In some embodiments, the antibody comprising the heavy and light chain sequences of SEQ ID NOs: 2 and 3 is afucosylated.

[0099] Exemplary Antibody Constant Regions In some embodiments, the anti-FGFR2 described herein comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from kappa and lambda.

[0100] In some embodiments, the antibodies described herein comprise a human IgG constant region. In some embodiments, when effector function is desired, an antibody comprising a human IgG1 heavy chain constant region or a human IgG3 heavy chain constant region is selected. In some embodiments, the antibodies described herein comprise a human IgG1 constant region. In some embodiments, the antibodies described herein comprise a human IgG1 constant region where N297 is afucosylated. In some embodiments, the antibodies described herein comprise a human IgG1 constant region and a human kappa light chain.

[0101] Throughout this specification and claims, unless otherwise specified or known to one of skill in the art, the numbering of residues in an immunoglobulin heavy chain is that of the EU index in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), expressly incorporated herein by reference. "EU index in Kabat" refers to the residue numbering of the human IgG1 EU antibody.

[0102] In certain embodiments, the antibodies of the present invention comprise a variant Fc region having at least one amino acid substitution compared to the Fc region of a wild-type IgG or wild-type antibody. In certain embodiments, the variant Fc region has two or more amino acid substitutions in the Fc region of a wild-type antibody. In certain embodiments, the variant Fc region has three or more amino acid substitutions in the Fc region of a wild-type antibody. In certain embodiments, the variant Fc region has at least one, two or more of the Fc region amino acid substitutions described herein. In certain embodiments, the variant Fc region herein has at least about 80% homology with the native sequence Fc region and / or the parent antibody Fc region. In certain embodiments, the variant Fc region herein has at least about 90% homology with the native sequence Fc region and / or the parent antibody Fc region. In certain embodiments, the variant Fc region herein has at least about 95% homology with the native sequence Fc region and / or the parent antibody Fc region.

[0103] In certain embodiments, the antibodies provided herein are modified to increase or decrease the extent to which the antibody is glycosylated. Adding or removing glycosylation sites to an antibody can be conveniently accomplished by modifying the amino acid sequence to create or remove one or more glycosylation sites.

[0104] If the antibody comprises an Fc region, the carbohydrate attached to the Fc region may be modified. Natural antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides, which are generally N-linked to Asn297 in the CH2 domain of the Fc region. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides may contain various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modification of the oligosaccharides in the antibodies of the invention may be performed to generate antibodies with specific improved properties.

[0105] The antibody may also have an amino acid terminal leader extension. For example, one or more amino acid residues of an amino acid terminal leader sequence are present at the amino terminus of any one or more heavy or light chains of the antibody. An exemplary amino terminal leader extension comprises or consists of three amino acid residues VHS, and is present on one or both light chains of the antibody.

[0106] The in vivo or serum half-life of human FcRn high affinity binding polypeptides can be evaluated, for example, in transgenic mice, humans, or non-human primates to which the polypeptides comprising variant Fc regions are administered.See, for example, Petkova et al. International Immunology 18(12):1759-1769 (2006).

[0107] Exemplary Chimeric Antibodies In certain embodiments, the anti-FGFR2 antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). As an example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. As a further example, a chimeric antibody is a "class-switched" antibody whose class or subclass has been changed from that of the parent antibody. A chimeric antibody includes an antigen-binding fragment thereof.

[0108] Non-limiting exemplary chimeric antibodies include chimeric antibodies against FGFR2 comprising the heavy chain HVR1, HVR2 and HVR3 and / or light chain HVR1, HVR2 and HVR3 sequences described herein.

[0109] In some embodiments, the chimeric antibodies described herein comprise one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from kappa and lambda. In some embodiments, the chimeric antibodies described herein comprise a human IgG constant region. In some embodiments, the chimeric antibodies described herein comprise a human IgG4 heavy chain constant region. In some embodiments, the chimeric antibodies described herein comprise a human IgG4 constant region and a human kappa light chain.

[0110] As mentioned above, whether effector function is desirable may depend on the particular therapeutic method for which the antibody is intended. Thus, in some embodiments, if effector function is desirable, a chimeric antibody comprising a human IgG1 heavy chain constant region or a human IgG3 heavy chain constant region is selected. In some embodiments, if effector function is undesirable, a chimeric antibody comprising a human IgG4 or IgG2 heavy chain constant region is selected. In some embodiments, the chimeric antibody described herein comprises a human IgG1 constant region with N297 afucosylation. In some embodiments, the chimeric antibody described herein comprises a human IgG1 constant region and a human kappa light chain.

[0111] Exemplary Humanized Antibodies In some embodiments, humanized antibodies that bind to FGFR2 are used.Humanized antibodies are useful as therapeutic molecules because they reduce or eliminate the human immune response against non-human antibodies (such as human anti-mouse antibody (HAMA) response), which can lead to an immune response against antibody therapeutics and reduce the effectiveness of therapeutics.

[0112] In certain embodiments, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains, in which the HVR or CDR (or a portion thereof) are derived from a non-human antibody and the FR (or a portion thereof) are derived from a human antibody sequence. The humanized antibody also optionally comprises at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are replaced with the corresponding residues of a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve the specificity or affinity of the antibody.

[0113] Humanized antibodies and methods for making them are reviewed, e.g., in Almagro and Fransson, (2008) Front. Biosci. 13:1619-1633, and further described, e.g., in Riechmann et al., (1988) Nature 332:323-329; Queen et al., (1989) Proc. Natl Acad. Sci. USA 86:10029-10033; U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., (2005) Methods 36:25-34 (describing SDR (a-CDR) grafting); Padlan, (1991) Mol. Immunol. 28:489-498 (describing "resurfacing"); Dall'Acqua et al., (2005) Methods 36:43-60 (describing "FR shuffling"); and Osbourn et al., (2005) Methods 36:61-68 and Klimka et al., (2000) Br. J. Cancer, 83:252-260 (describing "guide selection" for FR shuffling).

[0114] Human framework regions that may be used for humanization include framework regions selected using the "best-fit" method (see, e.g., Sims et al. (1993) J. Immunol. 151:2296); framework regions derived from consensus sequences of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. (1992) Proc. Natl. Acad. Sci. USA, 89:4285; and Presta et al. (1993) J. Immunol, 151:2623); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, (2008) Front. Biosci. 13:1619-1633); and framework regions obtained from screening of FR libraries (see, e.g., Baca et al., (1997) J. Biol. Chem. 272:10678-10684 and Rosok et al., (1998) J. Immunol. 272:10678-10684). al., (1996) J. Biol. Chem. 271:22611-22618).

[0115] In some embodiments, a humanized antibody comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from kappa and lambda.

[0116] In some embodiments, the humanized antibodies described herein comprise a human IgG constant region. In some embodiments, where effector function is desired, the antibody comprises a human IgG1 heavy chain constant region or a human IgG3 heavy chain constant region. In some embodiments, the humanized antibodies described herein comprise a human IgG1 constant region. In some embodiments, the humanized antibodies described herein comprise a human IgG1 constant region where N297 is afucosylated. In some embodiments, the humanized antibodies described herein comprise a human IgG1 constant region and a human kappa light chain.

[0117] Human antibodies Human anti-FGFR2 antibodies can be produced by any suitable method. Non-limiting exemplary methods include producing human antibodies in transgenic mice that contain human immunoglobulin loci. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551-55 (1993); Jakobovits et al., Nature 362:255-8 (1993); Lonberg et al., Nature 368:856-9 (1994); and U.S. Patent Nos. 5,545,807, 6,713,610, 6,673,986, 6,162,963, 5,545,807, 6,300,129, 6,255,458, 5,877,397, 5,874,299, and 5,545,806.

[0118] Non-limiting exemplary methods also include generating human antibodies using phage display libraries. See, e.g., Hoogenboom et al., J. Mol. Biol. 227:381-8 (1992); Marks et al., J. Mol. Biol. 222:581-97 (1991); and PCT International Publication No. WO 99 / 10494.

[0119] In some embodiments, the human antibodies comprise one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from kappa and lambda. In some embodiments, the human antibodies described herein comprise a human IgG constant region. In some embodiments, the human antibodies described herein comprise a human IgG4 heavy chain constant region. In some such embodiments, the human antibodies described herein comprise a S241P mutation in the human IgG4 constant region. In some embodiments, the human antibodies described herein comprise a human IgG4 constant region and a human kappa light chain.

[0120] In some embodiments, when effector function is desired, a human antibody comprising a human IgG1 heavy chain constant region or a human IgG3 heavy chain constant region is selected. In some embodiments, when effector function is undesired, a human antibody comprising a human IgG4 or IgG2 heavy chain constant region is selected. In some embodiments, the humanized antibodies described herein comprise a human IgG1 constant region that is afucosylated at N297. In some embodiments, the humanized antibodies described herein comprise a human IgG1 constant region and a human kappa light chain.

[0121] Exemplary Antibody Conjugates In some embodiments, anti-FGFR2 antibody is conjugated to a label and / or a cytotoxic agent.As used herein, a label is a moiety that facilitates the detection of the antibody and / or the detection of the molecule to which the antibody binds.Non-limiting exemplary labels include, but are not limited to, radioisotopes, fluorescent groups, enzyme groups, chemiluminescent groups, biotin, epitope tags, metal binding tags, etc.Those skilled in the art can select suitable targets according to the intended application.

[0122] As used herein, a cytotoxic agent is a moiety that reduces the proliferation ability of one or more cells. A cell has reduced proliferation ability when it is no longer able to proliferate, for example, because the cell undergoes apoptosis or otherwise dies, the cell does not progress through the cell cycle and / or does not divide, the cell differentiates, etc. Non-limiting exemplary cytotoxic agents include, but are not limited to, radioisotopes, toxins, and chemotherapeutic agents. Those skilled in the art can select a suitable cytotoxic agent depending on the intended application.

[0123] In some embodiments, the label and / or cytotoxic agent are conjugated to the antibody in vitro using chemical methods. Non-limiting exemplary chemical conjugation methods are known in the art and include commercially available services, methods and / or reagents from, for example, Thermo Scientific Life Science Research Produces (formerly Pierce; Rockford, IL), Prozyme (Hayward, CA), SACRI Antibody Services (Calgary, Canada), AbD Serotec (Raleigh, NC), etc. In some embodiments, when the label and / or cytotoxic agent is a polypeptide, the label and / or cytotoxic agent can be expressed from the same expression vector that includes at least one antibody chain to produce a polypeptide that includes the label and / or cytotoxic agent fused to the antibody chain. Those skilled in the art can select a suitable method for conjugating the label and / or cytotoxic agent to the antibody depending on the intended application.

[0124] Nucleic acid molecules encoding antibodies Nucleic acid molecules are provided that include a polynucleotide encoding one or more chains of an antibody. In some embodiments, the nucleic acid molecule includes a polynucleotide encoding a heavy chain or a light chain of the antibody. In some embodiments, the nucleic acid molecule includes both a polynucleotide encoding a heavy chain of the antibody and a polynucleotide encoding a light chain of the antibody. In some embodiments, a first nucleic acid molecule includes a first polynucleotide encoding a heavy chain and a second nucleic acid molecule includes a second polynucleotide encoding a light chain.

[0125] In some such embodiments, the heavy and light chains are expressed as two separate polypeptides from one nucleic acid molecule, or from two separate nucleic acid molecules, in some embodiments, for example when the antibody is an scFv, a single polynucleotide encodes a single polypeptide comprising both the heavy and light chains linked together.

[0126] In some embodiments, a polynucleotide encoding an antibody heavy or light chain comprises a nucleotide sequence encoding a leader sequence, which, when translated, is located at the N-terminus of the heavy or light chain. As mentioned above, the leader sequence may be the native heavy or light chain leader sequence or another heterologous leader sequence.

[0127] The nucleic acid molecule can be constructed using recombinant DNA techniques conventional in the art. In some embodiments, the nucleic acid molecule is an expression vector suitable for expression in a selected host cell.

[0128] Antibody Expression and Production vector A vector is provided that includes a polynucleotide encoding the heavy and / or light chain of an antibody. A vector is also provided that includes a polynucleotide encoding the heavy and / or light chain of an antibody. Such vectors include, but are not limited to, DNA vectors, phage vectors, viral vectors, retroviral vectors, and the like. In some embodiments, the vector includes a first polynucleotide sequence encoding a heavy chain and a second polynucleotide sequence encoding a light chain. In some embodiments, the heavy and light chains are expressed as two separate polypeptides from the vector. In some embodiments, the heavy and light chains are expressed as part of a single polypeptide, for example, when the antibody is an scFv.

[0129] In some embodiments, the first vector comprises a polynucleotide encoding a heavy chain and the second vector comprises a polynucleotide encoding a light chain. In some embodiments, the first vector and the second vector are transfected into the host cell in similar amounts (such as similar molar amounts or similar masses). In some embodiments, a molar or mass ratio of the first vector and the second vector of 5:1 to 1:5 is transfected into the host cell. In some embodiments, the vector encoding the heavy chain and the vector encoding the light chain are used in a mass ratio of 1:1 to 1:5. In some embodiments, the vector encoding the heavy chain and the vector encoding the light chain are used in a mass ratio of 1:2.

[0130] In some embodiments, a vector is selected that is optimized for expression of a polypeptide in CHO or CHO-derived cells, or NSO cells. Exemplary such vectors are disclosed, for example, in Running Deer et al., Biotechnol. Prog. 20:880-889 (2004).

[0131] In some embodiments, the vector is selected for in vivo expression of antibody heavy chains and / or antibody light chains in animals, including humans. In some such embodiments, expression of the polypeptide is under the control of a promoter that functions in a tissue-specific manner. For example, liver-specific promoters are described, for example, in PCT International Publication No. WO2006 / 076288.

[0132] host cell In various embodiments, the antibody heavy and / or light chains may be expressed in prokaryotic cells, such as bacterial cells, or eukaryotic cells, such as fungal cells (such as yeast), plant cells, insect cells, and mammalian cells. Such expression may be performed, for example, according to procedures known in the art. Exemplary eukaryotic cells that may be used to express the polypeptide include, but are not limited to, COS cells, including COS7 cells, 293 cells, including 293-6E cells, CHO cells, including CHO-S and DG44 cells, PER.C6® cells (Crucell), and NSO cells. In some embodiments, the antibody heavy and / or light chains may be expressed in yeast. See, for example, U.S. Patent Application Publication No. US2006 / 0270045A1. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the antibody heavy and / or light chains. For example, in some embodiments, CHO cells produce polypeptides that are more sialylated than the same polypeptides produced in 293 cells.

[0133] Introduction of one or more nucleic acids into a desired host cell can be performed by any method, including, but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection, etc. Non-limiting exemplary methods are described, for example, in Sambrook et al., Molecular Cloning, A Laboratory Manual, 3 rdCold Spring Harbor Laboratory Press, ed., 2001. The nucleic acid may be transiently or stably transfected into the desired host cell according to any suitable method.

[0134] In some embodiments, one or more polypeptides may be produced in vivo in an animal that has been engineered or transfected with one or more nucleic acid molecules encoding the polypeptides, according to any suitable method.

[0135] Antibody purification Antibodies can be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography. Suitable affinity ligands include antigens and ligands that bind to antibody constant regions. For example, protein A, protein G, protein A / G, or antibody affinity columns can be used to bind to the constant region and purify the antibody. Hydrophobic interaction chromatography, such as butyl or phenyl columns, is also suitable for purifying some polypeptides. Numerous methods of purifying polypeptides are known in the art.

[0136] Cell-free production of antibodies In some embodiments, the antibodies are produced in a cell-free system. Non-limiting exemplary cell-free systems are described, for example, in Sitaraman et al., Methods Mol. Biol. 498:229-44 (2009); Spirin, Trends Biotechnol. 22:538-45 (2004); Endo et al., Biotechnol. Adv. 21:695-713 (2003).

[0137] Modified version FOLFOX6 Modified FOLFOX6 (mFOLFOX6) chemotherapy regimen includes a combination of oxaliplatin (e.g., Eloxatin®), leucovorin (e.g., leucovorin calcium or folinic acid) and 5-fluorouracil (5-FU) administered intravenously for a total of about 2 consecutive days. Modified FOLFOX6 is used as a first-line treatment for advanced gastric cancer. A randomized phase 3 trial comparing mFOLFOX6 with 5-FU / LV / cisplatin (FLP) in the treatment of 220 patients with gastric cancer reported a statistically insignificant improvement in progression-free time, but mFOLFOX6 was associated with a meaningful reduction in grade 3 / 4 adverse events, including neutropenia, anemia and peripheral neuropathy (Al-Batran et al., J. Clin. Oncol. 26:1435-42 (2008)). Subsequent studies confirmed the safety and efficacy of mFOLFOX6 in advanced gastric cancer (B. Keam, BMC Cancer, 8:148 (2008)).

[0138] In some embodiments, a combination of oxaliplatin (e.g., Eloxatin®), leucovorin (e.g., leucovorin calcium or folinic acid), and 5-fluorouracil (5-FU) are administered by IV infusion or IV bolus, respectively, over about 2-8 hours, followed by a further infusion of 5-FU by IV infusion over about 44-48 hours. In some embodiments, the mFOLFOX6 regimen consists of 50-100 mg / m on day 1. 2 oxaliplatin given by IV, for example, over 2 hours, followed by 100-400 mg / m on day 1. 2 leucovorin given by IV over, say, 2 hours, followed by 100-400 mg / m2, all on day 1. 2 , 5-FU administered by IV bolus or IV infusion, followed by 2000–2500 mg / m 2 In some embodiments, the mFOLFOX6 regimen includes an additional IV infusion of 5-FU at 75-100 mg / m on day 1 over 44-48 hours, e.g., 46 hours. 2oxaliplatin given by IV, for example, over 2 hours, followed by 200-400 mg / m on day 1. 2 leucovorin given by IV over 2 hours, then 200-400 mg / m2, all on day 1. 2 , 5-FU administered by IV bolus or IV infusion, followed by 2200–2400 mg / m 2 In some embodiments, the mFOLFOX6 regimen includes an additional IV infusion of 5-FU at 75-90 mg / m on day 1 over 44-48 hours, e.g., 46 hours. 2 oxaliplatin given by IV, for example, over 2 hours, followed by 300-400 mg / m on day 1. 2 leucovorin given by IV over 2 hours, followed by 300-400 mg / m2, all on day 1. 2 , 5-FU administered by IV bolus or IV infusion, followed by 2200–2400 mg / m 2 This includes a further IV infusion of 5-FU at 0.5° C. for 44 to 48 hours, for example 46 hours.

[0139] In some embodiments, the mFOLFOX6 regimen comprises 85 mg / m 2 oxaliplatin given by IV over, for example, 2 hours, then 400 mg / m on day 1 2 leucovorin given by IV over 2 hours, then 400 mg / m2, all on day 1. 2 , 5-FU administered by IV bolus or IV infusion, followed by 2400 mg / m 2 For example, the starting dose of mFOLFOX6 as first-line treatment for gastric cancer includes a further IV infusion of 5-FU at 85 mg / m 2 of oxaliplatin, 350 mg of calcium folinate (folinic acid), 400 mg / m 2 at a dose of 2400 mg / m2 infused over 46 hours. 2 A dose of fluorouracil may be included.

[0140] In some embodiments, the mFOLFOX6 regimen can be administered once every 10 to 21 days, e.g., once every 10 to 15 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, or once every 21 days.

[0141] In some embodiments, mFOLFOX6 may be administered once every "2 weeks," which, as used in the context of the general dosing regimens herein, means once every 14 days ± 3 days, or once every 11 to 17 days.

[0142] Therapeutic compositions and methods How to Treat Cancer In some embodiments, a method for treating cancer is provided, comprising administering an effective amount of an anti-FGFR2 antibody, such as the anti-FGFR2-IIIb antibody described herein, in combination with a modified FOLFOX6 chemotherapy regimen (mFOLFOX6).In some embodiments, the cancer is gastrointestinal (GI) cancer, such as gastric cancer, colon cancer, and pancreatic adenocarcinoma.In some embodiments, the cancer is unresectable, locally advanced, or metastatic gastric cancer.

[0143] In some embodiments of the method, the anti-FGFR2-IIIb antibody is administered at a dose of 6-15 mg / kg, 10-15 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg. In some embodiments, the anti-FGFR2-IIIb antibody is administered once every 7-21 days, once every 7-15 days, once every 7-10 days, once every 10-14 days, once every 11-17 days, once every 12-16 days, once every 13-15 days, once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, or once every 21 days. In some embodiments, the anti-FGFR2-IIIb antibody may be administered once every 2 weeks, which means once every 14 days ± 3 days, or once every 11-17 days.

[0144] In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosage regimen of 6-15 mg / kg every 2 weeks. In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosage regimen of 6-15 mg / kg every 13-15 days. In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosage regimen of 6-15 mg / kg every 14 days. In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosage regimen of 6, 10 or 15 mg / kg every 2 weeks. In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosage regimen of 6, 10 or 15 mg / kg every 13-15 days. In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosage regimen of 6, 10 or 15 mg / kg every 14 days.

[0145] In some embodiments, a dosing regimen is used in which two doses are administered two weeks apart, and an intermediate boost is administered once between the two doses, the intermediate boost being less than two doses. Administration in such a regimen can help maintain circulating antibodies at an appropriate or relatively stable concentration over time. For example, if the concentration of circulating antibodies after administration drops to a trough about one week after administration, administering a low boost at or near the trough, followed by another normal dose about one week after the boost, can help stabilize the overall concentration of circulating antibodies over time and prevent the concentration from becoming too low between doses.

[0146] Thus, in some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosing regimen of 6-15 mg / kg every two weeks, with an intermediate booster dose that is a lower dose than the 6-15 mg / kg dose being administered one week (meaning 7±2 days or 5-9 days) after the first of two 6-15 mg / kg doses and one week (i.e., 5-9 days) before the second of two 6-15 mg / kg doses. In some such embodiments, the booster dose is 3-8 mg / kg. In some embodiments, the booster dose is half the dose of the immediately preceding or immediately following dose. In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosing regimen of 6-15 mg / kg every two weeks, with an intermediate booster dose of 3-8 mg / kg being administered 6-8 days after the first of two 6-15 mg / kg doses and 6-8 days before the second of two 6-15 mg / kg doses. In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dosing regimen of 10-15 mg / kg every two weeks with an intermediate booster dose of 5-8 mg / kg administered 6-8 days after the first of two 10-15 mg / kg doses and 6-8 days before the second of two 10-15 mg / kg doses. In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dosing regimen of 15 mg / kg every two weeks with an intermediate booster dose of 7-8 mg / kg administered 6-8 days after the first of two 15 mg / kg doses and 6-8 days before the second of two 15 mg / kg doses. In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dosing regimen of 15 mg / kg every 13-15 days with an intermediate booster dose of 7-8 mg / kg administered 6-8 days after the first of two 15 mg / kg doses and 6-8 days before the second of two 15 mg / kg doses. In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dosing regimen of 15 mg / kg every 14 days with an intermediate booster dose of 7-8 mg / kg administered 6-8 days after the first of two 15 mg / kg doses and 6-8 days before the second of two 15 mg / kg doses.In some embodiments, the anti-FGFR2-IIIb antibody is administered in a dosing regimen of 15 mg / kg every 14 days, with an intermediate booster dose of 7-8 mg / kg administered 7 days after the first of two 15 mg / kg doses and 7 days before the second of two 15 mg / kg doses. In some of the above embodiments, the booster dose is administered to the patient only once, e.g., between the first and second antibody administrations. In other embodiments, the booster dose is administered only twice, e.g., between the first and second antibody administrations and between the second and third antibody administrations.

