Cancer treatment with an antibody drug conjugate

Abstract

The present invention relates to a method of treating a tumor in a human subject, the method comprising administering to the human subject an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target, and further administering G-CSF to the human subject after the first administration of said ADC if the human subject fulfils specific baseline characteristics. Furthermore, the invention relates to setting a maximum dose per administration for the ADC to avoid toxicity.

Description

CANCER TREATMENT WITH AN ANTIBODY DRUG CONJUGATETECHNICAL FIELD

[0001] The present disclosure generally relates to the treatment of tumors (cancer) in human subjects using topoisomerase 1 inhibitors, and in particular, to the prevention of neutropenia and / or its associated complications in particular patient groups upon treatment with antibody-drug conjugates that comprise a topoisomerase 1 inhibitor conjugated to tumor target binding antibody.BACKGROUND

[0002] The antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S; previously also referred to as PRO 1184) is developed to target FOLR1 and includes a FOLR1 antibody and drug units, each of which comprises the topoisomerase 1 inhibitor exatecan connected to the antibody through a hydrophilic linker. Rina-S has been shown to induce cytotoxicity in cancer cells and demonstrate antitumor activities, both in vitro and in vivo. However, ADCs that include a topoisomerase 1 inhibitor as the drug, such as the ADC Rina-S, may cause adverse events, including cytopenias, such as neutropenias, anemia, leukopenias, and thrombocytopenias, G-CSF has been used reactively to treat neutropenia developed after multiple cycles of Rina-S administration in clinical trials. There is still a need for effective methods of administering topoisomerase 1 inhibitors, in particular ADCs comprising a topoisomerase 1 inhibitor, such as the ADC Rina-S, which methods reduce the frequency and / or severity of certain of such adverse events, in particular neutropenia.SUMMARY

[0003] In one aspect, the present invention provides a method of treating a tumor in a human subject, the method comprising administering an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said ADC. or. preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5,or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0004] In preferred embodiments, the tumor target is FOLR1.

[0005] In preferred embodiments, the topoisomerase 1 inhibitor is exatecan. In certain preferred embodiments the ADC comprises a linker-drug PA038 as set forth in structure 1.

[0006] In preferred embodiments the ADC is rinatabart sesutecan (Rina-S).

[0007] In alternative aspects, the invention also provides an ADC as defined herein for use in treatment of cancer, according to various aspects of the methods of treatment according to the invention. In alternative aspects, the invention also provides G-CSF for use in treatment of cancer, according to various aspects of the methods of treatment according to the invention. In alternative aspects, the invention also provides the combination of G-CSF and an ADC as defined herein for use in treatment of cancer, according to various aspects of the methods of treatment according to the invention. In other alternative aspects, the invention also provides an ADC as defined herein for manufacturing a medicament for the treatment of cancer, according to various aspects of the methods of treatment according to the invention. In further aspects, the invention further provides an agent for the treatment of cancer comprising an ADC as defined herein. Where a method of treatment is set out herein, the invention also provides the corresponding product for use in the method, as well as use of the product for the manufacture of a medicament for the stated method and vice versa. In further aspects, the invention provides a method for reducing the risk of severe neutropenia and / or its associated complications in a human subject that is treated with an ADC as defined herein.

[0008] In a further aspect, the invention relates to a method of treating a tumor in a human subject, the method comprising administering Rina-S to a human subject that has the tumor, wherein the Rina-S is administered at a dosage of 100 mg / m2or 120 mg / m2, with a maximal total dose per administration of 250 mg.

[0009] In certain aspects, the invention relates to a method of treating a tumor in a human subject, the method comprising administering a dosage of 250 mg Rina-S to the human subject, wherein the subject has a body surface area of at least 2.084 m2.

[0010] Additional features will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following and the accompanying drawings or may be learned by production or operation of the examples. The features of the present disclosure may be realized and attained by practice or use of various aspects of the methodologies, instrumentalities, and combinations set forth in the detailed examples discussed below.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The present disclosure is further described in terms of non-limiting exemplary embodiments, some of which are described in detail with reference to the drawings, wherein:

[0012] FIG. 1 is a graph illustrating the study 1 design for the PRO 1184-001 drug dosage schedule.

[0013] FIG. 2 is a graph illustrating the change from baseline in target lesion tumor burden.

[0014] FIG. 3 is a graph illustrating the percentage change in tumor size over time for each dose level.

[0015] FIG. 4 is a graph illustrating the reduction in CA-125 (cancer antigen 125) levels per subject.

[0016] FIG. 5 is a graph illustrating treatment emergent adverse events (TEAEs) in the Rina-S 100 mg / m2and Rina-S 120 mg / m2groups.

[0017] FIG. 6 shows the odds ratio