[0147] In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dosage regimen of 15 mg / kg every 14 days, with an intermediate booster dose of 7.5 mg / kg administered 7 days after the first of two 15 mg / kg doses and 7 days before the second of two 15 mg / kg doses. In some embodiments, the anti-FGFR2-IIIb antibody is administered at a dose of 15 mg / kg once every 14 days, beginning on day 1, and then the anti-FGFR2-IIIb antibody is administered at a booster dose of 7.5 mg / kg 7 days after the first dose of the anti-FGFR2-IIIb antibody (i.e., day 8). In some such embodiments, the booster dose of 7.5 mg / kg is administered only once, e.g., between the first and second antibody doses of 15 mg / kg.

[0148] The anti-FGFR2-IIIb antibody and mFOLFOX6 may be administered simultaneously, e.g., on the same day (e.g., the antibody is infused by IV before the start of the mFOLFOX6 regimen), or sequentially, e.g., on different days. In some embodiments, mFOLFOX6 is administered at least once or at least twice before the start of treatment with the anti-FGFR2-IIIb antibody. In some embodiments, both the antibody and mFOLFOX6 are administered once every 7-21 days, once every 7-15 days, once every 7-10 days, once every 10-14 days, once every 11-17 days, once every 12-16 days, once every 13-15 days, once every 7 days, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, or once every 21 days. In some embodiments, the anti-FGFR2-IIIb and mFOLFOX6 may be administered once every 2 weeks, which means once every 14 days ± 3 days, or once every 11-17 days.

[0149] In some embodiments, the anti-FGFR2-IIIb antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:8, The light chain variable region is (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:11, Anti-FGFR2-IIIb antibodies were administered intravenously at a dose of 10-15 mg / kg, followed by 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin, and 400 mg / m2 of 5-fluorouracil (5-FU) administered by IV infusion or IV bolus at 2400 mg / m for 44 to 48 hours. 2 mFOLFOX6 including 100 mg of 5-FU administered by IV infusion will be administered, and anti-FGFR2-IIIb and mFOLFOX6 will be administered every 2 weeks.

[0150] In some embodiments, the subject has a gastric cancer that comprises an FGFR2 gene amplification, while in some embodiments, the cancer does not comprise an FGFR2 amplification. In some embodiments, fluorescent in situ hybridization (FISH) is used to assess gene amplification, for example, with a probe to the locus and chromosome 10 centromere. In some embodiments, where amplification occurs, the FGFR2 amplification is represented by an FGFR2:CEN10 (chromosome 10 centromere) ratio of >3. In some embodiments, the FGFR2 amplification is represented by an FGFR2:CEN10 ratio of >=2. However, in other embodiments, the FGFR2 level is represented by an FGFR2:CEN10 ratio between 1 and 2, not indicating an FGFR2 amplification.

[0151] In some embodiments, the subject has a gastric cancer that overexpresses FGFR2 or overexpresses FGFR2-IIIb. In some embodiments, the cancer overexpresses FGFR2-IIIb more than FGFR2-IIIc. In some embodiments, the cancer does not contain gene amplification but overexpresses FGFR2-IIIb, and in other embodiments, the cancer contains both FGFR2 gene amplification and overexpression of FGFR2-IIIb. In some embodiments, the cancer that contains FGFR2 amplification expresses FGFR2-IIIb at a normalized level that is 2-fold, 3-fold, 5-fold, or 10-fold higher than the normalized FGFR2-IIIc expression level. In some embodiments, the expression level is normalized to GUSB. In some embodiments, the overexpression is overexpression of mRNA. In some embodiments, the overexpression is overexpression of protein. In some embodiments, a point mutation or translocation can cause overexpression of FGFR2.

[0152] In some embodiments, overexpression of FGFR2 or FGFR2-IIIb is determined by immunohistochemical staining (IHC). For example, overexpression can be determined by 1+, 2+, or 3+ IHC signal in at least 10% of tumor cells, for example, at least 20%, 30%, 40%, or 50% of tumor cells. For example, in some such embodiments, the treated patient can have, for example, 2+ or 3+ IHC signal for FGFR2-IIIb in at least 10% of tumor cells (for example, cell membrane). In some embodiments, the patient can have 3+ signal in at least 10% of tumor cells. In some embodiments, the patient can have at least 1+ signal in at least 10% of tumor cells.

[0153] In some embodiments, overexpression of FGFR2 or FGFR2-IIIb may be reported as an "H score". To determine the H score, first, the staining intensity of the cell membrane is determined in a fixed field, for example by IHC, and a score of 0, 1+, 2+, or 3+ may be obtained, and the H score may be calculated using the following formula: 1×(% of cells visualized with IHC intensity of 1+)+2×(% of cells visualized with IHC intensity of 2+)+3×(% of cells visualized with IHC intensity of 3+). Theoretically, the H score may range from 0 to 300, and is equal to 300 when all cells in the field have an IHC staining of 3+. In some embodiments, the patient to be treated has an initial H score for FGFR2, for example FGFR2-IIIb, of >20, for example, >30, >40, >50, or >100, or in the range of 20 to 300, 20 to 100, 20 to 50, 20 to 40, or 20 to 30. In some embodiments, patients have an H-score >10, or within the range of 10 to 20 or 15 to 20. In other embodiments, patients have an H-score of 0 to 10, which may indicate no overexpression.

[0154] In some embodiments, the cancer, e.g., gastric cancer, has already been determined to overexpress FGFR2-IIIb and / or have FGFR2 gene amplification. In other embodiments, the methods herein evaluate one or both of FGFR2IIIb expression and FGFR2 gene amplification status prior to administration of treatment, e.g., to determine whether treatment with an anti-FGFR2-IIIb antibody is warranted. In some embodiments, the methods herein are used to treat gastric cancer that has been determined to (a) overexpress FGFR2-IIIb, as indicated by an IHC signal of 2+ or 3+ in at least 10% of tumor cells, and / or (b) have FGFR2 gene amplification in ctDNA. In some embodiments, the methods herein are used to treat gastric cancer that has been determined to (a) overexpress FGFR2-IIIb, as indicated by an IHC signal of 3+ in at least 10% of tumor cells, and / or (b) have FGFR2 gene amplification in ctDNA.

[0155] Routes of Administration, Carriers and Additional Pharmaceutical Compositions In various embodiments, the antibody may be administered in vivo by a variety of routes, including but not limited to oral, intraarterial, parenteral, intranasal, intravenous, intramuscular, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or by implantation or inhalation. The subject antibody may be formulated into a preparation in solid, semisolid, liquid, or gas form, including but not limited to tablets, capsules, powders, granules, ointments, liquids, suppositories, enemas, injections, inhalants, and aerosols. The nucleic acid molecule encoding the antibody may be coated onto gold particles and delivered intradermally by a biolistic device or "gene gun" as described in the literature (see, e.g., Tang et al., Nature 356:152-154 (1992)). The appropriate formulation and route of administration may be selected depending on the intended application.

[0156] In various embodiments, compositions comprising antibodies are provided as formulations comprising a wide variety of pharma- ceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 2011). th ed.(2003);Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems,7 th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3 rd ed., Pharmaceutical Press (2000). A variety of pharma- ceutically acceptable carriers can be used, including vehicles, adjuvants, and diluents. In addition, a variety of pharma- ceutically acceptable auxiliary substances can be used, such as pH adjusting and buffering agents, isotonicity agents, stabilizers, wetting agents, and the like. Non-limiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

[0157] Also provided herein is a composition comprising an anti-FGFR2 antibody as described herein and one or more of the mFOLFOX6 chemotherapeutic agents described herein, including oxaliplatin, leucovorin, and 5-FU. In some embodiments, the FGFR2 inhibitor and the chemotherapeutic agent are each contained in a separate container, or each contained in a separate compartment of a single container, so that they are not mixed together. In some embodiments, the composition includes instructions for use, such as instructions for use in cancer treatment. EXAMPLES

[0158] The examples discussed below are purely for the purpose of illustrating the present invention and are not to be construed as limiting the present invention in any way. The examples are not intended to represent that the experiments below are all or the only experiments performed.

[0159] Example 1: A Phase 3, randomized, double-blind, placebo-controlled study, followed by a Phase 1, dose-finding safety run-in phase, of an anti-FGFR2-IIIb antibody in combination with modified FOLFOX6 in patients with previously untreated advanced gastric or gastroesophageal cancer Protocol Overview The following protocol will be conducted globally at up to 250 different study sites. The study will be conducted in two parts: Part 1: a Phase 1 dose-finding safety run-in phase and Part 2: a Phase 3 study.

[0160] The primary objectives of Part 1 are (a) to determine the recommended dose (RD) of anti-FGFR2-IIIb when administered in combination with fixed-dose infusional 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients with advanced gastrointestinal (GI) tumors, and (b) to evaluate the safety profile of escalating doses of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with GI tumors. Secondary objectives of Part 1 are (a) to evaluate the safety and tolerability of prolonged exposure to anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with GI tumors, (b) to characterize the pharmacokinetic (PK) profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with GI tumors, and (c) to characterize the immunogenicity of anti-FGFR2-IIIb. Part 1 will also characterize the pharmacodynamic (PD) profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 by evaluation of exploratory biomarkers in blood and hair follicle samples from patients with GI tumors.

[0161] The primary endpoints of Part I were the occurrence of grade ≥2 adverse events (AEs) assessed by the investigator as related to anti-FGFR2-IIIb and laboratory abnormalities defined as dose-limiting toxicities (DLTs). Secondary endpoints of Part 1 were (a) the occurrence of AEs, laboratory abnormalities, corneal and retinal findings, and electrocardiogram (ECG) abnormalities, and (b) PK parameters of anti-FGFR2-IIIb derived from serum concentration-time profiles, e.g., area under the serum concentration-time curve (AUC), maximum serum concentration (C max ), trough serum concentration (C trough ), clearance (CL), elimination half-life (t 1 / 2 ), volume of distribution and rate of accumulation (if appropriate and applicable), and (c) immune response to anti-FGFR2-IIIb as determined by immunogenicity testing. This part may also explore biomarkers in blood and hair follicle samples.

[0162] In Part 2, the primary objective is to evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of progression-free survival (PFS) in patients with FGFR2b-selected gastric or gastroesophageal cancer (hereafter referred to as gastric cancer or GC). Secondary objectives are: (a) to evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of overall survival (OS) in patients with FGFR2b-selected GC; (b) to evaluate the safety and tolerability of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 in patients with FGFR2b-selected GC; (c) to characterize the PK profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with FGFR2b-selected GC; (d) to characterize the immunogenicity of anti-FGFR2-IIIb; and (e) to characterize the PD profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of immune cell infiltration and other exploratory biomarkers in pre- and on-treatment tumor biopsies.The study will also assess the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of PFS based on blinded independent review committee (BIRC) progression assessment; (b) to assess the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of objective response rate (ORR) in patients with FGFR2b-selected GCs; (c) to assess the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of ORR based on BIRC progression assessment; (d) to assess the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of 1-year OS in patients with FGFR2b-selected GCs; (e) to assess the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of 1-year OS in patients with FGFR2b-selected GCs. (f) explore the association between FGFR2 status (tumor tissue and / or blood-based biopsy [ctDNA] assay) and clinical outcomes; (g) explore the concordance between FGFR2 status of tumor tissue and FGFR2 amplification using blood-based biopsy (ctDNA) assay; (h) characterize the PD profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by evaluating exploratory biomarkers in blood samples of patients with FGFR2b-selected GCs; and (i) evaluate patient-reported outcomes (PROs) and quality of life (QOL) outcomes in patients with FGFR2b-selected GCs when anti-FGFR2-IIIb is administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6.

[0163] Endpoints for Part 2 included the primary endpoint PFS, defined as the time from randomization to the date of radiological progression based on investigator assessment (per RECIST v.1.1) or death from any cause, whichever occurred first, and various secondary endpoints, including (a) OS, defined as the time from randomization to the date of death from any cause, (b) objective tumor response based on investigator assessment of tumor lesions per RECIST v1.1, (c) occurrence of AEs, laboratory abnormalities, corneal and retinal findings, and ECG abnormalities, and (d) PK parameters of anti-FGFR2-IIIb in RD when administered in combination with mFOLFOX6 derived from serum concentration-time profiles, e.g., AUC, C max , C trough ,CL,t 1 / 2 (e) immune response as determined by immunogenicity testing; and (f) levels of immune cell infiltration and other exploratory biomarkers in tumor biopsy samples before and during treatment. The studies may also evaluate (a) 1-year OS, defined as the proportion of patients who received at least one dose of anti-FGFR2-IIIb and are alive at 1 year; (b) DOR, limited to patients with a response as determined by the investigator per RECIST v1.1 and defined as the time from first response as determined by the investigator per RECIST v1.1 to progression or death, whichever occurs first; (c) correlation between FGFR2 status as determined by tumor tissue and / or blood-based biopsy (ctDNA) assay and objective tumor response per RECIST v1.1; (d) correlation between FGFR2 status as determined by tumor tissue and FGFR2 amplification in blood-based biopsy (ctDNA) assay; (e) exploratory blood-based biomarkers; and (f) change from baseline in QoL as measured by EQ-5D-5L and EORTC QLQ-C30.

[0164] The study design is as follows: The study is a two-part, multicenter study to evaluate the safety, tolerability, PK, PD, and efficacy of anti-FGFR2-IIIb when administered in combination with mFOLFOX6. The study includes an open-label, part 1 dose escalation, and a randomized, double-blind, placebo-controlled, part 2 study in patients with FGFR2b+ gastric cancer. Part 1 will consist of a minimum of two planned dose cohorts of anti-FGFR2-IIIb in combination with mFOLFOX6 in eligible patients with advanced GI tumors to determine the RD of anti-FGFR2-IIIb administered in combination with mFOLFOX6. Part 2 will consist of two expansion arms (1:1 randomized) and will aim to evaluate the safety and efficacy of anti-FGFR2-IIIb in RD in combination with mFOLFOX6 compared to placebo and mFOLFOX6 in patients with advanced GC selected for FGFR2b (determined by prospective immunohistochemical staining (IHC) analysis of FGFR2b expression and / or blood-based assays showing FGFR2 amplification). Patients will be enrolled in either Part 1 or Part 2 of the study, but not both. After an initial screening period of up to 14 days (2 weeks), patients will be treated with mFOLFOX6 (with or without anti-FGFR2-IIIb) every 2 weeks in 14-day cycles. Patients may have initiated or received mFOLFOX6 chemotherapy prior to enrollment in Part 1, but eligibility requires that patients be candidates to receive at least two additional mFOLFOX6 chemotherapy cycles (there is no upper limit to the number of FOLFOX cycles patients may receive in Part 1, and they may not receive any). Each patient enrolled in Part 1 will be observed for 28 days (DLT period) for safety assessments and occurrence of dose-limiting toxicities. At the completion of the DLT period, patients may continue anti-FGFR2-IIIb in combination with mFOLFOX6 at the discretion of the investigator. Additional treatment may be administered every 2 weeks in 14-day cycles until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any of the other protocol-specified withdrawal criteria. There is no upper limit to the number of doses of anti-FGFR2-IIIb.Continuation of the mFOLFOX6 regimen after the DLT period will follow local standard of care. In part 2, patients whose tumors are FGFR2b positive by IHC (score 2+ or 3+) or blood, who have completed two cycles of mFOLFOX6 chemotherapy, the standard first-line treatment for advanced gastric cancer, and who have signed informed consent will be randomized 1:1 to receive treatment every 2 weeks in 14-day cycles with anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo and mFOLFOX6, with the RD selected after evaluation of the data obtained in part 1. Enrolled patients may continue treatment every 2 weeks in 14-day cycles until radiological or clinical progression as assessed by the investigator, unacceptable toxicity, or until the patient meets any of the other withdrawal criteria specified in the protocol. All treatment decisions will be made by the investigator using local evaluations. After discontinuation of study treatment for reasons other than progression or withdrawal of consent, tumor evaluation will continue until the patient starts additional anticancer therapy. In addition, patients in both Parts 1 and 2 will undergo long-term follow-up for survival via in-site visits or telephone approximately every 3 months ± 28 days after the EOT visit until a maximum of 24 months after the last patient was enrolled in the study or until death, loss to follow-up, withdrawal of consent, or study discontinuation by the sponsor, whichever occurs first.

[0165] Part 1 is an open-label, dose-escalation study of anti-FGFR2-IIIb administered in combination with mFOLFOX6. Patients eligible for Part 1 have unselected GI cancer (with or without tumors overexpressing FGFR2b) with unresectable, locally advanced or metastatic disease and are candidates to receive both anti-FGFR2-IIIb and mFOLFOX6 chemotherapy. FGFR2 status will be determined retrospectively by IHC and blood-based biopsy (ctDNA) assays. Patients enrolled in Part 1 will be treated with escalating doses of anti-FGFR2-IIIb in combination with a fixed-dose backbone chemotherapy regimen of mFOLFOX6 every 2 weeks in 14-day cycles as follows:

[0166] Anti-FGFR2-IIIb Administration: Anti-FGFR2-IIIb IV will be administered every 2 weeks prior to administration of mFOLFOX6 chemotherapy on day 1 of each cycle. Anti-FGFR2-IIIb will be administered as an approximately 30-minute IV infusion via a peripheral vein or central venous catheter with an in-line filter.

[0167] Backbone chemotherapy regimen: Administration of mFOLFOX6 chemotherapy will begin on day 1 of each treatment cycle, after administration of anti-FGFR2-IIIb (after a 30-minute rest period). The mFOLFOX6 regimen will be administered every 2 weeks as follows: oxaliplatin 85 mg / m 2 infused IV over 120 minutes, leucovorin 400 mg / m 2 infused IV over 120 minutes, followed by fluorouracil (5FU) 400 mg / m 2 IV bolus, followed by 5-FU 2400 mg / m as a continuous IV infusion for 46 hours. 2 Oxaliplatin administration does not require pre-hydration. Antiemetic premedication, such as serotonin antagonists (with or without dexamethasone), may be used according to local standard of care at the investigator's discretion if clinically indicated. Dose Levels (Part 1) In Part 1, two dose cohorts of anti-FGFR2-IIIb are planned in a standard 3+3 dose escalation design, with a minimum of three patients enrolled in each cohort. Planned dose levels are: dose level 1: 10 mg / kg anti-FGFR2-IIIb, dose level 2: 15 mg / kg anti-FGFR2-IIIb, dose level-1: 6 mg / kg anti-FGFR2-IIIb (only if dose reduction from dose level 1 is required).

[0168] All dose escalation decisions will be based on evaluation of DLTs, overall safety, and tolerability and will occur after the last patient enrolled in each cohort has completed the 28-day DLT period (after completion of two treatment cycles). Dose escalation decisions will be in consensus by a Cohort Review Committee (CRC) comprised of sponsors and investigators. Consideration of safety and PK parameters may inform the decision to add cohorts at alternative dose levels to achieve optimal target exposure. Dose level -1 will be enrolled only if ≥2 DLTs are observed at dose level 1. DLTs are defined below:

[0169] Dose escalation decisions are based on the following algorithm: if none of the three patients in a cohort have a DLT, the next cohort can be started; if 1 / 3 of the patients in a cohort have a DLT, enroll three more patients in the same cohort; if 2 / 3 or 3 / 3 of the patients in a cohort have a DLT, enrollment is stopped and three more patients are admitted to the lower cohort (i.e., lower dose level) if there were only three in the previous cohort; if 1 / 6 of the patients in a cohort have a DLT, the next cohort can be started; if 2 / 6 or more have a DLT, enrollment is stopped and three more patients are admitted to the lower dose level if there were only three patients in that cohort.

[0170] The RD of anti-FGFR2-IIIb for part 2 will be identified by the CRC based on the assessment of overall safety, tolerability and PK. Thus, the RD may or may not be the same as the identified maximum tolerated dose (MTD). For example, if the MTD is not reached or if data from subsequent treatment cycles in part 1 provide further insight into the safety profile, the RD may not exceed the MTD but may be at a different dose than the MTD. The MTD is defined as the highest dose at which less than 33% of patients experience a DLT during the DLT period. If a DLT is observed in 1 out of 3 patients at a given dose level, 3 additional patients will be enrolled at the same dose level. Dose escalation may continue (dosage level not exceeding 15 mg / kg) until 2 out of 3-6 patients treated at a dose level experience a DLT. The next lower dose is then considered the MTD. Once the MTD or RD is reached, up to 6 additional patients may be added to further explore the safety and PK at that dose level. Thus, the total enrollment in part 1 is approximately 9-12 patients. Any patient who does not receive two doses of anti-FGFR2-IIIb in combination with mFOLFOX6 during the DLT period will be considered unevaluable and will be replaced. Replaced patients may continue on the study after discussion with the sponsor. No more than two doses of anti-FGFR2-IIIb or two cycles of mFOLFOX6 may be administered during the 28-day DLT period. Upon completion of the DLT period, patients may continue to receive anti-FGFR2-IIIb in combination with mFOLFOX6 administered every 2 weeks in 14-day cycles until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any of the other protocol-specified withdrawal criteria. Dose modification criteria for anti-FGFR2-IIIb and mFOLFOX6 are described below.In the event of discontinuation of mFOLFOX6 chemotherapy for any reason prior to progression (e.g., cumulative toxicity or completion of mFOLFOX6 chemotherapy per local practice standards), anti-FGFR2-IIIb may be continued as monotherapy and administered every 2 weeks until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-defined withdrawal criteria. If a cycle of mFOLFOX6 is delayed for more than 14 days due to chemotherapy-related toxicity, anti-FGFR2-IIIb administration should not be delayed and may continue to be administered every 2 weeks. The start of a new cycle of mFOLFOX6 after a delayed administration should be synchronized with the administration of anti-FGFR2-IIIb infusions, if possible (although this is not a study requirement).

[0171] In the event of discontinuation of anti-FGFR2-IIIb for any reason prior to progression (e.g., cumulative toxicity), mFOLFOX6 chemotherapy may be continued according to local regional practice standards or until investigator-assessed radiological or clinical progression, unacceptable toxicity, or the patient meets other protocol-specified withdrawal criteria.

[0172] Patients will be enrolled in Part 2, which aims to characterize the safety and efficacy of anti-FGFR2-IIIb in combination with mFOLFOX6 compared to placebo and mFOLFOX6 in an FGFR2b-selected gastric cancer patient population. Enrollment in Part 2 will begin only if RD (not to exceed 15 mg / kg) of anti-FGFR2-IIIb is identified by CRC in Part 1. Part 2 will be double-blind and will consist of a total of up to approximately 360 FGFR2b-selected gastric cancer patients randomized 1:1 to receive one of two treatment arms: Arm 1: anti-FGFR2-IIIb with RD and mFOLFOX6 administered every 2 weeks, or Arm 2: placebo and mFOLFOX6 administered every 2 weeks. Enrollment in Part 2 will commence at the sponsor's discretion. Gastric cancer patients with unresectable, locally advanced, or metastatic disease who are eligible for first-line mFOLFOX6 chemotherapy and have received two cycles of mFOLFOX6 will be enrolled in part 2 of the study. Patients will be selected for enrollment based on FGFR2b overexpression and / or FGFR2 amplification as determined by validated IHC or blood-based biopsy (ctDNA) assays, respectively. Patients who do not demonstrate either FGFR2b overexpression using IHC or amplification using blood-based biopsy (ctDNA) assays will not be eligible for enrollment, but positivity based on one or both assays will be sufficient to meet eligibility requirements (e.g., positive blood-based biopsy [ctDNA] assay but negative IHC). Enrolled patients may continue treatment every 2 weeks in 14-day cycles until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any of the other protocol-specified withdrawal criteria. All treatment decisions will be made by the investigator using local.

[0173] Inclusion criteria are as follows: Patients enrolled in either Part 1 or Part 2 of the study must be 18 years of age or older, have unresectable, locally advanced, or metastatic disease, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, provide tumor tissue for FGFR2 status determination, provide informed consent, and meet all other eligibility criteria described below. Patients enrolled in Part 1 of the study (dose escalation safety run-in phase) must also meet the following inclusion criteria: histologically or cytologically confirmed gastrointestinal malignancies (e.g., gastric cancer, colorectal cancer, pancreatic adenocarcinoma) for which mFOLFOX6 is considered an appropriate treatment; have had 2 or fewer prior chemotherapy regimens for metastatic disease (not including prior adjuvant chemotherapy with 5-FU and / or oxaliplatin); and patients must be candidates for at least 2 cycles of mFOLFOX6 chemotherapy.

[0174] Patients enrolling in Part 2 (dose expansion) of the study must also meet the following inclusion criteria: histologically documented gastric or gastroesophageal junction adenocarcinoma. FGFR2b overexpression as determined by IHC and / or FGFR2 amplification as determined by blood-based biopsy (ctDNA) assay. No prior chemotherapy for metastatic or unresectable disease (unless described in inclusion criterion #20 for mFOLFOX6). No prior platinum-based chemotherapy (unless described in inclusion criterion #20 for mFOLFOX6). If receiving prior adjuvant or neoadjuvant therapy (chemotherapy and / or chemoradiation), more than 6 months must have elapsed between the end of adjuvant therapy and enrollment.

[0175] Patients must be candidates for mFOLFOX6 chemotherapy and have received 2 cycles of mFOLFOX6 chemotherapy (but not more than 2 cycles) prior to study enrollment. Patients enrolling in either Part 1 or Part 2 will be excluded if they have the following: untreated or symptomatic central nervous system (CNS) metastases; cardiac dysfunction or clinically significant cardiac disease; high QTcF; peripheral sensory neuropathy of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher; positive HER2 status; or any other condition that may increase the risk associated with study participation. No waiver of these inclusion or exclusion criteria will be granted.

[0176] In Part 1, anti-FGFR2-IIIb will be provided in a sterile vial for dilution into an intravenous bag to be administered at the study site over approximately 30 minutes every 14 days (± 3 days) until investigator-assessed radiological or clinical progression, unacceptable toxicity, or other protocol-specified reasons for study withdrawal.

[0177] In part 2, blinded IP (anti-FGFR2-IIIb / placebo) will be provided and administered in a similar manner to the open-label anti-FGFR2-IIIb in part 1.

[0178] Oxaliplatin, 5-FU, and leucovorin will be provided to each center per usual institutional practice. The mFOLFOX6 regimen will be administered every 14 days (± 3 days) until investigator-assessed radiological or clinical progression, unacceptable toxicity, or other protocol-defined reasons for withdrawal from study. Please refer to current local drug package inserts and full prescribing information.

[0179] PK parameters of anti-FGFR2-IIIb, e.g., AUC, C max , C trough ,CL,t 1 / 2Blood samples will be taken to assess efficacy, volume of distribution and accumulation rate, etc. In Part 1, blood samples will be taken of all enrolled patients at the time points outlined below to measure serum levels of anti-FGFR2-IIIb. In Part 2, blood samples will be taken of the first 60 patients randomized to Part 2 at the time points outlined below. For Parts 1 and 2, blood samples for anti-FGFR2-IIIb antibodies will be taken at the designated time points.

[0180] Tumor response assessment will be performed by both the investigator and by blinded central radiological review per RECIST v.1.1 guidelines. Full details regarding the independent review by the BIRC will be provided in the Independent Imaging Review Letter.

[0181] Efficacy measures will include tumor assessments consisting of clinical examinations and appropriate imaging techniques, preferably computed tomography (CT) scans of the chest, abdomen, and pelvis with appropriate slice thickness per RECIST guidelines, with other assessments (magnetic resonance imaging [MRI], x-ray, positron emission tomography [PET], and ultrasound) performed as needed. Tumor assessments will be performed at screening (within 2 weeks of Day 1 of Cycle 1 in Part 1 and Part 2), then every 6 weeks from the first dose for 24 weeks, and approximately every 12 weeks thereafter. If an initial complete response (CR) or partial response (PR) is observed, a confirmatory scan should be performed 4-6 weeks later.

[0182] Safety measures will include AEs, hematology, clinical chemistry, urinalysis, vital signs, weight, concomitant medications / treatments, ECOG performance status, subject physical examination, ECG, and ophthalmologic examination. An independent Data Monitoring Committee (DMC) will evaluate safety study data (AEs and SAEs) periodically throughout the treatment period in Part 2.

[0183] In Part 1, tumor tissue submitted for evaluation of FGFR2 status will be retrospectively analyzed for FGFR2b overexpression by use of IHC. Samples for blood-based biopsy (ctDNA) assays will be collected prior to the first dose of study drug (Cycle 1 Day 1) and will be retrospectively analyzed for FGFR2 amplification. Blood samples for exploratory biomarker analysis will be collected pre-dose on Day 1 of Cycles 1 and 2, 48 hours (Day 3) after dosing on Day 1 of Cycle 1 and Day 1 of Cycle 2, pre-dose on Day 1 of Cycle 3 for patients who continue treatment beyond the 28-day DLT period, and at the EOT visit. Hair follicle samples will be collected pre-dose on Day 1 of Cycle 1, Day 1 of Cycle 3, and Day 1 of Cycle 5, and at the EOT visit, from all patients available for sampling.

[0184] In Part 2, tumor tissue will be submitted to assess FGFR2 status and will be prospectively analyzed for FGFR2b overexpression by use of IHC. Blood samples for ctDNA assessment will be prospectively analyzed for FGFR2 amplification. In addition, blood-based biopsies (ctDNA) assays will be taken longitudinally every 6 weeks from the first dose for 24 weeks and approximately every 12 weeks thereafter and will be retrospectively analyzed for FGFR2 amplification. For all patients in Part 2, samples will also be taken at the EOT visit. For all patients in Part 2, samples will also be taken at the EOT visit. Blood samples for exploratory biomarker analysis will be taken pre-dose on Day 1 of Cycles 1 and 2, 48 hours (Day 3) after doses on Day 1 of Cycle 1 and Day 1 of Cycle 2, pre-dose on Day 1 of Cycle 3, and at the EOT visit.

[0185] Fresh tumor biopsies are mandatory whenever feasible and will be performed pre-treatment and on-treatment within 7 days prior to Day 1 of Cycle 3 (and at least 24 hours prior to dosing) for up to 30 patients randomized to Part 2. Feasibility at each time point will be assessed by the investigator and will include consideration of patient safety. If the investigator assesses that a biopsy is not feasible, the decision must be documented in the source documents. For patients with a biopsy taken within 12 weeks prior to enrollment, the sample may meet the requirement for a fresh pre-treatment biopsy if sufficient sample is available for PD analysis (single paraffin-embedded block or approximately 10 slides). Part 2 patients may also undergo, after discussion with the sponsor, an optional on-treatment biopsy when tumor response is documented and / or an optional post-treatment biopsy when tumor progression is documented.

[0186] The planned total enrollment for this study is up to approximately 372 patients. Following a standard 3+3 design, up to approximately 12 patients evaluable for any dose-limiting toxicity will be enrolled in Part 1. For Part 2, up to approximately 360 patients with FGFR2b-selected gastric cancer will be enrolled and randomized 1:1 to receive anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo and mFOLFOX6 to test efficacy and tolerability. Eligible patients will be stratified according to geographic region (US and Europe vs. Asia vs. rest of the world), prior treatment status (de novo vs. adjuvant / neoadjuvant), and measurable disease status (measurable vs. non-measurable).

[0187] In part 1, all analyses are descriptive and presented by dose group and overall, as appropriate. Descriptive statistics include number of observations, mean, standard deviation, median, range, and interquartile range for continuous variables, and number and percentage for categorical variables, with 95% confidence intervals presented as appropriate. In part 2, the primary efficacy analysis is a comparison of PFS in patients treated with anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo and mFOLFOX6. The primary endpoint, PFS, is defined as the time from randomization to the date of radiological progression based on investigator assessment (per RECIST v.1.1) or death from any cause, whichever occurs first. Secondary efficacy endpoints include OS and ORR. There are interim and primary analyses of PFS, both of which are event-based analyses. At the interim analysis after 48 events (50% of the target 96 PFS events in the primary PFS analysis) have been observed in enrolled patients, only a futility test for PFS will be performed to avoid an HR of >0.806 for the combination of anti-FGFR2-IIIb and mFOLFOX6 compared with placebo and mFOLFOX6. The interim analysis is estimated to be performed approximately 20 months after the first patient is enrolled. The primary analysis of PFS will be performed when at least 96 PFS events have been observed in the first 156 enrolled patients and will be performed using the intention-to-treat (ITT) population. The primary analysis will include only investigator-determined radiological progression events and deaths according to RECIST v.1.1. The primary analysis of PFS will be performed using a stratified log-rank two-sided test (significance level 0.05). The stratification factors will be the same as those used to stratify the randomization schedule documented in the Interactive Voice Response / Web Registration System (IXRS). If the p-value of the stratified log-rank test is statistically significant (<0.05 two-sided) and the HR is less than 1, the null hypothesis of no difference in PFS is rejected and PFS is estimated to be statistically longer in the group receiving anti-FGFR2-IIIb in combination with mFOLFOX6 compared to the group receiving placebo and mFOLFOX6. The median PFS and associated 95% confidence intervals for each treatment group are estimated using the Kaplan-Meier method. Hazard ratios (HR = λ 抗FGFR2-IIIb+mFOLFOX6 / λ mFOLFOX6) are estimated using Cox regression models with treatment group as the only main effect, stratified by the same stratification factors used in the log-rank test. Unstratified HRs are also shown.

[0188] Analysis of secondary endpoints including OS and ORR will be performed when the primary endpoint PFS is statistically significant, and formal hypotheses of OS and ORR will be tested hierarchically at the 0.05 level. OS will be tested first, and if it is significant, ORR will be tested next. The probability of type I error in testing the primary and secondary endpoints will be controlled by adopting this fixed order testing procedure (0.05 level). If the test of PFS is statistically significant, interim and final analyses of OS will be planned. The interim analysis of OS will be performed at the time of the main analysis of PFS. If an analysis of OS is performed, the interim (i.e., when at least 96 PFS events have been observed) and final (i.e., when 249 deaths have been observed) OS analyses will be performed on the ITT population. Hypothesis testing of OS will be performed using a stratified log-rank two-sided test (0.05 level of significance). Interim and final analyses of OS will use group sequential methods to determine the probability of type I error based on O'Brien-Fleming boundaries and the probability of type II error based on Gamma family (parameter -4). The stratification factors will be the same as those used to stratify the randomization schedule documented in the IXRS. The median OS and associated 95% confidence intervals for each treatment group will be estimated using the Kaplan-Meier method. HRs will be estimated using a Cox regression model with treatment group as the only main effect, stratified by the same stratification factors used in the log-rank test. Unstratified HRs are also shown. ORR will be defined as the proportion of patients with a partial or complete response as defined by the investigator according to RECIST v.1.1. The primary analysis of ORR will be performed among patients with measurable disease at baseline. In the analysis of ORR, patients without adequate post-baseline tumor evaluation will be counted as non-responders. Formal hypothesis testing of ORR will be performed using a stratified Cochran-Mantel-Haenszel test. The stratification factors were the same as those used to stratify the randomization schedule documented in the IXRS.

[0189] Power and Sample Size: The study will be designed to provide sufficient power for the primary analysis of PFS. Based on the median PFS (mPFS) of patients receiving placebo and mFOLFOX6 for 6 months, approximately 156 patients (1:1 randomized) and a target of 96 PFS events will be required to demonstrate a hazard ratio (HR) of 0.5 (2-sided, α=0.05) with 90% power for mPFS of the combination of anti-FGFR2-IIIb and mFOLFOX6 compared with placebo and mFOLFOX6 after 24 months of intake and 6 months of follow-up. Assuming an exponential distribution of PFS, this corresponds to an increase in mPFS of 6 to 12 months. In the current design, the minimum observed effect that would result in statistical significance in PFS is a 50% improvement from 6 to 9 months (HR=0.67). The study will also be powered for the primary analysis of OS. Based on the median OS (mOS) of patients receiving placebo and mFOLFOX6 for 10 months, after an intake period of 36 months and a follow-up period of 10 months from the last patient enrollment, to demonstrate a HR of 0.7 with 80% power at an overall type I error level of 0.05 for mOS of the combination of anti-FGFR2-IIIb and mFOLFOX6 compared with placebo and mFOLFOX6, the study would continue enrollment up to approximately 360 patients, targeting 249 death events. Assuming an exponential distribution of OS, this corresponds to a 43% increase in median OS from 10 to 14.3 months. With the current design, the minimum observed effect that would result in statistical significance in OS in the final analysis is a 28% improvement from 10 to 12.8 months (HR = 0.78).

[0190] Safety Analysis: The safety analysis will include all patients who received either study drug (anti-FGFR2-IIIb and mFOLFOX6 or placebo and mFOLFOX6) during the study period and will provide any post-treatment safety information. All AEs will be coded using the Medical Dictionary for Clinical Trials (MedDRA). Investigators will classify the severity of AEs using CTCAE v4.03. Treatment-emergent adverse events (TEAEs) will be defined as any event with an onset date after the first dose of study drug, or any event that was present before treatment and worsened after treatment. Only TEAEs with an onset date prior to the date of last dose + 30 days will be included in the summary table. The number and percentage of patients who experienced AEs will be summarized by system organ class, preferred term, relationship to study drug, and severity for each treatment group. Patient-specific listings will be provided for patients who experienced SAEs, including death, or AEs related to early withdrawal from the study or discontinuation of study drug. Laboratory data will be summarized by laboratory test type. The number and percentage of patients who experienced abnormalities (i.e., outside reference range) and / or clinically significant abnormalities after administration of study drug will be presented for each laboratory measurement. For each laboratory measurement, descriptive statistics will be provided for baseline and all subsequent scheduled post-treatment visits. Changes from baseline to post-treatment visits will also be provided. Descriptive statistics for vital signs will be provided as well. In addition, shifts from baseline in CTCAE grade (if applicable) and shifts by high / low flag (if CTCAE grade is not defined) will be presented by treatment group. No formal comparisons of safety endpoints are planned.

[0191] PK Analysis: PK parameters will be estimated using non-compartmental analysis, although compartmental analysis may be used where appropriate.

[0192] Protocol Details 1. Introduction Background of anti-FGFR2-IIIb The role of the fibroblast growth factor (FGF) receptor (FGFR) pathway in cancer is well known. FGFs can stimulate the transformation and proliferation of tumor cells and stimulate angiogenesis. There are 22 known human FGFs, and the expression of individual FGFs is generally restricted to specific tissues, cell types, and / or developmental stages. FGF signaling is mediated by a family of transmembrane tyrosine kinase receptors encoded by four distinct genes that produce FGF receptor subtypes, termed FGFR1–4 (Turner and Grose 2010).

[0193] FGFR2 has two splicing variants, b and c. In general, FGFR2b is expressed in tissues of epithelial origin (e.g., stomach, skin) (Miki 1992). The main ligands that signal through FGFR2b are FGF7, FGF10, and FGF22. Alterations in signaling in the FGF / FGFR2 pathway (e.g., overexpression of FGFR2b protein or amplification of the FGFR2 gene) are associated with gastric, breast, and other cancers and may signify poor prognosis (Wu 2013, Turner and Grose 2010). Indeed, as early as 1990, a subset of patients with gastric cancer (approximately 3-9%) and breast cancer (1-2%) was identified to have amplification of the FGFR2 gene located on chromosome 10q26. In gastric cancer, amplification of FGFR2 results in high levels of expression of the FGR2b receptor on the cell surface.

[0194] FGFR2b specific antibody Anti-FGFR2-IIIb is a humanized monoclonal antibody (IgG1 isotype) specific for the human FGFR2b receptor (NCBI reference sequence ID NP_001138385.1) and blocks FGF ligand binding to the receptor. Anti-FGFR2-IIIb targets the third Ig region of the FGFR2b receptor isoform, which is alternatively spliced ​​and controls ligand specificity. The antibody is glycosylated but lacks core fucose in the polysaccharide portion of the antibody, as it is produced in a Chinese Hamster Ovary (CHO) cell line lacking the FUT8 gene (α1,6-fucosyltransferase). The absence of core fucose confers a higher affinity for the Fc receptor FcγRIIIa compared to fucosylated molecules, potentially enhancing immune cell-mediated tumor cell killing (Shinkawa 2003). Therefore, the antibodies have been glycosylated to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) (Gemo 2014). Anti-FGFR2-IIIb inhibits FGF ligand-stimulated FGFR2b phosphorylation and cell proliferation in cell cultures of gastric and breast cancer cell lines overexpressing FGFR2b. Anti-FGFR2-IIIb also inhibits tumor growth in gastric and breast xenograft models overexpressing FGFR2b. Thus, the three potential mechanisms of action of anti-FGFR2-IIIb include blocking ligand binding and downstream signaling, reducing expression of FGFR2b driver proteins, and enhancing ADCC.

[0195] Anti-FGFR2-IIIb can produce complete and durable tumor growth inhibition in gastric cancer xenografts in immunodeficient mice that overexpress FGFR2b and have FGFR2 gene amplification, where FGFR2b is thought to be an inducer of tumor growth (Gemo 2014). In addition, anti-FGFR2-IIIb shows NK cell recruitment and associated inhibition of tumor growth in the 4T1 allograft tumor model, which has moderate expression of FGFR2b. These data suggest that ADCC may be effective in patients with moderate FGFR2b overexpression and no FGFR2 gene amplification, and that ADCC activity may be a major contributing factor to the mechanism of action in these patients.

[0196] Furthermore, anti-FGFR2-IIIb is specific for the FGFR2b receptor and therefore does not interfere with the signaling of other FGF / FGFRs (including FGFR2c). In contrast to FGFR tyrosine kinase inhibitors (TKIs), anti-FGFR2-IIIb does not inhibit FGF23 signaling. FGF23 is a ligand involved in calcium / phosphate metabolism. Therefore, treatment with anti-FGFR2-IIIb is not expected to cause the significant dose-limiting hyperphosphatemia associated with FGFR TKIs (Andre 2013, Brown 2005, Dienstmann 2014, Sequist 2014).

[0197] mFOLFOX6 Infusional 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is an approved chemotherapy agent and the standard of care for first-line treatment of metastatic gastric cancer. 5-FU is the main chemotherapy agent used to treat gastric cancer worldwide and is frequently combined with other therapies after studies showed that combination chemotherapy with 5-FU resulted in improved clinical outcomes (Keam 2008). The standard of care, Adrucil®, also known as 5-fluorouracil (5-FU), is a widely used chemotherapy agent that is currently indicated for the treatment of colorectal, breast, gastric, and pancreatic cancers.

[0198] Justification for the starting dose of anti-FGFR2-IIIb and mFOLFOX6 Part 1 of this dose-escalation safety lead-in phase study will involve a starting dose of 10 mg / kg anti-FGFR2-IIIb administered by IV infusion every 2 weeks in a 28-day cycle.

[0199] In a previous Phase I clinical trial, dose escalation was performed in patients with solid tumors (n=19) and gastric cancer (n=8). During dose escalation, there were no dose-limiting toxicities (DLTs) at any dose level. Thus, a maximum tolerated dose (MTD) of anti-FGFR2-IIIb was not identified. 15 mg / kg was selected as the expansion dose based on preclinical modeling of target drug concentrations and observed tolerability, as well as evidence of observed efficacy. At 15 mg / kg every 2 weeks, the majority of patients achieved steady-state anti-FGFR2-IIIb trough concentrations (C ) obtained from a mouse efficacy study using the OCUM2 FGFR2-growing gastric cancer xenograft model. trough ss ) is expected to reach 60 μg / mL.

[0200] Based on published data from population PK analyses, no clinically meaningful differences were observed in the PK of antibody therapeutics by race, including bevacizumab (Genentech Inc.), trastuzumab (Genentech Inc.), pertuzumab (Genentech Inc. 2016), and ramucirumab (Eli Lilly and Company). Importantly, clinical data from ongoing anti-FGFR2-IIIb studies support that a dose of 10 mg / kg is tolerated in humans. Anti-FGFR2-IIIb has also demonstrated an acceptable safety profile in a first-in-human study treating 53 patients at doses up to 15 mg / kg.

[0201] The starting dose of mFOLFOX6 was 85 mg / m 2 of oxaliplatin, 350 mg of calcium folinate (folinic acid), 400 mg / m 2 Fluorouracil at a dose of 2400 mg / m 2The combination regimen includes fluorouracil in small doses. Oxaliplatin and calcium folinate are co-administered via IV infusion using a 3-way stopcock / Y-site connector. The lower dose of fluorouracil is given as an IV bolus and the higher dose of fluorouracil is given as an IV infusion over 46 hours. mFOLFOX6 is administered every 14 days.

[0202] Part 2 Prescreening Rationale Anti-FGFR2-IIIb is an antibody designed to recognize the FGFR2b receptor when expressed on gastric cancer tumors. The current hypothesis is that the presence of FGFR2b is an important predictor of response in patients with FGFR2b-selected gastric or gastroesophageal cancer (part 2). This is based on preclinical observations in a xenograft study where only tumors overexpressing FGFR2b responded to anti-FGFR2-IIIb treatment, as well as early results from an ongoing world first-in-human trial showing a greater degree of anti-FGFR2-IIIb activity in FGFR2b-positive patients.

[0203] Patients in Part 2 will be selected for enrollment based on FGFR2b overexpression and / or FGFR2 amplification as determined by validated IHC (score of 2+ or 3+) or blood-based biopsy assay, respectively. Patients who demonstrate neither FGFR2b overexpression using IHC nor amplification using the blood-based biopsy assay will not be eligible for enrollment, but positivity based on one or both assays will be sufficient to meet eligibility requirements (e.g., positive blood-based biopsy assay but negative IHC).

[0204] Patients in Part 2 must have had no prior chemotherapy for metastatic or unresectable disease, and if they have received prior adjuvant or neoadjuvant therapy (chemotherapy and / or chemoradiotherapy), >6 months must have elapsed between the end of adjuvant therapy and enrollment. These patients have unresectable, locally advanced or metastatic disease and are therefore expected to start treatment (mFOLFOX6) shortly after their diagnosis.

[0205] Because IHC results can take up to several weeks to complete, patients with a negative blood-based assay may have their chemotherapy treatment initiation delayed while they await confirmation of eligibility by IHC. For this reason, all patients entering the study are required to have received two cycles of mFOLFOX6 at the time of enrollment. Patients cannot receive more than two or fewer than two cycles. This is because this could result in treatment imbalances among study participants, potentially confounding the interpretation of study results. It is expected that IHC results will be available during the time it takes to administer the first two cycles of mFOLFOX6. During this period, mFOLFOX6 will be administered according to local practice standards, and adverse events will not be recorded as part of the study, as patients have not yet enrolled in the study. Patients provide prescreening informed consent for blood and IHC assays. If the IHC result is positive, the patient will complete the second course of mFOLFOX6 and enter a screening period. They will then be enrolled in the study once they have met all other eligibility criteria, including providing informed consent. If the IHC result is negative and the blood-based biopsy is also negative, the patient is not eligible to participate in the study.

[0206] Rationale for Tumor Biopsy and Blood Evaluation Patients in Part 2 of the study will require both tissue and blood results; therefore, patients will not be eligible if they are unable to provide both tissue and plasma. Patients who do not demonstrate either FGFR2b overexpression using IHC or amplification using the blood-based biopsy assay will not be eligible for enrollment, but positivity based on one or both assays is sufficient to meet eligibility requirements (e.g., positive blood-based biopsy assay but negative IHC). The blood test reveals DNA amplification of FGFR2, whereas the IHC test indicates the degree of protein expression. Five Prime is developing an anti-FGFR2b antibody for preclinical use that is optimized for sensitivity and specificity to detect FGFR2b by IHC.

[0207] In studies evaluating gastric cancer samples, FGFR2 amplification has consistently been associated with significant FGFR2b surface expression as detected by IHC (Gemo 2014). The antitumor activity of anti-FGFR2-IIIb observed in preclinical studies was predicted based on FGFR2b overexpression in tumor cell lines. Patients without FGFR2b overexpression are unlikely to derive significant benefit from treatment with anti-FGFR2-IIIb and mFOLFOX6. Selection of patients with FGFR2b-positive tumors for treatment with anti-FGFR2-IIIb is supported by data from the ongoing world's first phase 1 human trial of anti-FGFR2-IIIb. Study Objectives and Endpoints

[0208] Part 1: Primary Objectives To determine the recommended dose (RD) of anti-FGFR2-IIIb when administered in combination with fixed-dose continuous infusion 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients with advanced gastrointestinal (GI) tumors.

[0209] To evaluate the safety profile of escalating doses of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with GI tumors.

[0210] Part 1: Secondary Objectives To evaluate the safety and tolerability of long-term exposure to anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with GI tumours.

[0211] To characterize the pharmacokinetic (PK) profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with GI tumors.

[0212] To characterize the immunogenicity of anti-FGFR2-IIIb.

[0213] Part 1: Exploratory Objectives To characterize the pharmacodynamic (PD) profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 by evaluation of exploratory biomarkers in blood and hair follicle samples from patients with GI tumors.

[0214] Part 2: Primary Objectives To evaluate the clinical benefit of anti-FGFR2-IIIb, when administered in combination with mFOLFOX6, compared with placebo and mFOLFOX6, by analysis of progression-free survival (PFS) in patients with FGFR2b-selected gastric or gastroesophageal cancer (hereafter referred to as gastric cancer or GC).

[0215] Part 2: Secondary Objectives To evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6 by analysis of overall survival (OS) in patients with FGFR2b-selected GC.

[0216] To evaluate the safety and tolerability of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6 in patients with FGFR2b-selected GC.

[0217] To characterize the PK profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 in patients with FGFR2b-selected GC.

[0218] To characterize the immunogenicity of anti-FGFR2-IIIb.

[0219] To characterize the PD profile of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared to placebo and mFOLFOX6 by analysis of immune cell infiltration and other exploratory biomarkers in pre- and on-treatment tumor biopsies.

[0220] Part 2: Exploratory Objectives To evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6 using PFS analysis based on Blinded Independent Review Committee (BIRC) progression assessment.

[0221] To evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6 by analysis of objective response rate (ORR) in patients with FGFR2b-selected GC.

[0222] To evaluate the clinical benefit of anti-FGFR2-IIIb compared with placebo and mFOLFOX6 when administered in combination with mFOLFOX6 by analysis of ORR based on BIRC progression assessment.

[0223] To evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6 by analysing 1-year OS in patients with FGFR2b-selected GC.

[0224] To evaluate the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6 by analysis of duration of response (DOR) in patients with FGFR2b-selected GC.

[0225] To explore the association between FGFR2 status (tumor tissue and / or blood-based biopsies) and clinical outcomes.

[0226] To explore the concordance between FGFR2 status in tumor tissues and FGFR2 amplification using blood-based biopsies.

[0227] To characterize the PD profile of anti-FGFR2-IIIb compared to placebo and mFOLFOX6 when administered in combination with mFOLFOX6 by evaluation of exploratory biomarkers in blood samples of patients with FGFR2b-selected GC.

[0228] To evaluate patient-reported outcomes (PROs) and quality of life (QOL) outcomes in patients with FGFR2b-selected GC when anti-FGFR2-IIIb was administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6.

[0229] Part 1: Primary Study Endpoint Incidence of grade ≥2 adverse events (AEs) assessed by the investigator as related to anti-FGFR2-IIIb and laboratory abnormalities defined as dose-limiting toxicities (DLTs).

[0230] Part 1: Secondary Endpoints Occurrence of AEs, clinical laboratory abnormalities, corneal and retinal findings, and electrocardiogram (ECG) abnormalities.

[0231] PK parameters of anti-FGFR2-IIIb derived from serum concentration-time profile, e.g., area under the serum concentration-time curve (AUC), maximum serum concentration (Cmax), trough serum concentration (Ctrough), clearance (CL), elimination half-life (t1 / 2), volume of distribution and accumulation rate (if appropriate and applicable).

[0232] To evaluate the immune response as determined by immunogenicity testing.

[0233] Part 1: Exploratory Endpoints Exploratory biomarkers in blood and hair follicle samples.

[0234] Part 2: Primary Endpoint PFS, defined as the time from randomization to the date of radiological progression based on investigator assessment (per RECIST v.1.1) or death from any cause, whichever occurs first.

[0235] Part 2: Secondary Endpoints OS, defined as the time from the date of randomization to death from any cause.

[0236] Objective response rate (ORR) based on investigator assessment of tumor lesions per RECIST v1.1.

[0237] Occurrence of AEs, clinical laboratory abnormalities, corneal and retinal findings, and electrocardiogram (ECG) abnormalities.

[0238] PK parameters of anti-FGFR2-IIIb in RD when administered in combination with mFOLFOX6 derived from serum concentration-time profiles, e.g., AUC, Cmax, Ctrough, CL, t1 / 2, volume of distribution, and accumulation rate (if appropriate and applicable).

[0239] Immune responses determined by immunogenicity testing.

[0240] Immune cell infiltration levels and other exploratory biomarkers in tumor biopsy samples before and during treatment.

[0241] Part 2: Exploratory Endpoints One-year OS, defined as the proportion of patients who received at least one dose of anti-FGFR2-IIIb and were alive at 1 year.

[0242] DOR, restricted to patients with a response as determined by the investigator per RECIST v1.1 and defined as the time from first response as determined by the investigator per RECIST v1.1 to progression or death, whichever occurs first.

[0243] Correlation of FGFR2 status determined in tumor tissue and / or blood-based biopsies with objective tumor response according to RECIST v1.1.

[0244] Correlation between FGFR2 status identified in tumor tissue and FGFR2 amplification in blood-based biopsies.

[0245] Exploratory biomarkers in blood samples.

[0246] Change from baseline in QoL as measured by EQ-5D-5L and EORTC QLQ-C30.

[0247] Overall study design and planning overview This is a two-part, multicenter study to evaluate the safety, tolerability, PK, PD, and efficacy of anti-FGFR2-IIIb when administered in combination with mFOLFOX6. The study includes an open-label, Part 1, dose-escalation safety run-in phase, and a randomized, double-blind, placebo-controlled, Part 2, dose expansion.

[0248] Part 1 will consist of a minimum of two planned dose cohorts of anti-FGFR2-IIIb in combination with mFOLFOX6 in eligible patients with advanced GI tumors to determine the RD of anti-FGFR2-IIIb administered in combination with mFOLFOX6. Part 2 will consist of two expansion arms (1:1 randomization) and will aim to evaluate the safety and efficacy of anti-FGFR2-IIIb in RD in combination with mFOLFOX6 compared to placebo and mFOLFOX6 in FGFR2b-selected patients with advanced GC (as determined by prospective IHC analysis of FGFR2b expression and / or blood-based assays indicating FGFR2 amplification). Patients will be enrolled in either Part 1 or Part 2 of the study, but not both.

[0249] After an initial screening period of up to 14 days (2 weeks), patients will be treated with mFOLFOX6 (with or without anti-FGFR2-IIIb) in 14-day cycles every 2 weeks. Patients may have initiated or received mFOLFOX6 chemotherapy prior to enrollment in Part 1, but eligibility requires that patients be candidates to receive at least 2 additional cycles of mFOLFOX6 chemotherapy (there is no upper limit to the number of FOLFOX cycles patients may receive in Part 1 and may not receive any).

[0250] Each patient enrolled in Part 1 will be observed for 28 days (DLT period) for safety assessments and occurrence of dose-limiting toxicities. Upon completion of the DLT period, patients may continue treatment at the discretion of the investigator. Additional treatment may be administered every 2 weeks thereafter in 14-day cycles if clinically indicated.

[0251] In part 2, patients whose tumors are FGFR2b positive by IHC or blood, who have completed two cycles of mFOLFOX6 chemotherapy, the standard first-line treatment for advanced gastric cancer, and who have signed informed consent, will be randomized 1:1 to receive either anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo in combination with mFOLFOX6 every 2 weeks in 14-day cycles, with RD selected after evaluation of data obtained in part 1.

[0252] Initial screening period Part 1 The screening period begins when the patient signs the informed consent form (ICF). All patients will undergo a screening assessment within 14 days (2 weeks) prior to the first dose of anti-FGFR2-IIIb. Any AEs not related to study procedures occurring after signing the informed consent form and prior to the first dose of anti-FGFR2-IIIb will not be collected during this period. Patients may have initiated or received mFOLFOX6 chemotherapy prior to enrollment in Part 1, but eligibility requires that patients be candidates to receive at least two additional mFOLFOX6 chemotherapy cycles (there is no upper limit to the number of FOLFOX cycles patients may receive in Part 1 and may not receive any).

[0253] Part 2 Part 2 will enroll patients whose tumors are FGFR2b positive by IHC or blood, who have completed two cycles of mFOLFOX chemotherapy, the standard first-line treatment for advanced gastric cancer, who have signed informed consent, and who meet other eligibility criteria.

[0254] Eligibility for Part 2 will be assessed in two stages: a prescreening period involving only positive FGFR2b tests by IHC and blood, followed by a screening period to confirm all remaining eligibility criteria.

[0255] Randomization Part 1 Part 1 is an open-label study in which eligible patients will be enrolled in sequence.

[0256] Part 2 During the pre-screening period, patients are tested for FGFR2b positivity. Patients who test positive by one or both methods (IHC and / or blood) are placed into the screening period. (Note: if the blood test is positive, there is no need to wait for the IHC results. At this point, the patient is eligible and should begin the screening period.)

[0257] Eligible patients will be randomized 1:1 to placebo combined with mFOLFOX6 or anti-FGFR2-IIIb combined with mFOLFOX6.

[0258] Part 1 (dose escalation safety run-in phase) Part 1 is an open-label, dose-escalation study of anti-FGFR2-IIIb when administered in combination with mFOLFOX6. Patients eligible for Part 1 have unselected GI cancer (with or without tumors overexpressing FGFR2b) with unresectable, locally advanced or metastatic disease and are candidates to receive both anti-FGFR2-IIIb and mFOLFOX6 chemotherapy. FGFR2 status will be determined retrospectively by IHC and blood-based biopsy.

[0259] Patients enrolled in Part 1 will be treated with escalating doses of anti-FGFR2-IIIb in combination with the fixed-dose backbone chemotherapy regimen mFOLFOX6 every 2 weeks in 14-day cycles as follows:

[0260] Anti-FGFR2-IIIb Administration: Anti-FGFR2-IIIb IV will be administered every 2 weeks prior to administration of mFOLFOX6 chemotherapy on day 1 of each cycle. Anti-FGFR2-IIIb will be administered as an approximately 30-minute IV infusion via a peripheral vein or central venous catheter with an in-line filter.

[0261] Backbone chemotherapy regimen: Administration of mFOLFOX6 chemotherapy will begin after administration of anti-FGFR2-IIIb (after a 30-minute rest period) on day 1 of each treatment cycle. The mFOLFOX6 regimen will be administered every 2 weeks as follows:

[0262] Oxaliplatin 85 mg / m 2 infused IV over 120 minutes, leucovorin 400 mg / m 2 infused IV over 120 minutes, followed by fluorouracil (5-FU) 400 mg / m 2IV bolus, followed by 5-FU 2400 mg / m as a continuous IV infusion for 46 hours. 2 .

[0263] Administration of oxaliplatin does not require pre-hydration. Antiemetic premedication, such as serotonin antagonists (with or without dexamethasone), may be used according to local standard of care at the investigator's discretion if clinically indicated.

[0264] Dose Levels (Part 1) Part 1 will have two dose cohorts of anti-FGFR2-IIIb in a standard 3+3 dose escalation design, with a minimum of three patients per cohort. The planned dose levels are as follows: [Table 1]

[0265] All dose escalation decisions will be based on evaluation of DLTs, overall safety, and tolerability and will occur after the last patient enrolled in each cohort has completed the 28-day DLT period (after completion of two treatment cycles). Dose escalation decisions will be in consensus by a Cohort Review Committee (CRC) comprised of sponsors and investigators. Consideration of safety and PK parameters may inform the decision to add cohorts at alternative dose levels to achieve optimal target exposure. Dose level -1 will be enrolled only if ≥2 DLTs are observed at dose level 1.

[0266] The algorithm shown in Table 2 will be used to determine dose escalation in Part 1: [Table 2]

[0267] The RD of anti-FGFR2-IIIb for part 2 will be identified by the CRC based on the assessment of overall safety, tolerability and PK. Thus, the RD may or may not be the same as the identified maximum tolerated dose (MTD). For example, if the MTD is not reached or if data from subsequent treatment cycles in part 1 provide further insight into the safety profile, the RD may be a dose that does not exceed the MTD but is different from the MTD.

[0268] The MTD is defined as the highest dose at which <33% of patients experience a DLT during the DLT period. If a DLT is observed in 1 of 3 patients at a given dose level, 3 additional patients are enrolled at the same dose level. Dose escalation may continue (no dose level exceeds 15 mg / kg) until 2 of 3-6 patients treated at a dose level experience a DLT. The next lower dose is then considered the MTD.

[0269] Once the MTD or RD is reached, 3 additional patients may be accrued to further explore safety and PK at that dose level, therefore total enrollment in part 1 will be approximately 9-12 patients.

[0270] Any patient who does not receive exactly two doses of anti-FGFR2-IIIb in combination with mFOLFOX6 during the DLT period will be considered unevaluable and will be replaced. Replaced patients may continue on the study after discussion with the sponsor. No more than two doses of anti-FGFR2-IIIb or two cycles of mFOLFOX6 should be administered during the 28-day DLT period.

[0271] Upon completion of the DLT period, patients may continue to receive anti-FGFR2-IIIb in combination with mFOLFOX6 administered every 2 weeks in 14-day cycles until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-specified withdrawal criteria. There is no upper limit to the number of doses of anti-FGFR2-IIIb. Continuation of the mFOLFOX6 regimen beyond the DLT period will follow local standard of care.

[0272] In the event of discontinuation of mFOLFOX6 chemotherapy for any reason prior to progression (e.g., cumulative toxicity or completion of mFOLFOX6 chemotherapy per local practice standards), anti-FGFR2-IIIb may be continued as monotherapy and administered every 2 weeks until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-defined withdrawal criteria. If a cycle of mFOLFOX6 is delayed for more than 14 days due to chemotherapy-related toxicity, anti-FGFR2-IIIb administration should not be delayed and may continue to be administered every 2 weeks. The start of a new cycle of mFOLFOX6 after a delayed administration should be synchronized with the administration of anti-FGFR2-IIIb infusions, if possible (although this is not a study requirement).

[0273] In the event of discontinuation of anti-FGFR2-IIIb for any reason prior to progression (e.g., cumulative toxicity), mFOLFOX6 chemotherapy may be continued according to local regional practice standards or until investigator-assessed radiological or clinical progression, unacceptable toxicity, or the patient meets other protocol-specified withdrawal criteria.

[0274] Part 2: Randomized double-blind dose expansion Patients will be enrolled in Part 2, which aims to characterize the safety and efficacy of anti-FGFR2-IIIb in combination with mFOLFOX6 compared to placebo and mFOLFOX6 in an FGFR2b-selected gastric cancer patient population. Enrollment in Part 2 will begin only if RD of anti-FGFR2-IIIb (not exceeding 15 mg / kg) is identified by CRC in Part 1.

[0275] Part 2 will be double-blind and will consist of a total of approximately 360 FGFR2b-selected gastric cancer patients randomized 1:1 to receive one of two treatment arms:

[0276] Arm 1: anti-FGFR2-IIIb and mFOLFOX6 in RD administered every 2 weeks, or

[0277] Arm 2: placebo and mFOLFOX6 administered every 2 weeks.

[0278] Enrolment for Part 2 will open at the sponsor's discretion.

[0279] Gastric cancer patients with unresectable, locally advanced or metastatic disease who are eligible for first-line mFOLFOX6 chemotherapy and have received two cycles of mFOLFOX6 will be enrolled in Part 2 of the study. Patients will be selected for enrollment based on FGFR2b overexpression and / or FGFR2 amplification, as determined by validated IHC or blood-based biopsy assays, respectively.

[0280] Enrolled patients may continue treatment every 2 weeks in 14-day cycles until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any of the other protocol-defined withdrawal criteria. All treatment decisions will be made by the investigator using local assessments. After discontinuation of study treatment for reasons other than progression or withdrawal of consent, tumor evaluations will continue until the patient begins additional anticancer therapy. In addition, patients in both Part 1 and Part 2 will undergo long-term follow-up for survival via site visits or telephone approximately every 3 months ± 28 days after the EOT visit until a maximum of 24 months after the last patient enrolled in the study or until death, loss to follow-up, withdrawal of consent, or sponsor-initiated discontinuation of the study, whichever occurs first.

[0281] In the event of discontinuation of mFOLFOX6 chemotherapy for any reason prior to progression (e.g., cumulative toxicity or completion of mFOLFOX6 chemotherapy per local practice standards), IP may be continued as monotherapy and administered every 2 weeks until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-specified withdrawal criteria. If a cycle of mFOLFOX6 is delayed for more than 14 days due to chemotherapy-related toxicity, IP administration should not be delayed and may continue to be administered every 2 weeks. The start of a new cycle of mFOLFOX6 after a delayed administration should be synchronized with the administration of IP infusions, if possible (although this is not a study requirement).

[0282] In the event of discontinuation of IP for any reason prior to progression (e.g., cumulative toxicity), mFOLFOX6 chemotherapy may be continued according to local regional practice or until investigator-assessed radiological or clinical progression, unacceptable toxicity, or the patient meets other protocol-specified withdrawal criteria.

[0283] Exam Schema The study schema is shown in Figure 1 (part 1) and Figure 2 (part 2).

[0284] Study design rationale This is a two-part, multicenter study to evaluate the safety, tolerability, PK, PD, and efficacy of anti-FGFR2-IIIb when administered in combination with mFOLFOX6. The study includes an open-label, Part 1, dose-escalation safety run-in phase, and a randomized, double-blind, placebo-controlled, Part 2, dose expansion.

[0285] Part 1 is a dose-escalation safety lead-in study of anti-FGFR2-IIIb when administered in combination with mFOLFOX6. A standard 3+3 design will be used. Patients enrolled in Part 1 will be treated with escalating doses of anti-FGFR2-IIIb in combination with a fixed-dose backbone chemotherapy regimen of mFOLFOX6 every 2 weeks in 14-day cycles. Each patient enrolled in Part 1 will be observed for 28 days (DLT period) for safety assessments and occurrence of dose-limiting toxicities, and data will be evaluated before selecting RD for Part 2.

[0286] Patients eligible for Part 1 will have unselected GI cancer (with or without tumors overexpressing FGFR2b) with unresectable, locally advanced or metastatic disease and are candidates to receive both anti-FGFR2-IIIb and mFOLFOX6 chemotherapy. FGFR2 status will be determined retrospectively by IHC and blood-based biopsy.

[0287] In Part 2, selected patients will be randomized 1:1 to be treated with anti-FGFR2-IIIb and mFOLFOX6 or placebo and mFOLFOX6 every 2 weeks in 14-day cycles. Patients in Part 2 must complete exactly 2 cycles of mFOLFOX6 (no more, no less).

[0288] Measuring PFS, ORR, and OS in randomized patients with FGFR2b-selected gastric cancer may highlight the clinical benefit of anti-FGFR2-IIIb when administered in combination with mFOLFOX6 compared with placebo and mFOLFOX6.

[0289] Study Eligibility and Withdrawal Criteria Planned number of patients and study sites Part 1 will have two dose cohorts of anti-FGFR2-IIIb in a standard 3+3 dose escalation design, with a minimum of three patients enrolled in each cohort. Once MTD or RD is reached, three additional patients may be enrolled to further explore safety and PK at that dose level. Thus, the total enrollment in Part 1 will be approximately 9-12 patients.

[0290] In Part 2, up to approximately 360 FGFR2b-selected gastric cancer patients will be randomized 1:1 to be treated every 2 weeks in 14-day cycles with anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo in combination with mFOLFOX6, with the RD selected after evaluation of data from Part 1. Enrollment for Part 2 will begin at the sponsor's discretion.

[0291] Total planned enrollment for this study is up to approximately 372 patients.

[0292] Testing will take place in up to 250 testing facilities worldwide.

[0293] Inclusion criteria for all cohorts Patients enrolled in either Part 1 or Part 2 of the study must meet all of the following inclusion criteria: 1) Unresectable, locally advanced, or metastatic disease 2) Understand and sign an Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved informed consent form (ICF) prior to any study-related evaluations. 3) Life expectancy of at least 3 months 4) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 5) 18 years of age or older at the time of signing the ICF 6) Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test within 72 hours prior to enrollment (only for women of childbearing potential) 7) Sexually active patients (women and men of childbearing potential) must be willing to use two effective methods of contraception, one of which must be a physical barrier method (condom, diaphragm, or cervical / vaginal vault cap), until 6 months after the last dose of anti-FGFR2-IIIb. Other effective forms of contraception include: Permanent sterilization (hysterectomy and / or bilateral oophorectomy, or surgical bilateral tubal ligation, or vasectomy) at least 6 months prior to screening Women of childbearing potential who have been using stable oral contraceptive therapy or an intrauterine or implant device, or who have abstained from sexual activity as a lifestyle for at least 90 days prior to the study 8) Adequate hematological and biological function as determined by the following laboratory values: Bone marrow function Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L Platelets>100×10 9 / L Hemoglobin ≥ 9g / dL Liver function Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN); ≤ 5 x ULN if liver metastases are present Bilirubin ≦1.5×ULN ·Kidney function Calculated creatinine clearance ≥ 50mL / min 9) Patients taking conventional anticoagulants must be on a stable dose of warfarin and have an INR within the therapeutic range for their condition, or be on a stable dose of low molecular weight heparin. 10) Measurable or non-measurable disease 11) Tumor tissue to determine FGFR2 status

[0294] Patients enrolled in Part 1 of the study (the dose escalation safety run-in phase) must also meet the following inclusion criteria: Histologically or cytologically confirmed gastrointestinal malignancies for which mFOLFOX6 is considered an appropriate treatment (e.g., gastric cancer, colorectal cancer, pancreatic adenocarcinoma)

[0295] No more than two prior chemotherapy regimens for metastatic disease (not including prior adjuvant chemotherapy with 5-FU and / or oxaliplatin).

[0296] Patients must be candidates for at least two cycles of mFOLFOX6 chemotherapy. Patients enrolled in Part 2 (dose expansion) of the study must also meet the following inclusion criteria: 1) Histologically documented gastric or gastroesophageal junction adenocarcinoma 2) FGFR2b overexpression as determined by IHC and / or FGFR2 amplification as determined by blood-based biopsy 3) No prior chemotherapy for metastatic or unresectable disease (unless stated in mFOLFOX6 inclusion criterion #20) 4) No prior platinum-based chemotherapy (unless stated in mFOLFOX6 inclusion criterion #20) 5) If the patient has received prior adjuvant or neoadjuvant therapy (chemotherapy and / or chemoradiotherapy), more than 6 months must have elapsed between the end of the adjuvant therapy and enrollment. 6) Patients must be candidates for mFOLFOX6 chemotherapy and must have received 2 cycles of mFOLFOX6 chemotherapy prior to study enrollment (but not more than 2 cycles)

[0297] Exclusion criteria for all cohorts Patients enrolling in either Part 1 or Part 2 will be excluded if they meet any of the following criteria:

[0298] Untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases are eligible as long as they have been clinically stable for at least 4 weeks and have not required interventions such as surgery, radiation, or any corticosteroid therapy to manage symptoms related to CNS disease.

[0299] Cardiac dysfunction or clinically significant cardiac disease, including any of the following: Unstable angina within 6 months prior to enrollment - Acute myocardial infarction within 6 months prior to enrollment New York Heart Association Class II to IV congestive heart failure Uncontrolled hypertension (defined as >160 / 90 despite optimal medical management) Cardiac arrhythmias requiring antiarrhythmic therapy other than beta-blockers or digoxin Active coronary artery disease 7) QTcF >450 ms (male) or >470 ms (female) 8) Peripheral sensory neuropathy of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher 9) Active infection or any uncontrolled infection requiring systemic treatment within 14 days prior to enrollment 10) Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS)-related disease, or history of chronic hepatitis B or C 11) History of interstitial lung disease (e.g., pneumonia or pulmonary fibrosis) 12) Evidence or history of bleeding tendency or coagulation disorder 13) Any investigational drug or therapy within 28 days prior to enrollment 14) Radiation therapy within 28 days of enrollment. Patients must have recovered from all radiation therapy-related toxicities. No use of radiopharmaceuticals (strontium, samarium) within 8 weeks of enrollment. 15) Prior treatment with any selective inhibitor of the FGF-FGFR pathway (e.g., AZD4547, BGJ398, JNJ-42756493, BAY1179470) 16) Ongoing adverse effects from prior treatment greater than NCI CTCAE grade 1 (excluding grade 2 alopecia) 17) Participation in another therapeutic clinical trial within 28 days of enrollment in this clinical trial or during this clinical trial 18) History of corneal defects, corneal ulcers, keratitis, keratoconus, corneal transplantation, or other known corneal abnormalities that may pose a risk to anti-FGFR2-IIIb therapy in the opinion of the ophthalmologist 19) Positive HER2 status (defined by a positive IHC test of 3+ or an IHC of 2+ and positive FISH). HER2 status is based on the gastric cancer scoring guidelines (HercepTest). 20) No major surgical procedures within 28 days prior to enrollment are permitted. Any procedures requiring local / epidural anesthesia must have been completed at least 72 hours prior to enrollment. In all cases, patients must be adequately recovered and stable prior to treatment. 21) Pregnant or lactating women (unless the patient discontinues lactation during study treatment and resumes it 6 months after discontinuation of the study); women of childbearing potential should not consider becoming pregnant during the study 22) Presence of any severe or unstable concomitant systemic disorder incompatible with a clinical trial (e.g., substance abuse, psychiatric disorder, or uncontrolled intercurrent illness, e.g., active infection, arterial thrombosis, and symptomatic pulmonary embolism). 23) The presence of any other condition that may increase the risks associated with participation in the study or that may interfere with the interpretation of the study results and that, in the opinion of the investigator, makes the patient unsuitable for participation in the study (e.g., dihydropyrimidine deficiency or pleural effusion). 24) Known allergy or hypersensitivity to anti-FGFR2-IIIb preparations containing polysorbate, or to any component of platinum-containing drugs, fluorouracil, or leucovorin 25) History of previous malignancy, except for another malignancy that, in the opinion of the investigator, would not affect the efficacy of the study drug No waiver of these inclusion or exclusion criteria will be permitted.

[0300] Patient Withdrawal and Replacement Patients must discontinue protocol-prescribed therapy if any of the following apply: Withdrawal of consent at the request of the patient or his / her legally authorized representative Investigator-assessed progression of a patient's disease Any event that poses an unacceptable safety risk to patients - Concomitant illnesses that significantly affect the assessment of clinical status A positive pregnancy test at any time during the study At the specific request of the sponsor or its authorized representative (for example, if a trial is stopped for patient safety reasons).

[0301] Patient Identification and Registration Patients must be able to provide written informed consent, meet all inclusion criteria, and not meet any exclusion criteria. Waivers of the inclusion or exclusion criteria will not be permitted by the investigator and sponsor or designee of any patient enrolled in the study. All eligibility criteria must be met prior to patient enrollment. Patients eligible for Part 1 of the study will be enrolled in the first available cohort. Patients may be enrolled in either Part 1 or Part 2 of the study, but not both.

[0302] In part 2, patients first undergo prescreening, which requires both a blood-based biopsy assay and tissue testing. Patients who test FGFR2 positive can enter the screening period immediately (i.e., patients with a positive blood test result do not need to wait for IHC results (see Table 3)). Part 2 patients must also have completed two (but not more than two) cycles of mFOLFOX6. [Table 3] a: Both tests are performed in a central laboratory. b: 2 x 10 mL required c: IHC: A minimum of 5 slides is required. A score of 2+ or 3+ is considered positive.

[0303] In both Parts 1 and 2, the investigator may repeat qualifying laboratory tests and vital signs / ECGs prior to enrollment if a disqualifying finding appears to be in error or if an acute finding would likely meet the eligibility criteria on repeat testing. Hematology and blood chemistry results must be obtained within 72 hours after dosing to confirm eligibility.

[0304] Test drug Identification information In Part 1, anti-FGFR2-IIIb will be provided in a sterile vial for dilution into an intravenous bag to be administered at the study site over approximately 30 minutes every 14 days (± 3 days) until investigator-assessed radiological or clinical progression, unacceptable toxicity, or other protocol-specified reasons for study withdrawal.

[0305] In part 2, placebo will be provided by the unblinded site pharmacist. Participants will be randomized in a 1:1 ratio to receive blinded IP (anti-FGFR2-IIIb / placebo). Investigators will remain blinded to each participant's assigned study treatment throughout the duration of the study. To maintain this blinding, the unblinded pharmacist will be responsible for reconstitution and distribution of all study treatment. In case of a quality assurance audit, auditor(s) will have access to the unblinded study treatment records at the site(s) and will verify that randomization / distribution has been performed accurately.

[0306] Oxaliplatin, 5-FU, and leucovorin will be provided to each center per usual institutional practice. The mFOLFOX6 regimen will be administered every 14 days (± 3 days) until investigator-assessed radiological or clinical progression, unacceptable toxicity, or other protocol-defined reasons for withdrawal from study. Please refer to current local drug package inserts and full prescribing information.

[0307] Administration 1. mFOLFOX6 Oxaliplatin, 5-FU, and leucovorin will be provided to each center according to usual institutional practice. The mFOLFOX6 regimen will be administered every 14 days (± 3 days) until progression, unacceptable toxicity, or other protocol-specified reasons for withdrawal from study.

[0308] The starting dose of mFOLFOX6 was 85 mg / m 2 of oxaliplatin, 350 mg of calcium folinate (folinic acid), 400 mg / m 2 Fluorouracil at a dose of 2400 mg / m 2 mFOLFOX6 contains fluorouracil in small doses. Oxaliplatin and calcium folinate are co-administered via IV infusion using a 3-way stopcock / Y-site connector. The lower dose of fluorouracil is given as an IV bolus and the higher dose of fluorouracil is given as an IV infusion over 46 hours. mFOLFOX6 can be administered every 14 days.

[0309] Refer to the most current drug package insert and complete prescribing information.

[0310] 2. Open-label anti-FGFR2-IIIb (Part 1) and blinded IP (Part 2) Anti-FGFR2-IIIb will be administered only to patients in this study using the procedures described in this protocol. The dose of Anti-FGFR2-IIIb will be based on body weight on Cycle 1 Day 1 and will be adjusted if the patient's body weight changes by more than 10% from Cycle 1 Day 1.

[0311] The pharmacist (or other responsible person) will prepare the solution for administration. After calculating the number of vials, the study drug will be diluted in 0.9% sodium chloride solution based on the patient's weight. The prepared anti-FGFR2-IIIb will be administered within 8 hours of preparation (ambient temperature). Anti-FGFR2-IIIb will be administered over approximately 30 minutes by IV infusion via a peripheral or central venous catheter with an in-line filter under physician supervision. For Part 2, a pharmacist not blinded to treatment allocation will provide the placebo.

[0312] Anti-FGFR2-IIIb infusions should be stopped, reduced, interrupted, or discontinued early. If a patient experiences an acute fluid reaction, the patient's vital signs (temperature, blood pressure, pulse, and respiratory rate) should be monitored during the infusion as well as every 30 minutes after the infusion for a minimum of 2 hours and until the acute fluid reaction has resolved.

[0313] Patients will receive two doses of anti-FGFR2-IIIb, separated by two weeks, during their participation in the study. In part 1, upon completion of the DLT period and if tolerated without progression, patients may continue to receive anti-FGFR2-IIIb in combination with mFOLFOX6 administered every 2 weeks in a 14-day cycle until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-specified withdrawal criteria.

[0314] Starting Dose and Dose Modifications 3. Part 1: Dose Escalation Safety Run-in Phase Patients enrolled in part 1 will be treated with escalating doses of anti-FGFR2-IIIb in combination with the fixed-dose backbone chemotherapy regimen mFOLFOX6 every 2 weeks in 14-day cycles, as described above.

[0315] Dose modification criteria 4. Open-label anti-FGFR2-IIIb (Part 1) and blinded IP (Part 2) Parts 1 and 2: Anti-FGFR2-IIIb dose reductions may be permitted for patients receiving treatment beyond the DLT period in Part 1 or for any patients in Part 2, according to the guidelines outlined in Table 4. Dose reductions or interruptions not deemed by the investigator to be within these guidelines require discussion with and approval by the Sponsor or designee. [Table 4]

[0316] Patients may resume study medication if events have resolved to baseline or grade ≤1, following the guidelines outlined in Table 4.

[0317] Scheduled dosing visits have a ±3 day window. Patients should not receive 2 consecutive doses of anti-FGFR2-IIIb within 7 days. The first dose of each cycle is considered day 1 of each cycle. Cycles are repeated every 14 days unless there is a treatment delay.

[0318] Intra-patient dose escalation beyond each patient's starting dose will not be permitted. If a patient's dose is reduced for a reason that is no longer relevant, dose escalation to the originally assigned dose may occur after review and approval by the Sponsor.

[0319] 5. mFOLFOX6 Parts 1 and 2: Patients must be closely monitored for mFOLFOX6 toxicity. Dose adjustments of 5-FU and oxaliplatin may be permitted for patients on treatment, but patients requiring dose adjustment or delay of any component of mFOLFOX during the DLT period will not be considered evaluable unless the dose adjustment or delay is due to an AE deemed to be anti-FGFR2-IIIb related, in which case the AE will be considered a DLT (see below for definition of DLT). Dose adjustments of any component of mFOLFOX for patients past the DLT period in Part 1 or any patient in Part 2 will be permitted according to guidelines outlined in the protocol.

[0320] If oxaliplatin administration is discontinued for any reason prior to progression, 5-FU / leucovorin therapy may be continued on a every 2-week schedule until progression, unacceptable toxicity, or other cause of study withdrawal.

[0321] Dose adjustments for mFOLFOX6 toxicity are shown in Table 5. [Table 5] Adapted from the following protocol: Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014;371:1609-18. DOI:10.1056 / NEJMoa1403108.

[0322] Dose-limiting toxicity DLT is defined as any of the following events occurring during the first 28 days of treatment and will be assessed by the investigator for anti-FGFR2-IIIb. Where appropriate, events will be classified according to the NCI CTCAE (version 4.03): ANC < 0.5 × 10 for more than 5 days 9 / L or febrile neutropenia (i.e., ANC < 1.0 × 10 9 / L and a single temperature of >38.3°C or a fever of >38°C for >1 hour). Use of G-CSF is permitted according to standard institutional procedures. Platelets <25×10 9 / L or platelets <50 × 10 9 / L and bleeding requiring medical intervention Prolonged (>7 days) grade 3 thrombocytopenia Grade 4 anemia (i.e., life-threatening effects; urgent intervention required) Any Grade 2 or higher ocular AE that does not resolve within 7 days AST / ALT > 3 x ULN and concomitant total bilirubin > 2 x ULN, unrelated to liver function due to cancer Any non-hematologic AE of Grade ≥ 3 (excluding nausea, vomiting, and diarrhea if adequately controlled with systemic treatment). Grade 3 or 4 laboratory values ​​that are not clinically significant in the agreement of the investigator and sponsor will not be considered DLTs. Any adverse event related to anti-FGFR2-IIIb resulting in a dose reduction or delay of any component of mFOLFOX6 for at least 4 days

[0323] Recommended Dose (RD) and Maximum Tolerated Dose (MTD) Toxicity at the lowest dose level If the first dose level of anti-FGFR2-IIIb (10 mg / kg Q2W) unexpectedly surpasses the MTD, a decision on how to proceed will be made based on safety, tolerability, and PK data and agreed upon between the investigator and sponsor.

[0324] Dose level-1 (anti-FGFR2-IIIb 6 mg / kg Q2W; 3-6 subjects) will be enrolled only if ≥2 DLTs are observed at dose level 1.

[0325] Within-cohort dose escalation Intrapatient dose escalation will not be permitted in Part 1.

[0326] In part 2, patients will be treated with the RD determined in part 1, and no dose escalation will be permitted.

[0327] Dose interruption during study drug infusion Anti-FGFR2-IIIb infusion must be stopped if any AE of grade 3 or higher occurs during the infusion. If the patient experiences bronchospasm or dyspnea during the infusion, the infusion should be stopped. Symptoms of acute infusion reactions may include fever, chills, hives, hypotension and hypertension with headache, wheezing, dyspnea, hypoxia, and pulmonary infiltrates.

[0328] In addition, if a less severe AE (Grade 1 or 2) occurs during the infusion, the infusion rate may be slowed or stopped, at the investigator's discretion. If a severe AE of Grade 3 or less does not resolve within 4 hours, the infusion may be resumed at half the previous rate. If the same AE reoccurs with the same severity at any time after the infusion is resumed, the infusion will be discontinued and no further administration of study drug will be administered without consultation with the sponsor or the sponsor's designee.

[0329] If a patient experiences an acute infusion reaction before completing the infusion, the infusion must be stopped and the patient should be promptly managed and monitored according to signs and symptoms and local clinical protocols until the event is fully resolved. For patients with either grade 1 or 2 infusion-related events that are fully resolved on the day of infusion, the infusion may be resumed at a slower rate with premedication, at the discretion of the investigator. All subsequent infusions to such patients should be administered at a reduced infusion rate with premedication. Premedication may include medications such as corticosteroids, diphenhydramine, acetaminophen and / or bronchodilators, if indicated. Anti-FGFR2-IIIb should be permanently discontinued for patients who experience grade 3 or higher infusion-related adverse events and for patients who experience resumption of infusion-related reactions after resumption of infusion despite premedication and slower infusion.

[0330] If a patient suffers from an acute fluid reaction, the patient's vital signs (temperature, blood pressure, pulse, and respiratory rate) should be monitored during the infusion and every 30 minutes after the infusion for a minimum of 2 hours and until the acute fluid reaction has resolved.

[0331] Dose interruptions and delays due to mFOLFOX6 toxicity are listed in Table 5 (see product labels for leucovorin, 5-FU, and oxaliplatin).

[0332] Evaluation parameters and methods Safety parameters Safety measures included AEs, hematology, clinical chemistry, urinalysis, vital signs, weight, concomitant medications / treatments, ECOG performance status, subject physical examination, ECG, and ophthalmologic examination.

[0333] 1.1 Tumor analysis for patient selection 1.1.1 Part 1 Patients eligible for Part 1 will have unselected GI cancer (with or without tumors overexpressing FGFR2b) with unresectable, locally advanced or metastatic disease and are candidates to receive both anti-FGFR2-IIIb and mFOLFOX6 chemotherapy. FGFR2 status will be determined retrospectively by IHC and blood-based biopsy.

[0334] 1.1.2 Part 2 Patients in Part 2 of the study must consent to tumor tissue and blood sample analysis. Patients will be selected for enrollment based on FGFR2b overexpression and / or FGFR2 amplification as determined by validated IHC or blood-based biopsy assays, respectively. Patients who demonstrate neither FGFR2b overexpression using IHC nor amplification using blood-based biopsy assays will not be eligible for enrollment, but positivity based on one or both assays is sufficient to meet eligibility requirements (e.g., positive blood-based biopsy assay but negative IHC). It is the responsibility of each investigator to obtain adequate tumor specimens for FGFR2b overexpression analysis for enrollment. Procedures for processing, labeling, and shipping of tumor slides or tumor block specimens are detailed in the laboratory manual distributed with the specimen collection kit.

[0335] A third-party clinical laboratory performs FGFR2b expression and FGFR2 amplification analysis using validated IHC and blood-based assays, respectively.

[0336] For Part 2, upon receipt of tumor and blood specimens, analyses will be performed as efficiently as possible and the Investigator or designee will be notified of the results.

[0337] 1.2 Fresh tumor biopsy for pharmacodynamic analysis 1.2.1 Part 2 only Tumor biopsies are also taken to assess the pharmacodynamic effects of anti-FGFR2-IIIb in the tumor microenvironment. These biopsies are taken before and during treatment and examined for immune infiltration and expression of selected tumor markers. Optional biopsies of tumors that respond and / or worsen during or after treatment are also taken to understand mechanisms of resistance. Tumor biopsies can be assessed for expression of immune or disease-related genes and / or proteins, as well as the presence of immune cell populations, using a variety of methods, including but not limited to IHC, qRT-PCR, gene mutation detection, and fluorescent in situ hybridization (FISH). These samples can also be subjected to RNA sequencing to determine the effects of anti-FGFR2-IIIb on gene expression pathways, and the identified gene expression signatures associated with response or response resistance. These analyses can help predict future therapeutic outcomes. Other methods of tumor biomarker expression are also evaluated.

[0338] Fresh biopsies, whenever practicable, of the primary or metastatic tumor site are mandatory and will be performed for up to 30 patients randomized to Part 2 at screening (at least 24 hours prior to dosing) and on treatment (and at least 24 hours prior to dosing) within 7 days prior to Cycle 3 Day 1. For patients with a biopsy taken within 12 weeks prior to enrollment, this sample may satisfy the requirement for a fresh pre-treatment biopsy, provided sufficient sample is available for PD analysis (single paraffin-embedded block or approximately 10 slides).

[0339] Patients in Part 2 may also undergo an optional on-treatment biopsy within 28 (± 7) days after tumor assessment if tumor response is documented. Patients in Part 2 may also undergo an optional post-treatment biopsy at the EOT visit if tumor progression is documented. In each case, consultation with the sponsor must take place prior to performing a biopsy. Both biopsies are optional.

[0340] The feasibility of obtaining fresh tumor samples at each time point will be assessed by the investigator and should include consideration of patient safety. If the investigator assesses that a biopsy is not feasible, this decision must be documented in the source documents.

[0341] Biopsy lesions may become inflamed, bleed, or change in size, which may lead to inaccurate tumor measurements. Therefore, it is strongly recommended that biopsy lesions not be used as target lesions when assessing response by RECIST v1.1 criteria. These biopsy specimens should be excision, incision, or core needle biopsies. Fine needle aspiration biopsies or other cytology specimens are not sufficient for downstream biomarker analysis. Tumor tissue specimens in the form of paraffin-embedded blocks or unstained slides should be submitted for central IHC review.

[0342] 1.3 Tumor assessment Tumor assessment will consist of clinical examination and appropriate imaging techniques (preferably CT scan with appropriate slice thickness per RECIST v1.1), with other assessments (MRI, radiographs, PET, and ultrasound) performed as needed. The same methods used to detect lesions at baseline will be used to follow the same lesions throughout the study. A screening tumor scan must be performed within 2 weeks of initiating treatment on Day 1 of Cycle 1.

[0343] Tumor response will be assessed both by the investigator and by blinded central radiological review according to RECIST 1.1 guidelines.

[0344] Tumor scans will be performed at screening (within 2 weeks of Day 1 of Cycle 1 in Parts 1 and 2), within 7 days prior to the start of Day 1 of Cycle 4, Day 1 of Cycle 7, Day 1 of Cycle 10, and Day 1 of Cycle 13, and approximately every 12 weeks thereafter. If a first CR or PR is achieved, a confirmatory scan should be performed 4-6 weeks later.

[0345] After discontinuation of study treatment for reasons other than progression or withdrawal of consent, tumor evaluations will continue until the patient begins additional anticancer therapy.

[0346] 1.3.1 Blood-based biopsy (ctDNA) In Part 1, samples for blood-based biopsy (ctDNA) assays will be collected prior to the first dose of study drug (Day 1 of Cycle 1) and retrospectively analyzed for FGFR2 amplification.

[0347] Part 2 will involve a prescreening blood-based biopsy (ctDNA) assay that will be prospectively analyzed for FGFR2 amplification. In addition, blood-based biopsies (ctDNA) will be taken longitudinally every 6 weeks for 24 weeks after first dose and approximately every 12 weeks thereafter and will be retrospectively analyzed for FGFR2 amplification. For all patients in Part 2, samples will also be taken at the EOT visit.

[0348] 1.4 Pharmacodynamic biomarker analysis using hair follicles In Part 1 only, hair follicles (approximately 10, if available) from the eyebrows or scalp will be collected from all patients who are able to sample. Hair follicles are known to express the FGFR2b receptor, and changes in FGFR2b levels and downstream signaling can be used to correlate the dose of anti-FGFR2-IIIb required to effectively block the FGFR2b receptor with downstream signaling, to guide the selection of RDs for Part 2 of the study.

[0349] 1.5 Pharmacodynamic biomarker analysis using blood Serum samples for exploratory biomarker analysis of the FGFR pathway (eg: FGF7, FGF10) will be collected from all patients prior to dosing at the time points specified in Appendix 3.

[0350] 1.6 Blood samples for ctDNA 1.7 Pharmacodynamic biomarker analysis using tumor biopsies Immune cell infiltration levels and other exploratory biomarkers will be analyzed in pre- and on-treatment tumor biopsies from all patients.

[0351] 1.8 FCGR polymorphism Blood samples will also be taken for frequent polymorphisms in Fc gamma receptors, such as FCGR2A and FCGR3A. These genes express Fc gamma receptors on leukocytes that are an integral part of the ADCC pathway, the predicted mechanism of action of anti-FGFR2-IIIb. Data will be collected for retrospective analysis upon completion of the study to correlate with patient response to anti-FGFR2-IIIb. These biomarker tests are considered exploratory.

[0352] 1.9 Quality of Life Scale The EQ-5D-5L quality of life (QoL) questionnaire and the EORTC QLQ-C30 will be administered on multiple occasions prior to dosing (see Appendix 1 for time points).

[0353] The EQ-5D-5L questionnaire, developed by the EuroQol group, is a standardized scale that provides utility values ​​for clinical and economic evaluations. It uses a descriptive system and a visual analogue scale (VAS). The descriptive system has five items: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, and each item has five levels: no problems, slight problems, moderate problems, severe problems, and extreme problems.

[0354] Respondents are asked to indicate their health status by checking the box corresponding to the most appropriate state for each of the five items. The numbers for the five items can be combined to form a five-digit number describing the respondent's health status. The health status defined by the EQ-5D-5L description system is converted into a single index value to calculate a utility value. The VAS represents the respondent's self-assessed health status on a 20 cm vertical VAS, with the endpoints described as "best imaginable health state" and "worst imaginable health state."

[0355] The European Organisation for Research in Cancer Treatment (EORTC) Quality of Life Questionnaire (QLQ) is an integrated system for assessing health-related quality of life in cancer patients participating in international clinical trials. EORTC uses a modular approach to QoL assessment, consisting of a core questionnaire (EORTC QLQ-C30) and modules specific to tumour site, treatment or QoL aspects administered together as appropriate (e.g., the gastric cancer-specific module is QLQ-STO22).

[0356] Patients provide responses to five functioning scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), and an overall health status / quality of life scale, and six single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties).

[0357] 1.10 ECOG Performance Status ECOG performance status will be assessed in all patients at the time points outlined in Appendix 1. ECOG performance status is a measure used to assess the progression of a patient's disease, evaluate the impact of the disease on the patient's ability to perform daily activities, and determine appropriate treatment and prognosis. The ECOG scale is presented in Appendix 4.

[0358] 1.11 Pharmacokinetic parameters Blood samples for determination of serum anti-FGFR2-IIIb concentrations will be obtained from each patient as outlined in the Pharmacokinetics, Immunogenicity and Pharmacodynamics Blood Sampling Study Flowchart (Appendix 3).

[0359] 2. Conducting the Test 2.1 Patient Assessment Overview A detailed patient evaluation schedule is provided in Appendix 1. A list of safety laboratory evaluations is provided in Appendix 2. The procedures for sample collection and PK, PD and immunogenicity data processing are described in the flow chart in Appendix 3.

[0360] 2.2 Study Visit Assessments and Procedures 2.2.1 Pre-screening Period (Part 2 only – Pre-trial) Signed, written informed consent (prescreening ICF) must be collected prior to any study-related procedures. Prospective IHC analysis of FGFR2b expression and blood-based assays showing FGFR2 amplification (see above).

[0361] 2.2.2 Screening Period (Day -14 to Day 0) Signed, written informed consent must be collected prior to any study-related procedures. Patients who fully consent to participate in the study will undergo a screening evaluation within 14 days (2 weeks) prior to the first infusion of Anti-FGFR2-IIIb. The following procedures will be performed: · Review / check eligibility criteria Medical history and illness history (including medication history) Collection of tumor tissue from archives or newly acquired material (required for Part 1 and Part 2 enrollment) Demographics and baseline characteristics Complete physical examination (including weight and height) ECOG performance status evaluation Vital signs (blood pressure, pulse, respiration, and temperature [℃]) 12-lead ECG after 5 minutes of rest before recording Comprehensive eye exam Safety blood tests (see Appendix 2) For women of childbearing potential, a serum pregnancy test (beta-human chorionic gonadotropin [β-HCG]) within the previous 72 hours Urine testing (including dipstick for protein, glucose, blood, pH and ketones) Tumor evaluation performed within 14 days prior to initiation of treatment, including clinical examination and appropriate imaging techniques, with other evaluations as needed (MRI, radiographs, PET, and ultrasound) Randomization (Part 2 patients only) For up to 30 patients randomized to Part 2: A fresh tissue biopsy of the primary or metastatic tumor site at least 24 hours prior to dosing. For patients whose biopsy was taken within 12 weeks prior to enrollment, this sample may satisfy the requirement for a fresh pre-treatment biopsy, provided sufficient sample is available for PD analysis (single paraffin-embedded block or approximately 10 slides). Blood-based biopsy (ctDNA) sampling, as outlined in Appendix 3 FOLFOX administration (for part 1, patients may have started mFOLFOX6 chemotherapy before study enrollment and must be candidates for at least 2 cycles of mFOLFOX6 chemotherapy to be eligible. For part 2, patients must have completed 2 cycles of mFOLFOX6 chemotherapy before randomization). AE reporting (if applicable)

[0362] 2.2.3 Duration of treatment 2.2.3.1 Cycle 1, Day 1 The following steps are performed: · Review / check eligibility criteria Updates to medical, disease and medication history to capture any changes from screening Limited physical examination (including weight and oral examination) Patient-reported outcomes (EQ-5D-5L and EORTC QLQ-C30) Vital signs (blood pressure, pulse, respiration, and temperature [℃]) before administration and at 0.5, 1, 2, and 4 hours after the start of anti-FGFR2-IIIb infusion Safety blood tests, results must be obtained within 72 hours prior to study drug administration to confirm eligibility (see Appendix 2). For women of childbearing potential, a serum pregnancy test (β-HCG) within 72 hours prior to dosing Urine testing (including dipstick for protein, glucose, blood, pH and ketones) Blood sampling for PK, immunogenicity studies, FCGR, ctDNA and exploratory biomarker analysis as outlined in Appendix 3. Blood-Based Biopsy (ctDNA) Sample Collection: In Part 1, blood-based biopsy (ctDNA) samples for retrospective analysis will be collected pre-dose on Day 1 of Cycle 1. Samples at this time point will not be required for patients in Part 2. In Part 1 only, scalp or brow hair follicle samples (approximately 10, if available) will be collected pre-dose on Day 1 of Cycle 1 from all patients who are available for sampling. ·AE report Consideration of concomitant medications

[0363] Study drug administration: Anti-FGFR2-IIIb was administered by IV infusion over 30 minutes mFOLFOX6 chemotherapy was administered after 30 minutes of rest.

[0364] 2.2.3.2 Cycle 1, Day 2 The following steps are performed: Vital signs (blood pressure, pulse, respiration, and temperature [℃]) measured before administration and 0.5, 1, and 2 hours after the start of anti-FGFR2-IIIb infusion Collect blood samples for PK and exploratory biomarker analysis as outlined in Appendix 3. Continue mFOLFOX6 administration ·AE report Consideration of concomitant medications

[0365] 2.2.3.3 Cycle 1, Day 3 The following steps are performed: Vital signs (blood pressure, pulse, respiration, and temperature [℃]) measured before administration and 0.5, 1, and 2 hours after the start of anti-FGFR2-IIIb infusion Blood sampling for PK analysis as outlined in Appendix 3 Continue mFOLFOX6 administration ·AE report Consideration of concomitant medications

[0366] 2.2.3.4 Cycle 1, Day 8 The following steps are performed: Limited physical examination (including weight and oral examination) Vital signs (blood pressure, pulse, respiration, and temperature [℃]) measured before administration and 0.5, 1, and 2 hours after the start of anti-FGFR2-IIIb infusion Safety blood tests, with results to be obtained within 72 hours prior to administration of the study drug (see Appendix 2). Blood sampling for PK analysis as outlined in Appendix 3 ·AE report Consideration of concomitant medications

[0367] 2.2.3.5 Cycle 2 Day 1 The following steps are performed: Limited physical examination (including weight and oral examination) Vital signs (blood pressure, pulse, respiration, and temperature [℃]) measured before administration and 0.5, 1, and 2 hours after the start of anti-FGFR2-IIIb infusion Safety blood tests, with results to be obtained within 72 hours prior to administration of the study drug (see Appendix 2). Blood samples for PK, immunogenicity studies and exploratory biomarker analysis as outlined in Appendix 3 ·AE report Consideration of concomitant medications

[0368] Administration of study medication: Anti-FGFR2-IIIb was administered by IV infusion over 30 minutes mFOLFOX6 chemotherapy was administered after 30 minutes of rest.

[0369] 2.2.3.6 Day 1 of Cycle 3 and Day 1 of subsequent odd-numbered cycles Upon completion of the DLT period, patients may continue to receive anti-FGFR2-IIIb in combination with mFOLFOX6 administered every 2 weeks in 14-day cycles until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-specified withdrawal criteria. There is no upper limit to the number of doses of anti-FGFR2-IIIb. Continuation of the mFOLFOX6 regimen beyond the DLT period will follow local standard of care.

[0370] The following steps are performed: Limited physical examination (including weight and oral examination) ECOG performance status evaluation Patient-reported outcomes (EQ-5D-5L and EORTC QLQ-C30) Vital signs (blood pressure, pulse, respiration, and temperature [℃]) performed before administration and 0.5, 1, and 2 hours after the start of anti-FGFR2-IIIb infusion Comprehensive eye exam Slit-lamp examination without OCT for patients in part 1 and for patients in part 2 randomized to receive anti-FGFR2-IIIb and FOLFOX6; every 6 weeks after day 1 of cycle 2 (before day 15 of cycle 3, day 1 of cycle 5, and day 15 of cycle 6), and then every 12 weeks after day 15 of cycle 6. Continue every 6 to 8 weeks if patients have any persistent corneal findings. Safety blood tests, with results to be obtained within 72 hours prior to administration of the study drug (see Appendix 2). For women of childbearing potential, a urine pregnancy test within 72 hours prior to dosing Urine testing (including dipstick for protein, glucose, blood, pH and ketones) Tumor assessment to be performed within 7 days of Cycle 3 Day 1, including clinical examination and appropriate imaging techniques, with other evaluations as needed (MRI, radiographs, PET, and ultrasound) A fresh biopsy, whenever practicable, from the primary or metastatic tumor site is required and will be performed within 7 days (and at least 24 hours prior to dosing) of Day 1 of Cycle 3 only for up to 30 patients randomized to Part 2. Blood sampling for PK, immunogenicity studies, blood-based biopsies (ctDNA) and exploratory biomarker analysis as outlined in Appendix 3. For Part 2 only, a blood-based biopsy (ctDNA) sample will be collected prior to treatment. Hair follicle samples from the scalp or eyebrows (approximately 10, if available) ·AE report Consideration of concomitant medications

[0371] Administration of study medication: Anti-FGFR2-IIIb administered by IV infusion over 30 minutes on day 1 of each cycle mFOLFOX6 chemotherapy was administered after 30 minutes of rest following anti-FGFR2-IIIb administration on day 1 of each cycle.

[0372] 2.2.3.7 Day 1 of Cycle 4 and Day 1 of subsequent even-numbered cycles The following steps are performed: Limited physical examination (including weight and oral examination) Patient-reported outcomes (EQ-5D-5L and EORTC QLQ-C30) Vital signs (blood pressure, pulse, respiration, and temperature [℃]) measured before administration and 0.5, 1, and 2 hours after the start of anti-FGFR2-IIIb infusion Slit-lamp examination without OCT for patients in part 1 and for patients in part 2 randomized to receive anti-FGFR2-IIIb and FOLFOX6; every 6 weeks after day 1 of cycle 2 (before day 15 of cycle 3, day 1 of cycle 5, and day 15 of cycle 6), and then every 12 weeks after day 15 of cycle 6. Continue every 6 to 8 weeks if patients have any persistent corneal findings. Safety blood tests, with results to be obtained within 72 hours prior to administration of the study drug (see Appendix 2). Tumor assessment performed within 7 days prior to the start of Cycle 4 Day 1, including clinical examination and appropriate imaging techniques, with other evaluations as needed (MRI, radiographs, PET, and ultrasound) For Part 2 only, a blood-based biopsy (ctDNA) sample will be collected prior to treatment. For Part 1, blood samples for PK taken within 4 hours prior to administration of anti-FGFR2-IIIb and 15 minutes (± 10 minutes) after the end of anti-FGFR2-IIIb infusion in the subsequent cycle. For Part 2, PK samples taken within 4 hours prior to administration of anti-FGFR2-IIIb and 15 minutes (± 10 minutes) after the end of anti-FGFR2-IIIb infusion AE reporting (only for patients randomized to anti-FGFR2-IIIb and mFOLFOX6 arms) ·AE report Consideration of concomitant medications

[0373] Study drug administration: Anti-FGFR2-IIIb administered by IV infusion over 30 minutes on day 1 of each cycle mFOLFOX6 chemotherapy was administered after 30 minutes of rest following anti-FGFR2-IIIb administration on day 1 of each cycle.

[0374] 2.2.4 End-of-treatment visit or early discontinuation Patients will return to the study site approximately 28 (± 3) days after the last study treatment dose or if the patient prematurely discontinues the study. The following assessments will be performed at the End of Study Visit: Limited physical examination (including oral examination) ECOG performance status evaluation Vital signs (pulse, blood pressure, respiration, and temperature [℃] in sitting position after 5 minutes of rest) 12-lead ECG after 5 minutes of rest Comprehensive eye exam Safety blood tests (see Appendix 2) For women of childbearing potential, a urine pregnancy test Urine testing (including dipstick for protein, glucose, blood, pH and ketones) Tumor scan. May be omitted if last scan was performed <6 weeks prior to EOT visit or if tumor progression was predetermined. Blood samples for immunogenicity testing For Part 2 only, blood-based biopsy (ctDNA) samples will be collected Hair follicle samples from the scalp or eyebrows (approximately 10, if available) Blood samples for PK for all patients in Part 1 and all patients receiving anti-FGFR2-IIIb in Part 2 Blood samples for biomarker evaluation ·AE report Consideration of concomitant medications

[0375] Note: After discontinuation of study treatment for reasons other than progression or withdrawal of consent, tumor evaluations will continue until the patient begins additional anticancer therapy. 2.2.5 Long-term follow-up Patients in both Part 1 and Part 2 will undergo long-term follow-up for survival via in-site visits or telephone approximately every 3 months ± 28 days after the EOT visit until a maximum of 24 months after the last patient was enrolled in the study or until death, loss to follow-up, withdrawal of consent, or study discontinuation by the sponsor, whichever occurs first. If the patient receives anticancer therapy during the follow-up period, this should be recorded. Any pregnancies occurring during the first 6 months of follow-up will be reported to the sponsor. Patients will be followed until death, loss to follow-up, withdrawal of consent, or discontinuation of the study by the sponsor. Any serious AE occurring after the EOT visit that the investigator deems to be causally related to the study drug will be reported by the investigator to the sponsor.

[0376] 3.Statistical methods Prior to database lock, a separate Statistical Analysis Plan (SAP) will be finalized describing the detailed methods of analysis as outlined below. Any deviations from the planned analysis will be documented and fully justified in the final study report.

[0377] 3.1 Study Patients 3.1.1 Patient breakdown The number and percentage of patients who entered and completed each period of the study (e.g., screening, cycle 1, and subsequent cycles if administered) will be presented. Reasons for withdrawal will also be summarized.

[0378] 3.1.2 Protocol Deviations A summary of the number and percentage of patients with major protocol deviations by deviation type will be provided. Deviations are defined in SAP prior to database lock.

[0379] 3.1.3 Analysis population The study will define the following analysis populations: Safety population - All patients who received at least one dose of anti-FGFR2-IIIb in any period. DLT-evaluable population - all patients enrolled in Part 1 of the study, who received at least two doses of anti-FGFR2-IIIb and either completed cycle 1 of treatment or experienced a DLT during cycle 1. PK-evaluable population - all patients who have received at least one dose of anti-FGFR2-IIIb and have PK assessments adequate for determination of the PK profile. Adequacy will be determined on an individual basis and assessed prior to analysis of blood samples. Intention-to-treat (ITT) population - all enrolled patients Efficacy-evaluable population - all patients who meet the eligibility criteria, have received at least one dose of anti-FGFR2-IIIb, and have at least one post-baseline disease assessment.

[0380] 3.2 General Considerations Total planned enrollment for the study is up to approximately 372 patients. Following a standard 3+3 design, up to approximately 12 patients evaluable for any DLTs will be enrolled in Part 1.

[0381] For Part 2, efficacy and tolerability will be tested by enrolling up to approximately 360 patients with FGFR2b-selected gastric cancer and randomizing 1:1 to receive anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo in combination with mFOLFOX6. Eligible patients will be stratified according to geographic region (US and Europe vs. Asia vs. rest of the world), prior treatment status (de novo vs. adjuvant / neoadjuvant), and measurable disease status (measurable vs. non-measurable).

[0382] Power and sample size The study is designed to provide sufficient power for the primary analysis of PFS.

[0383] Based on the mPFS of patients receiving placebo and mFOLFOX6 for 6 months, approximately 156 patients (randomized 1:1) and a target of 96 PFS events would be required to demonstrate a hazard ratio (HR) of 0.5 (2-sided, α=0.05) with 90% power for mPFS of the combination of anti-FGFR2-IIIb and mFOLFOX6 compared with placebo and mFOLFOX6 after a 24-month intake period and 6 months follow-up.

[0384] Assuming an exponential distribution of PFS, this corresponds to an increase in median PFS from 6 to 12 months. In the current design, the minimum observed effect that would result in statistical significance in PFS is a 50% improvement from 6 to 9 months (HR = 0.67).

[0385] The study will also be powered for the primary analysis of OS.

[0386] Based on mOS for patients receiving placebo and mFOLFOX6 for 10 months, after 36 months of intake and 10 months of follow-up from the last patient enrolled, the study will continue to enroll up to approximately 360 patients, targeting 249 death events, to demonstrate a HR of 0.7 with 80% power at an overall type I error level of 0.05 for mOS for the combination of anti-FGFR2-IIIb and mFOLFOX6 compared with placebo and mFOLFOX6. Interim and final analyses of OS will use group sequential methods to determine the probability of type I error based on O'Brien-Fleming bounds and the probability of type II error based on Gamma family (parameter -4).

[0387] Assuming an exponential distribution of OS, this corresponds to a 43% increase in median OS from 10 to 14.3 months. In the current design, the minimum observed effect that would result in statistical significance for OS in the final analysis is a 28% improvement from 10 to 12.8 months (HR = 0.78).

[0388] Power and sample size estimates were estimated using EAST® (V6.4).

[0389] 3.3 Demographics, Baseline Characteristics, and Concomitant Medications Demographic data, medical history, comorbidities, and concomitant medications will be summarized by cohort and overall. Corresponding tables and listings will be provided to determine whether study inclusion criteria were met. These will include descriptions of patients who did not meet the eligibility criteria, evaluation of protocol violations, accountability for study medication, and other data that may affect the overall conduct of the study.

[0390] Baseline characteristics of the safety population will be summarized. Patients who die or withdraw before starting treatment, or who do not complete the required safety observations, will be described and evaluated separately.

[0391] 3.4 Treatment Compliance Treatment administration will be summarized by cohort, including dose administration, dose modifications or delays, cumulative dose, mean dose, number of infusions, and duration of treatment.

[0392] 3.5 Efficacy Analysis In Part 1, all analyses will be descriptive and presented by dose group and overall, as appropriate. Descriptive statistics will include number of observations, mean, standard deviation, median, range, and interquartile range for continuous variables, and counts and percentages for categorical variables, with 95% confidence intervals as appropriate.

[0393] 3.5.1 Primary Efficacy Analysis In part 2, the primary efficacy analysis will be a comparison of PFS in patients treated with anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo and mFOLFOX6.

[0394] The primary endpoint, PFS, was defined as the time from randomization to the date of radiological progression based on investigator assessment (per RECIST v.1.1) or death from any cause, whichever occurred first. Secondary efficacy endpoints included OS and ORR.

[0395] There will be an interim analysis and a primary analysis of PFS, both of which will be event-based analyses. At the interim analysis after 48 events (50% of the target 96 PFS events in the primary PFS analysis) have been observed in enrolled patients, only a futility test for PFS will be performed to avoid the HR exceeding 0.806 for the combination of anti-FGFR2-IIIb and mFOLFOX6 compared to placebo and mFOLFOX6. The interim analysis is estimated to be performed approximately 20 months after the first patient is enrolled.

[0396] The primary analysis of PFS will occur when at least 96 PFS events have been observed in the first 156 enrolled patients and will be performed using the intention-to-treat (ITT) population.

[0397] The primary analysis included investigator-determined radiological progression events and deaths according to RECIST v.1.1.

[0398] The primary analysis of PFS will be performed using a stratified two-sided log-rank test with a significance level of 0.05. The stratification factors will be the same as those used to stratify the randomization schedule documented in the Interactive Voice Response / Web Registration System (IXRS).

[0399] If the p-value of the stratified log-rank test is statistically significant (<0.05 two-sided) and the HR is less than 1, the null hypothesis of no difference in PFS is rejected and it is estimated that PFS is statistically prolonged in the group receiving anti-FGFR2-IIIb in combination with mFOLFOX6 compared to the group receiving placebo and mFOLFOX6.

[0400] Median PFS and associated 95% confidence intervals for each treatment group will be estimated using the Kaplan-Meier method. Hazard ratios (HR = λ anti-FGFR2-IIIb + mFOLFOX6 / λ mFOLFOX6) will be estimated using a Cox regression model with treatment group as the only main effect, stratified by the same stratification factors used in the log-rank test. Unstratified HRs are also shown. OS analysis of secondary endpoints will be performed when the primary endpoint PFS is statistically significant, and formal hypotheses for OS will be tested in a hierarchical manner at the 0.05 level. The probability of type I error in testing the primary and secondary endpoints will be controlled by adopting this fixed order testing procedure (0.05 level).

[0401] 3.5.2 Secondary Efficacy Analyses Analysis of secondary endpoints including OS and ORR will be performed when the primary endpoint PFS is statistically significant, and the formal hypotheses of OS and ORR will be tested hierarchically at the 0.05 level. OS will be tested first, and if it is significant, ORR will be tested next. The probability of type I error in testing the primary and secondary endpoints will be controlled by adopting this fixed order testing procedure (0.05 level).

[0402] If the PFS test is statistically significant, interim and final analyses of OS are planned. The interim analysis of OS will be performed at the time of the primary PFS analysis. If an OS analysis is performed, the interim (i.e., when at least 96 PFS events have been observed) and final (i.e., when 249 deaths have been observed) OS analyses will be performed on the ITT population.

[0403] Hypothesis testing for OS will be performed using a stratified two-sided log-rank test (significance level 0.05). Interim and final analyses of OS will use group sequential methods to determine the probability of type I error based on O'Brien-Fleming bounds and the probability of type II error based on Gamma family (parameter -4). Stratification factors will be the same as those used to stratify the randomization schedule documented in the IXRS.

[0404] Median OS and associated 95% confidence intervals for each treatment group are estimated using the Kaplan-Meier method. HRs are estimated using Cox regression models with treatment group as the only main effect, stratified by the same stratification factors used in the log-rank test. Unstratified HRs are also shown.

[0405] ORR will be defined as the proportion of patients with partial or complete response as defined by the investigator per RECIST v.1.1. The primary analysis of ORR will be performed among patients with measurable disease at baseline. For the analysis of ORR, patients without adequate post-baseline tumor evaluation will be counted as non-responders. Formal hypothesis testing of ORR will be performed using a stratified Cochran-Mantel-Haenszel test. Stratification factors will be the same as those used to stratify the randomization schedule documented in the IXRS.

[0406] 3.5.3 Exploratory Efficacy Analyses Exploratory efficacy endpoints include duration of response among responding patients, 1-year OS rate, and change from baseline in QoL as measured by EQ-5D-5L and EORTC QLQ-C30 for all enrolled patients.

[0407] Duration of response will be defined as the time from first radiological documentation of objective tumor response by RECIST 1.1 to progression or death from any cause for patients with objective tumor response. Median duration of response and its associated 95% CI will be estimated by treatment group using the Kaplan-Meier method. Differences between treatment groups will be analyzed using the stratified log-rank test, using the same stratification used for randomization.

[0408] One-year OS rates, defined as the proportion of patients surviving at 1 year, will be estimated during the analysis of overall survival using the Kaplan-Meier method. The variance of the rates will be estimated using Greenwood's formula. Overall comparisons of the difference in 1-year survival between the two treatment groups will be calculated using the z-statistic (t=1 year).

[0409] For change from baseline in QoL as measured by EQ-5D-5L and EORTC QLQ-C30, summary statistics will be presented for each post-baseline assessment and change from baseline at the end of treatment. Where applicable, repeated measures analyses will be used to analyze differences between treatment groups.

[0410] Blinded Independent Review Committee (BIRC) A BIRC will be established to assess concordance between investigator and BIRC assessments. A pre-specified audit plan will be included in the imaging review document, detailing the percentage of patients, identification of imaging subsets, criteria for auditing all images, and comparison of PFS outcomes between local review and audit.

[0411] 3.6 Safety analysis Safety analyses will include all patients who received either study drug (anti-FGFR2-IIIb in combination with mFOLFOX6 or placebo and mFOLFOX6) during the study period and will provide any post-treatment safety information. All AEs will be coded using the Medical Dictionary for Clinical Practice (MedDRA). Investigators will classify the severity of AEs using CTCAE v4.03.

[0412] Treatment-emergent adverse events (TEAEs) are defined as any event with an onset date after the first dose of study drug, or any event that was present before treatment and worsened after treatment. Only TEAEs with an onset date prior to the last dose +30 days are provided in the summary tables. The number and percentage of patients who experienced AEs are summarized by system organ class, preferred term, relationship to study drug, and severity for each treatment group. Patient-specific listings are provided for patients who experienced SAEs, including death, or AEs related to premature withdrawal from the study or discontinuation of study drug. Laboratory data are summarized by laboratory test type. The number and percentage of patients who experienced abnormalities (i.e., outside reference ranges) and / or clinically significant abnormalities after administration of study drug are presented for each laboratory measurement. Descriptive statistics are provided for each laboratory measurement at baseline and all subsequent scheduled post-treatment visits. Changes from baseline to post-treatment visits are also provided. Descriptive statistics for vital signs are provided as well. Additionally, shift from baseline in CTCAE grade (if applicable) and shift by high / low flag (if CTCAE grade is not defined) will be presented by treatment group. No formal comparisons of safety endpoints are planned.

[0413] 3.7 Pharmacokinetic analysis PK parameters will be estimated using non-compartmental analysis, although compartmental analysis may be used where appropriate. Individual and mean (± SD) serum anti-FGFR2-IIIb concentration-time data will be tabulated and plotted by dose level. Anti-FGFR2-IIIb PK parameters will be estimated from serum test drug concentration-time data using non-compartmental analysis (NCA) methods with intravenous infusion input data. Alternative methods may be considered. Individual and mean (± SD) PK parameter estimates will be tabulated and summarized by dose level. Other descriptive statistics may be reported for serum anti-FGFR2-IIIb concentration-time data and PK parameter estimates. Dose proportionality, test drug accumulation, and attainment of steady state will be evaluated, where data permit.

[0414] The effect of immunogenicity on anti-FGFR2-IIIb exposure will be evaluated.

[0415] 3.8 Interim Analysis To avoid the HR of PFS of the combination of anti-FGFR2-IIIb and mFOLFOX6 compared with placebo and mFOLFOX6 exceeding 0.806, there will be an interim analysis of PFS where only the futility test of PFS will be performed after 48 events (50% of the target 96 PFS events in the main PFS analysis) are observed in the first 156 enrolled patients. In addition, if the PFS test is statistically significant, an interim analysis of OS will be planned. The interim analysis of OS will be performed at the time of the main PFS analysis. When analyzing OS, the OS analysis at the interim analysis will be performed in the ITT population, and the probability of type I error at the interim analysis will be determined by performing the Lan-DeMets O'Brien-Fleming alpha-spending function according to part of the information at the time of analysis (death events).

[0416] In addition, safety data will be reviewed periodically by the sponsor's and CRO's medical monitors. During the dose escalation phase, the medical monitor and investigator(s) will review safety data from each dose cohort prior to dose escalation or deescalation. AE data from all cycles will be submitted to the medical monitor when available.

[0417] 3.9 Changes to Planned Analyses If there is a discrepancy between the statement of the statistical analysis planned in the protocol and the final SAP, no protocol amendment will occur and the SAP will take precedence. References Andre F, Ranson M, Dean E, Varga A, Van der Noll R, Stockman P, et al.Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor(FGFR), in patients with advanced solid tumors.ProcAACR abstract,2013:LB-145. Brown A,Courtney C,King L,Groom S,Graziano M.Cartilage dysplasia and mineralization in the rat following administration of a FGF receptor tyrosine kinase inhibitor.Toxicol Pathol,2005;33:449-455. Cunningham D, Starling N, Rao S, et al.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med.2008(358):36-46. 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Shinkawa T,Nakamura k,Yamane N,Shoji-Hosaka E,Kanda Y et al.The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity.JBC,2003;278:3466-3473. Takahashi T,Saikawa Y,Kitagawa Y.Gastric cancer:current status of diagnosis and treatment.Cancers 2013;5(1):48-63. Thuss-Patience,P.,A.Kretzschmar,D.Bichev,et al.Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer- A randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie(AIO).Eur J Cancer 2011;47:2306-2314. Turner N, Grose R. Fibroblast growth factor signaling: from development to cancer.Nature,2010;10:116-129. Ueda S, Hironaka S, Yasui H, et al.Randomized phase III study of irinotecan(CPT-11)versus weekly paclitaxel(wPTX)for advanced gastric cancer(AGC)refractory to combination chemotherapy(CT)of fluoropyrimidine plus platinum(FP):WJOG4007 trial,J Clin Oncol(Meeting Abstracts).2012,vol.3 Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D. Gastric cancer:ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Annals of Oncology.2013 Oct 1;24(suppl 6):vi57-63. Wu,YM,Su,F,Kalyana-Sundaram S,Identification of Targetable FGFR Fusions in Diverse Cancers.Cancer Discovery,2013;3:636-647. [Table 6] JPEG2025004195000009.jpg249170JPEG2025004195000010.jpg127170 [Table 7] Remarks:C max1 = maximum serum concentration observed after the first dose; C max1 / Dose = C normalized by dose max1 ;C trough1 = observed serum concentration at the end of the first dosing interval; AUC last = area under the concentration-time curve observed from the time of dosing to the last quantifiable concentration after the first dose. AUC last / Dose = AUC normalized by dose last ; and t 1 / 2 = Elimination half-life. NC = C below LLOQ trough1 Summary statistics could not be reported in 2 of 3 patients due to; ND = PK parameter that could not be precisely determined. a n = 3. Data for one patient could not be reported as the patient completed the study without data on C1D15; b n = 2. Elimination was characterized as less than one half-life in 1 of 3 patients; therefore, this patient's data were excluded from the half-life summary statistics as specified in the data analysis plan; c One of six study patients received a partial dose, and thus the parameter was omitted from the summary statistics; d n=3. Elimination was characterized as less than one half-life in 2 of 5 patients; therefore, these patients were excluded from the half-life summary statistics as specified in the data analysis plan. Appendix 1: Evaluation Schedule - Dose Escalation Safety Run-in Phase (Part 1) and Dose Expansion (Part 2) [Table 8] JPEG2025004195000013.jpg255170JPEG2025004195000014.jpg232170 [Table 9] JPEG2025004195000016.jpg249170JPEG2025004195000017.jpg239170 [Table 10] [Table 11] JPEG2025004195000020.jpg149170 [Table 12]

[0418] Example 2: Phase 1 / 3 study of an anti-FGFR2-IIIb antibody in combination with modified FOLFOX6 versus modified FOLFOX6 in patients with previously untreated advanced gastric and gastroesophageal cancer Protocol Overview This study is a modified version of the study described in Example 1 herein, and is a multicenter study to evaluate the safety, tolerability, efficacy, PK, and PD of anti-FGFR2-IIIb antibody in combination with mFOLFOX6. The study includes an open-label Phase 1 safety run-in phase in GI tumor patients (not FGFR2 selected), followed by a randomized open-label Phase 3 in FGFR2-selected GC patients (determined by prospective IHC analysis of FGFR2b overexpression and / or ctDNA blood assay showing FGFR2 gene amplification). After an initial screening period, patients are treated with mFOLFOX6 in combination with anti-FGFR2-IIIb antibody or mFOLFOX6 alone in 2-week cycles.

[0419] Phase 1: Dose escalation safety run-in phase Phase 1 is an open-label dose escalation of anti-FGFR2-IIIb antibody in combination with mFOLFOX6. Eligible patients have any type of unresectable, locally advanced or metastatic GI cancer and are candidates for at least two doses of mFOLFOX6 chemotherapy. FGFR2 status is not a requirement for enrollment. FGFR2 status will be tested retrospectively by IHC (if tissue is available) and samples will be obtained from ctDNA blood assays.

[0420] Phase 1 will consist of at least two dose cohorts of anti-FGFR2-IIIb antibody in combination with mFOLFOX6 to determine the RD for Phase 3 of anti-FGFR2-IIIb antibody administered in combination with mFOLFOX6. Patients may or may not have started or received prior mFOLFOX6 chemotherapy. There is no upper limit to the number of prior mFOLFOX6 doses patients may have received.

[0421] Each enrolled patient will be observed for safety assessments, PK, and occurrence of dose-limiting toxicities for 28 days (DLT period) from the first day of treatment with the anti-FGFR2-IIIb antibody (Day 1 of Cycle 1 [Study Day 1]). Cohorts of patients will be treated with escalating doses of the anti-FGFR2-IIIb antibody in combination with a standard-dose chemotherapy regimen of mFOLFOX6 in 2-week cycles.

[0422] Administration of anti-FGFR2-IIIb antibody Anti-FGFR2-IIIb antibody IV is administered every 2 weeks on day 1 of each cycle (2 weeks = 1 cycle) and before mFOLFOX6 chemotherapy. Only patients treated in cohort 2 will receive one additional dose of anti-FGFR2-IIIb antibody on day 8 of cycle 1 (no mFOLFOX6 is administered on this day). Anti-FGFR2-IIIb antibody is administered as an approximately 30-minute IV infusion via a peripheral vein or central venous catheter. The IV administration set for anti-FGFR2-IIIb antibody infusion must be equipped with a 0.22 μm inline filter or a 0.22 μm syringe filter.

[0423] Administration of mFOLFOX6 Administration of mFOLFOX6 chemotherapy will also begin 30 minutes after the end of the anti-FGFR2-IIIb antibody infusion on Day 1 of Cycle 1 (Study Day 1) of each treatment cycle. mFOLFOX6 will be administered every 2 weeks as follows: Day 1: Oxaliplatin 85 mg / m2 IV infusion over 120 minutes. Day 1: Leucovorin 400 mg / m2 IV infusion over 120 minutes. If a Y-connector is used, it may be given concomitantly with oxaliplatin, otherwise, they may be given sequentially. Day 1: 5FU 400 mg / m2 bolus over approximately 5 minutes immediately after oxaliplatin and leucovorin. Day 1: 5-FU bolus immediately followed by 5-FU 2400 mg / m2 continuous IV infusion over 46 hours.

[0424] After the 28-day DLT period, patients may have their mFOLFOX6 or anti-FGFR2-IIIb doses maintained or reduced based on toxicity analysis. Premedication may be used according to local standard of care at the investigator's discretion.

[0425] Phase 1 cohort In Phase 1, the first dose cohort of anti-FGFR2-IIIb antibody to be tested is 6 mg / kg. Planned dose levels are as follows: Cohort 1: anti-FGFR2-IIIb antibody 6 mg / kg every 2 weeks; Cohort 2: Anti-FGFR2-IIIb antibody 15 mg / kg every 2 weeks; one 7.5 mg / kg dose on day 8 (Cycle 1 only); -Cohort 3 (if needed): anti-FGFR2-IIIb antibody 15 mg / kg every 2 weeks; - Cohort 4 (if necessary): Dose level lower than Cohort 3 but higher than Cohort 1 to achieve tolerability at optimal target exposure.

[0426] If the first cohort of 6 mg / kg clears the 28-day DLT period, a second dose cohort at 15 mg / kg every 2 weeks, including a 7.5 mg / kg dose on day 8 (cycle 1 only), will be studied in a Rolling-6 design and six patients will be enrolled. The decision to escalate will be based on the evaluation of DLTs, overall safety and tolerability. The decision to escalate will be made after the last patient enrolled in each cohort has completed the 28-day DLT period (after completion of two treatment cycles of anti-FGFR2-IIIb antibody and mFOLFOX6). The decision to escalate will be made in consensus by a Cohort Review Committee (CRC) consisting of the sponsor and the investigator. If ≥2 DLTs are observed in cohort 2, dose levels between cohorts 1 and 2 can be evaluated in a Rolling-6 (15 mg / kg every 2 weeks) design (cohort 3). If ≥2 DLTs are observed in cohort 3, a dose level lower than in cohort 3 but higher than in cohort 1 may be evaluated in a Rolling 6 design (cohort 4). A DLT will be defined as any of the following that the investigator considers to be related to the anti-FGFR2-IIIb antibody: ANC < 0.5 × 10 for more than 5 days 9 / L or febrile neutropenia (i.e., ANC < 1.0 × 10 9 / L and a single temperature of >38.3°C or a fever of >38°C for >1 hour). Use of G-CSF is permitted according to standard institutional procedures. Platelets <25×10 9 / L or platelets <50 × 10 9 / L and bleeding requiring medical intervention Long-term (>3 days) <50×10 9 / L of platelets Grade 4 anemia (i.e., life-threatening effects; urgent intervention required) Any grade 2-3 ocular AE that does not resolve within 7 days Grade 4 ocular AEs AST / ALT ≥ 3xULN and concurrent total bilirubin ≥ 2xULN, unrelated to liver function due to cancer Any non-hematologic AE of Grade 3 or greater (excluding nausea, vomiting, and diarrhea). Grade 3 nausea, vomiting, or diarrhea that does not resolve with 72 hours of supportive care Grade 3 laboratory values ​​that do not resolve within 72 hours and are deemed to be of no clinical significance in the agreement of the investigator and sponsor. Grade 4 nausea, vomiting, or diarrhea Any laboratory test result of grade 4

[0427] The following algorithm in Table 7 below will be used to determine dose escalation: [Table 13]

[0428] The RD of the anti-FGFR2-IIIb antibody for phase 3 will be identified by the CRC based on the overall safety, tolerability, and PK evaluation and will not exceed 15 mg / kg administered IV every 2 weeks, including 7.5 mg / kg administered only on day 8 of cycle 1. In determining the RD, the CRC will take into account any toxicities observed during the DLT evaluation period, any toxicities observed after the DLT evaluation period, and dose reductions and discontinuations of mFOLFOX6 or anti-FGFR2-IIIb antibody due to toxicities that do not meet DLT criteria. Based on the entire data, the RD of the anti-FGFR2-IIIb antibody selected is a dose that is expected not to reduce the dose intensity of mFOLFOX6 administered. Thus, the RD may or may not be the same as the identified maximum tolerated dose (MTD). For example, if the MTD is not reached or if data from subsequent treatment cycles of phase 1 provide further insight into the safety profile, the RD may not exceed the MTD but may be a different dose than the MTD.

[0429] The MTD is defined as the highest dose at which less than 33% of patients experience DLT during the dose-limiting toxicity period. If a DLT is observed in 1 of 3 patients in cohort 1, 3 additional patients are enrolled at that dose level. Dose escalation can continue (doses levels do not exceed the maximum dose level tolerated in phase 1) until 2 of 3-6 patients treated at a dose level experience a DLT. The next lower dose is then considered the MTD.

[0430] Study design Once we begin enrollment in cohort 2 (which includes the 15 mg / kg every 2 weeks cohort with one 7.5 mg / kg dose on day 8 [cycle 1 only]), we will enroll 6 patients and study safety and efficacy. Total enrollment in phase 1 will be approximately 9-21 patients.

[0431] During the DLT period, any patient who does not receive all doses of anti-FGFR2-IIIb antibody defined in the cohort and 2 complete doses of mFOLFOX6 due to reasons other than DLT or anti-FGFR2-IIIb antibody related AEs will be considered unevaluable and will be replaced. Replaced patients may continue in the study after the investigator's discretion and discussion with the sponsor. During the 28-day DLT period, no additional doses of anti-FGFR2-IIIb or more than 2 doses of mFOLFOX6 should be administered. The administration of anti-FGFR2-IIIb antibody and mFOLFOX6 on day 1 of cycle 2 does not need to be synchronized. For example, if mFOLFOX6 is delayed due to an AE that appears to be related only to mFOLFOX6 and not to anti-FGFR2-IIIb antibody, anti-FGFR2-IIIb antibody should be administered as planned in cycles 1 and 2, regardless of the delay in the mFOLFOX6 administration schedule.

[0432] Upon completion of the DLT period, patients may continue to receive anti-FGFR2-IIIb antibody in combination with mFOLFOX6 at the discretion of the investigator. Additional treatment may be administered every 2 weeks (1 cycle) until investigator-assessed radiological or clinical progression, unacceptable toxicity, or until the patient meets any other protocol-specified withdrawal criteria.

[0433] During the first three cycles (42 days) of treatment, if the mFOLFOX6 cycle is delayed for more than 2 weeks due to chemotherapy-related toxicity, the anti-FGFR2-IIIb antibody should be administered according to the schedule (± 3 days). After the first three cycles, the anti-FGFR2-IIIb antibody can be delayed by up to ± 7 days to be synchronized with the administration of mFOLFOX6. There is no specified upper limit on the number of doses of the anti-FGFR2-IIIb antibody or mFOLFOX6. Continuation of the mFOLFOX6 regimen after the DLT period will follow the following schedule: The starting dose of mFOLFOX6 was 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of calcium folinate (folinic acid), 400 mg / m 2 bolus of 5-FU, and 2400 mg / m 2 The study included 5-FU administered as a continuous infusion over 46 hours. The mFOLFOX6 regimen will be administered every 2 weeks (± 3 days) until investigator-assessed radiological progression (Phase 3 only), clinical progression (Phase 1 only), unacceptable toxicity, or the patient meets other protocol-specified withdrawal criteria. Day 1: Oxaliplatin 85 mg / m 2 IV infusion over 120 minutes Day 1: Leucovorin 400 mg / m 2 Infused IV over 120 minutes. Can be administered simultaneously with oxaliplatin if a Y-connector is used, or sequentially if a Y-connector is not used. Day 1: 5FU 400 mg / m2 over approximately 5 minutes, immediately after oxaliplatin and leucovorin 2Bolus Day 1: 5-FU 2400mg / m immediately after 5-FU bolus 2 was administered by continuous IV infusion over 46 hours.

[0434] Any modifications to continued mFOLFOX6 administration may be made based on the following guidelines: Dosage should be recalculated if there is a change in body weight of at least 10%. Advise patients to avoid exposure to cold weather during and for approximately 72 hours after each infusion. Correct hypokalemia and hypomagnesemia before initiating oxaliplatin. · The presence of severe diarrhea, mucositis, and myelosuppression after 5-FU should prompt evaluation for dihydropyrimidine dehydrogenase deficiency. Leucovorin should be given as a d,l-racemic mixture. For LEVO-Leucovorin (l-leucovorin), use half the dose. If oxaliplatin is discontinued for any reason prior to progression, 5-FU / leucovorin may be continued on a every 2-week schedule until progression, unacceptable toxicity, or other reason for withdrawal from study. If 5-FU / leucovorin is discontinued, oxaliplatin must also be discontinued.

[0435] Some dose adjustments for mFOLFOX6 toxicity are shown in Table 8 below. [Table 14] JPEG2025004195000024.jpg232170

[0436] If anti-FGFR2-IIIb antibody is permanently discontinued for any reason during the Phase 1 portion of the study, patients will have an end-of-treatment (EOT) follow-up visit approximately 28 days after the last dose of anti-FGFR2-IIIb antibody. No further follow-up will be performed for these patients, and the end of the anti-FGFR2-IIIb antibody treatment follow-up visit marks the end of the study. If mFOLFOX6 is discontinued for any reason other than investigator-assessed progression or any other protocol-specified withdrawal criteria, anti-FGFR2-IIIb antibody may be continued as monotherapy at the investigator's discretion.

[0437] Randomized open-label portion of Phase 3 Enrollment into Phase 3 will begin if a RD of the anti-FGFR2-IIIb antibody is identified by CRC, and this RD does not exceed the maximum dose level evaluated and tolerated in Phase 1. Patients may be enrolled in either Phase 1 or Phase 3, but not in both phases of the study. Enrollment initiation for the Phase 3 portion of the study will be at the sponsor's discretion.

[0438] Eligibility for enrollment requires patients to have unresectable, locally advanced or metastatic GC, be candidates for standard first-line mFOLFOX6 chemotherapy, and have tumors that are FGFR2 positive by IHC tissue testing and / or ctDNA blood assays performed at a central site. A prescreening informed consent form (ICF) must be signed by patients prior to submission of tissue (archived or fresh) and blood samples for FGFR2 testing. Because it may take approximately 2 weeks to receive the results of central FGFR2 testing, patients will be allowed to receive up to one dose of mFOLFOX6 during this interim period (prescreening period) at the discretion of the investigator. This single dose of chemotherapy is not a requirement of the study and is not considered part of the clinical trial.

[0439] Patients whose tumors test positive for FGFR2b by IHC and / or positive for FGFR2 gene amplification by ctDNA blood assay can consent to full study participation (sign the full study ICF) and enter the screening period. The time from signing the full study ICF to study enrollment will be considered the screening period (maximum 21 days). During the screening period, patients will undergo protocol-specified screening procedures to ensure they meet all eligibility criteria.

[0440] The Phase 3 portion of the study will be randomized, open-label, and will enroll 548 FGFR2-selected GC patients randomized 1:1 to receive anti-FGFR2-IIIb antibody in RD in combination with mFOLFOX6 versus mFOLFOX6 to evaluate the efficacy of the combination. Patients must receive their first dose of study treatment within 3 days of randomization. Treatment arms will consist of: Arm 1: anti-FGFR2-IIIb antibody administered in combination with mFOLFOX6 every 2 weeks, or -Arm 2: mFOLFOX6 administered every 2 weeks.

[0441] Discontinuation of any component of the study treatment (mFOLFOX6, a component of mFOLFOX6, or anti-FGFR2-IIIb antibody) for any reason other than disease progression does not mandate discontinuation of the other components. The exception is discontinuation of 5-FU for any reason, which requires discontinuation of oxaliplatin and leucovorin. Continuation of the mFOLFOX6 regimen may be provided as described above.

[0442] For the first three cycles of treatment, anti-FGFR2-IIIb antibody shall be administered on schedule (± 3 days), regardless of delays in mFOLFOX6 treatment. If mFOLFOX6 is delayed, anti-FGFR2-IIIb antibody may be delayed up to 7 days and synchronized with mFOLFOX6 administration after the first three cycles of anti-FGFR2-IIIb antibody. However, synchrony of anti-FGFR2-IIIb antibody and mFOLFOX6 administration is not a protocol requirement. If the patient is still unable to receive mFOLFOX6 after 7 days, IMP shall continue as monotherapy every 2 weeks (± 3 days).

[0443] Patients who discontinue all study treatment (anti-FGFR2-IIIb antibody and all components of mFOLFOX6) for any reason other than withdrawal of consent will have an EOT safety follow-up visit approximately 28 days after the last dose of any treatment component (oxaliplatin, leucovorin, 5-FU, or anti-FGFR2-IIIb antibody).

[0444] However, patients who discontinue study treatment (anti-FGFR2-IIIb antibody and / or mFOLFOX6) for reasons other than progression or withdrawal of consent will continue to undergo tumor evaluations according to the protocol schedule until radiological progression or initiation of additional anticancer therapy, at which point patients will undergo long-term follow-up for survival.

[0445] Long-term follow-up for survival will be completed approximately every 3 months (± 1 month) after the EOT visit, up to a maximum of 24 months after the last patient was enrolled in the study or until death, loss to follow-up, withdrawal of consent, or study withdrawal by the sponsor, whichever occurs first, by site visit, telephone, or using patient registries (in accordance with national and general data protection laws).

[0446] Phase 1 and Phase 3 Inclusion Criteria Patients enrolled in either Phase 1 or Phase 3 of the study must meet all of the following inclusion criteria: Unresectable, locally advanced or metastatic disease Understand and sign an Institutional Review Board (IRB) / Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) prior to any study-related evaluations. - Life expectancy of at least 3 months in the opinion of the investigator Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 -Age 18 or older at the time of signing the ICF Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test within 96 hours prior to treatment on Day 1 of Cycle 1 (women of childbearing potential only) Sexually active patients (women and men of childbearing potential) must be willing to use two effective methods of contraception, one of which must be a physical barrier method (condom, diaphragm, or cervical / vaginal cap), until 6 months after the last dose of anti-FGFR2-IIIb antibody. Other effective forms of contraception include: Permanent sterilization (hysterectomy and / or bilateral oophorectomy, or surgical bilateral tubal ligation, or vasectomy) at least 6 months prior to screening Women of childbearing potential who have been using stable oral contraceptive therapy or an intrauterine or implant device, or who have abstained from sexual activity as a lifestyle for at least 90 days prior to the study Adequate hematological and biological function within 96 hours of Day 1 of Cycle 1, as confirmed by the following laboratory values: Bone marrow function Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L Platelets ≥ 100 × 10 9 / L Hemoglobin ≥ 9g / dL Liver function Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3×ULN; <5×ULN if liver metastases present Bilirubin < 1.5 x ULN renal function Creatinine clearance calculated using the Cockroft Gault formula ≥ 50 mL / min Patients taking conventional anticoagulants must have been taking a stable dose of warfarin for 6 weeks prior to enrollment, with an international normalized ratio (INR) within the therapeutic range for their condition, or be taking a stable dose of low molecular weight heparin. Measurable or non-measurable disease Patients enrolled in Phase 1 of the study must also meet the following inclusion criteria: Histologically or cytologically confirmed GI malignancies in which mFOLFOX6 is considered an appropriate treatment (e.g., GC, colorectal cancer, pancreatic adenocarcinoma) Tumor tissue for retrospective determination of FGFR2b overexpression by IHC (if available) Patients must be candidates to receive at least two doses of mFOLFOX6 chemotherapy. Doses are as follows and subject to toxicity guidelines above: · Administration of mFOLFOX6 chemotherapy will begin 30 minutes after the end of anti-FGFR2-IIIb antibody infusion on Day 1 of Cycle 1 (Study Day 1) of each treatment cycle. mFOLFOX6 will be administered every 2 weeks as follows: Day 1: Oxaliplatin 85 mg / m 2 was administered IV over 120 minutes. Day 1: Leucovorin 400 mg / m 2 infused IV over 120 minutes. May be given simultaneously with oxaliplatin if Y-connector is used. Sequential administration if Y-connector is not available. Day 1: 5FU 400 mg / m2 over approximately 5 minutes, immediately after oxaliplatin and leucovorin 2 Bolus. Day 1: 5-FU 2400mg / m immediately after 5-FU bolus 2 as a continuous IV infusion over 46 hours. After the first dose, patients may undergo dose reduction, delay, or discontinuation based on toxicity per guidelines.

[0447] Patients enrolled in Phase 3 of the study must also meet the following inclusion criteria: Histologically documented adenocarcinoma of the stomach or gastroesophageal junction (defined as the proximal and distal 5 cm of the GEJ) Radiological imaging of the chest, abdomen, and pelvis (computed tomography (CT) preferred, magnetic resonance imaging (MRI) acceptable) performed within 28 days of C1D1 Tumor tissue with FGFR2b overexpression as determined by IHC testing performed at a central site and / or FGFR2 gene amplification as determined by a ctDNA blood-based assay performed at a central site Patients must be candidates for mFOLFOX6 chemotherapy No prior chemotherapy for metastatic or unresectable disease (excluding up to one dose of mFOLFOX6 administered while awaiting results of FGFR2 testing during the prescreening period) No prior platinum-based chemotherapy (unless stated in inclusion criterion #18) If the patient has received prior adjuvant or neoadjuvant therapy (chemotherapy and / or chemoradiotherapy), more than 6 months must have elapsed between the end of the adjuvant therapy and enrollment.

[0448] Phase 1 and Phase 3 Exclusion Criteria Patients enrolling in either Phase 1 or Phase 3 will be excluded if they meet any of the following criteria: Untreated or symptomatic central nervous system (CNS) metastases (CNS imaging is not required). Patients with asymptomatic CNS metastases are eligible as long as they have been clinically stable for at least 4 weeks and have not required interventions such as surgery, radiation, or any corticosteroid therapy to manage symptoms related to their CNS disease. Cardiac dysfunction or clinically significant cardiac disease, including any of the following: Unstable angina within 6 months prior to enrollment - Acute myocardial infarction within 6 months prior to enrollment New York Heart Association Class II to IV congestive heart failure Uncontrolled hypertension (defined as ≥ 160 / 90 despite optimal medical management) Uncontrolled cardiac arrhythmias requiring antiarrhythmic therapy other than beta-blockers or digoxin Active coronary artery disease QTcF≧480 Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or higher peripheral sensory neuropathy Active infection or any uncontrolled infection requiring systemic treatment within 14 days prior to enrollment Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) related disease, or known active or chronic hepatitis B or C History of interstitial lung disease (e.g., pneumonia or pulmonary fibrosis) Evidence or history of bleeding tendency or coagulation disorder Radiation therapy within 28 days of enrollment. Patients must have recovered from all acute radiation therapy-related toxicities. No use of radiopharmaceuticals (strontium, samarium) within 8 weeks of enrollment. Prior treatment with any selective inhibitor of the FGF-FGFR pathway (e.g., AZD4547, BGJ398, JNJ-42756493, BAY1179470) Ongoing adverse effects from prior systemic therapy greater than NCI CTCAE Grade 1 (excluding Grade 2 alopecia) Participation in another therapeutic clinical trial or receipt of any investigational drug within 28 days of enrollment in this clinical trial or during this clinical trial · Corneal defects, corneal ulcers, keratitis, keratoconus, history of corneal transplants, or other known corneal abnormalities that may increase the risk of developing a corneal ulcer Known positive HER2 (defined by a positive IHC test of 3+ or an IHC of 2+ and positive FISH) No major surgical procedures within 28 days prior to enrollment are permitted. Any procedures requiring local / epidural anesthesia must be completed at least 72 hours prior to enrollment. In all cases, patients must be sufficiently recovered and stable prior to treatment. Pregnant or breastfeeding women (unless the patient discontinues breastfeeding while receiving the study treatment and resumes it 6 months after discontinuation of the study); women of childbearing potential should not consider becoming pregnant during the study The presence of any serious or unstable concomitant systemic disorder incompatible with clinical trials (e.g., substance abuse, psychiatric disorders, or uncontrolled intercurrent illnesses, e.g., arterial thrombosis, and symptomatic pulmonary embolism). The presence of any other condition that may increase the risks associated with participation in the study or that may interfere with the interpretation of the study results and that, in the opinion of the investigator, makes the patient unsuitable for participation in the study. Known allergy or hypersensitivity to anti-FGFR2-IIIb antibody preparations that contain polysorbate, or to any component of platinum-containing drugs, 5-FU, or leucovorin. History of previous malignancies, except for: Curatively treated non-melanoma skin malignancies ·Cervical cancer in situ -Definitively treated ductal or lobular carcinoma in situ of the breast and not currently receiving systemic therapy Definitively treated solid tumors with no evidence of recurrence for more than 5 years.

[0449] No waiver of these inclusion or exclusion criteria will be permitted.

[0450] Test treatment: In phase 1, the anti-FGFR2-IIIb antibody will be provided in a sterile vial for dilution into an intravenous (IV) bag to be administered at the study site over approximately 30 minutes (±10 minutes) every 2 weeks (±3 days) prior to administration of mFOLFOX6 chemotherapy. Only patients treated in cohort 2 will receive one additional dose of the anti-FGFR2-IIIb antibody on day 8 of cycle 1. From cycle 2 onwards, all patients will receive the anti-FGFR2-IIIb antibody on day 1 of each cycle every 2 weeks until investigator-assessed radiological or clinical progression, unacceptable toxicity, or the patient meets any other protocol-specified withdrawal criteria. The IV administration set for FP144 infusion must be equipped with a 0.22 μm inline filter or a 0.22 μm syringe filter.

[0451] In Phase 3, the anti-FGFR2-IIIb antibody will be prepared and administered in a manner similar to that of the anti-FGFR2-IIIb antibody in Phase 1. Administration of the anti-FGFR2-IIIb antibody will continue until investigator-assessed radiological or clinical progression, unacceptable toxicity, or the patient meets any other protocol-specified withdrawal criteria.

[0452] Oxaliplatin, 5-FU, and leucovorin (mFOLFOX6) will be administered every 2 weeks (± 7 days) at each center (as above).

[0453] Pharmacokinetic evaluation Blood samples will be collected from all patients enrolled in Phase 1 and Phase 3 at designated time points to measure serum levels of anti-FGFR2-IIIb.

[0454] PK parameters will be estimated using non-compartmental analysis, although compartmental analysis may be used where appropriate. Serum concentration-time data from this clinical trial will be pooled with data from other studies for integrated population PK analysis and evaluation of exposure-response relationships.

[0455] Immunogenicity assessment Blood samples for anti-(anti-FGFR2-IIIb antibody) antibodies will be collected for all patients enrolled in Phase 1 and Phase 3. Immunogenicity, defined as the immune response to anti-FGFR2-IIIb antibody, will be assessed by measuring total antibodies to anti-FGFR2-IIIb antibody from all patients. Immunogenicity testing consists of screening, confirmation, and titration. Further characterization of confirmed antibody responses to anti-FGFR2-IIIb antibody may be considered.

[0456] Efficacy evaluation Tumor response assessment during Phase 3 will be performed by the investigator per RECIST v.1.1 guidelines. Efficacy measures will include tumor assessment consisting of clinical examination and appropriate imaging techniques, preferably CT scans of the chest, abdomen and pelvis with appropriate slice thickness per RECIST v.1.1 guidelines (MRI is also acceptable). Scans will be performed during the screening period (within 21 days of Cycle 1 Day 1). Scans performed prior to screening as part of standard of care are acceptable provided they are performed 28 days or less prior to enrollment. Scans will be performed every 8 weeks (± 7 days) from Cycle 1 Day 1.

[0457] Safety assessment Safety measures in both Phase 1 and Phase 3 included AEs, hematology, clinical chemistry, urinalysis, vital signs, weight, concomitant medications / treatments, ECOG performance status, subject physical examination, ECG, and ophthalmologic examination.

[0458] Pharmacodynamic evaluation Phase I PD assessments will be collected at specified time points. When available, tumor tissue submitted for assessment of FGFR2 status will be analyzed retrospectively for FGFR2b overexpression by use of IHC. Blood samples submitted for assessment of FGFR2 status will be collected prior to the first dose of study treatment and will be analyzed retrospectively for FGFR2 gene amplification using a ctDNA blood assay. Blood samples for exploratory biomarker analysis of the FGFR pathway will be collected longitudinally.

[0459] Phase 3 Tumor tissue will be submitted to assess FGFR2 status and will be prospectively analyzed for FGFR2b overexpression by use of IHC. Blood samples will be submitted to assess FGFR2 status and will be prospectively analyzed for FGFR2 gene amplification by use of a ctDNA blood assay. Positive results from either tissue or blood (but not both) must be obtained prior to enrollment.

[0460] The planned total enrollment for this study is up to approximately 569 patients. Approximately 9-21 patients evaluable for any dose-limiting toxicities will be enrolled in Phase 1. For Phase 3, approximately 548 patients with FGFR2-selected GC will be enrolled and randomized 1:1 to receive anti-FGFR2-IIIb antibody in combination with mFOLFOX6 or mFOLFOX6 alone to evaluate efficacy and tolerability. Eligible patients will be stratified by geographic region (US and Europe vs. Japan vs. rest of Asia [including China] vs. rest of the world), prior treatment status (de novo vs. adjuvant / neoadjuvant), and receipt of a single dose of mFOLFOX6 prior to enrollment (yes or no).

[0461] In phase 1, all analyses will be descriptive and presented by dose group and overall, as appropriate. Descriptive statistics will include number of observations, mean, standard deviation, median, range, and interquartile range for continuous variables, and number and percentage for categorical variables, with 95% confidence intervals presented as appropriate. In addition, the occurrence of TEAEs leading to dose reduction or discontinuation will be tabulated and summarized. In phase 3, the primary efficacy analysis will be a comparison of OS between patients treated with anti-FGFR2-IIIb antibody in combination with mFOLFOX6 and patients treated with mFOLFOX6 alone.

[0462] The primary endpoint, OS, is defined as the time from randomization to death from any cause. Secondary efficacy endpoints include PFS and ORR, where PFS is defined as the time from randomization to the date of radiological or clinical progression based on investigator assessment (per RECIST v.1.1) or death from any cause, whichever occurs first, while ORR is defined as the proportion of patients with baseline measurable disease and a partial or complete response as determined by the investigator per RECIST v.1.1.

[0463] This phase 3 study is designed to evaluate the hazard ratio (HR) for overall survival (OS) of the combination of anti-FGFR2-IIIb antibody and mFOLFOX6 compared to mFOLFOX6 alone. 374 primary death events provide 80% power to detect an OS HR of 0.75 using Cox regression analysis (one-sided) with a false positive error rate of 2.5%. Assuming an exponential distribution of OS, this corresponds to an approximately 33% increase in median survival from 10 months to 13.3 months. Statistical significance for OS occurred at an estimated HR = 0.815, which corresponds to an approximately 22.6% increase in median survival from 10 months to 12.26 months.

[0464] To achieve the target number of primary events, approximately 548 patients will be randomized (1:1) during an enrollment period of 44 months, with approximately 24 months of further follow-up.

[0465] The hypothesis of OS will be tested first. There are two analyses for OS: an interim analysis and a primary analysis, both of which are event-based analyses.

[0466] Two interim analyses of OS are planned, one after 50% of OS events (approximately 187 events) and one after 75% of OS events (approximately 281 events). To allow flexibility in the number and timing of these interim analyses, O'Brien-Fleming monitoring boundaries as implemented by Lan-DeMets will be used to maintain a 2.5% false positive error rate.

[0467] The primary analysis of OS will be performed using the intention-to-treat (ITT) population and will be performed using a stratified log-rank test. The stratification factors will be the same as those used to stratify the randomization schedule documented in the Interactive Voice Response / Web Registration System (IXRS).

[0468] Median OS and associated 95% confidence intervals for each treatment group will be estimated using the Kaplan-Meier method. Hazard ratios (HR = λ 抗-FGFR2-IIIB抗体+mFOLFOX6 / λ mFOLFOX6 ) are estimated using Cox regression models with treatment group as the only main effect, stratified by the same stratification factors used in the stratified log-rank test. Unstratified HRs are also shown.

[0469] The analyses of the secondary endpoints PFS and ORR will be tested hierarchically if the analysis of the primary endpoint OS is statistically significant. Formal hypotheses regarding the impact on PFS and ORR will be tested hierarchically at the 0.05 level. PFS will be tested first and, if significant, ORR will be tested next. The probability of family-wise type I error in the testing of the primary and secondary endpoints will be controlled by adopting this gatekeeping test procedure (0.05 level).

[0470] If the test for OS is significant, progression-free survival (PFS) will be tested using a stratified log-rank test at the 0.05 level based on all PFS events observed at the time the OS analysis was performed. The primary analysis of PFS will be performed using the stratified log-rank test (two-sided). The stratification factors will be the same as those used to stratify the randomization schedule documented in the Interactive Voice Response / Web Registration System (IXRS).

[0471] Median PFS and associated 95% confidence intervals for each treatment group will be estimated using the Kaplan-Meier method. HRs will be estimated using Cox regression models with treatment group as the only main effect, stratified by the same stratification factors used in the stratified log-rank test. Unstratified HRs are also shown. PFS analyses will be performed on the ITT population.

[0472] If the test for PFS is significant, an analysis of ORR will be performed among patients with measurable disease at baseline. In the analysis of ORR, patients without adequate post-baseline tumor evaluation will be counted as non-responders. Formal hypothesis testing of ORR will be performed using a stratified Cochran-Mantel-Haenszel test (two-sided, 0.05 level). Stratification factors will be the same as those used to stratify the randomization schedule documented in the IXRS.

[0473] Safety Analysis: All AEs will be coded using the Medical Dictionary for Clinical Trials (MedDRA). Investigators ...

Claims

1. 1. A medicament for use in a method for treating gastric or gastroesophageal cancer in a subject, the medicament comprising: an afucosylated anti-fibroblast growth factor receptor 2 IIIb (anti-FGFR2-IIIb) antibody, 50-100 mg / m ２ of oxaliplatin, 100-400 mg / m ２ of leucovorin, and / or 100-400 mg / m ２ and 5-fluorouracil (5-FU), the method comprising administering to the subject therapeutically effective amounts of the anti-FGFR2-IIIb antibody and the oxaliplatin, leucovorin, and 5-fluorouracil (5-FU); (a) the anti-FGFR2-IIIb antibody is administered at a dose of 6-15 mg / kg once every 13-15 days, the method further comprising administering an intermediate dose of the anti-FGFR2-IIIb antibody 7 days after the first administration of the anti-FGFR2-IIIb antibody, the intermediate dose being 7.5 mg / kg; (b) the anti-FGFR2-IIIb antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 4, which contains a total of 1 to 10 amino acid substitutions in the sequence, and a light chain variable region having the amino acid sequence of SEQ ID NO: 5, or a heavy chain variable region having the amino acid sequence of SEQ ID NO: 4 and a light chain variable region having the amino acid sequence of SEQ ID NO: 5, which contains a total of 1 to 10 amino acid substitutions in the sequence, and the anti-FGFR2b-IIIb antibody retains the ability of a reference antibody comprising the heavy chain variable region of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 5 to selectively bind to FGFR2-IIIb but not to FGFR2-IIIc; The drug.

2. The drug described in claim 1, wherein the anti-FGFR2-IIIb antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 4 containing a total of 1 to 10 amino acid substitutions in the sequence, and a light chain variable region having the amino acid sequence of SEQ ID NO:

5.

3. The agent described in claim 1, wherein the anti-FGFR2-IIIb antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 4 and a light chain variable region having the amino acid sequence of SEQ ID NO: 5 containing a total of 1 to 10 amino acid substitutions in the sequence.

4. the anti-FGFR2-IIIb antibody lacks fucose at position Asn297; The drug according to any one of claims 1 to 3.

5. The method according to any one of claims 1 to 3, wherein the gastric cancer is locally advanced, unresectable or metastatic.

6. The heavy chain variable region of the afucosylated anti-FGFR2-IIIb antibody comprises: (i) a heavy chain hypervariable region 1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO:6; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8 wherein the light chain variable region comprises: (iv) a light chain hypervariable region 1 (HVR-L1) comprising the amino acid sequence of SEQ ID NO: 9; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11 The drug according to any one of claims 1 to 3, comprising:

7. The method of any one of claims 1 to 6, wherein the anti-FGFR2-IIIb antibody is administered at a dose of 15 mg / kg once every 14 days.

8. The method of claim 7, wherein the anti-FGFR2-IIIb antibody and the oxaliplatin, leucovorin, and 5-FU are administered simultaneously.

9. The method of claim 7, wherein the anti-FGFR2-IIIb antibody and the oxaliplatin, leucovorin, and 5-FU are administered sequentially.

10. The method of claim 7, wherein the oxaliplatin, leucovorin, and 5-FU are administered prior to administration of the anti-FGFR2-IIIb antibody.

11. The method of claim 10, wherein the two administrations of oxaliplatin, leucovorin, and 5-FU are administered prior to administration of the anti-FGFR2-IIIb antibody.

12. The method of claim 7, wherein the anti-FGFR2-IIIb antibody is administered on the same day as the oxaliplatin, leucovorin, and 5-FU or prior to administration of the oxaliplatin, leucovorin, and 5-FU.

13. The method comprises administering to a patient a ２ of oxaliplatin, 400 mg / m ２ of leucovorin, and 400 mg / m ２ The medicament according to any one of claims 1 to 3, comprising administration of 5-fluorouracil (5-FU) by intravenous (IV) infusion or IV bolus.

14. The method comprises administering to a patient a ２ of oxaliplatin, 400 mg / m ２ of leucovorin, and 400 mg / m ２ of 5-fluorouracil (5-FU) administered by intravenous (IV) infusion or IV bolus at 2,400 mg / m for 44-48 hours. ２ The method according to any one of claims 1 to 3, comprising administering by IV infusion of 5-FU of

15. 4. The method of claim 1, wherein the oxaliplatin, leucovorin, and 5-FU are administered once every 10-21 days, once every 10-15 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 14 days, once every 15 days, once every 16 days, once every 17 days, once every 18 days, once every 19 days, once every 20 days, or once every 21 days.

16. The method of claim 15, wherein the oxaliplatin, leucovorin, and 5-FU are administered once every 14 days.

17. The method comprises administering a dose of 85 mg / m2 once every 14 days. ２ of oxaliplatin, 400 mg / m ２ of leucovorin, and 400 mg / m ２ of 5-fluorouracil (5-FU) administered by intravenous (IV) infusion or IV bolus at 2,400 mg / m for 44-48 hours. ２ The method of claim 15, comprising administering 5-FU by IV infusion.

18. 18. The method of claim 1, wherein: (a) the anti-FGFR2-IIIb antibody is administered intravenously at a dose of 15 mg / kg; (b) the anti-FGFR2-IIIb antibody, oxaliplatin, leucovorin, and 5-FU are administered on the same day every 14 days; and (c) a single dose of 7.5 mg / kg of anti-FGFR2-IIIb antibody is administered 7 days after a first dose of 15 mg / kg of anti-FGFR2-IIIb antibody and 7 days before a second dose of 15 mg / kg of anti-FGFR2-IIIb antibody.

19. The method according to any one of claims 1 to 3, wherein the gastric or gastroesophageal cancer is predetermined or determined to overexpress FGFR2-IIIb and / or the gastric or gastroesophageal cancer is predetermined or determined to have FGFR2 gene amplification.

20. The method according to claim 19, wherein the overexpression of FGFR2-IIIb is determined by immunohistochemical staining (IHC).

21. The agent of claim 20, wherein the overexpression is predetermined or determined by an IHC signal of +2 or 3+ in at least 10%, 20%, 30%, 40%, or 50% of the tumor cells.

22. 20. The method of claim 19, wherein the FGFR2 gene amplification is predetermined or determined by obtaining a ratio of FGFR2 to chromosome 10 centromere (CEN10) using fluorescent in situ hybridization (FISH), wherein the FGFR2 gene is considered to be amplified when the FGFR2 / CEN10 ratio determined by FISH is 2 or greater.

23. The agent of claim 22, wherein the FGFR2 amplification was previously detected or is to be detected in circulating tumor DNA (ctDNA).

24. 23. Use of an anti-FGFR2-IIIb antibody, oxaliplatin, leucovorin, and / or 5-FU for the preparation of a medicament according to any one of claims 1 to 3, 7 to 12, 16, 17, or 20 to 22 for treating gastric or gastroesophageal cancer in a patient according to a method comprising administering to the patient therapeutically effective amounts of an anti-FGFR2-IIIb antibody, oxaliplatin, leucovorin, and 5-FU.

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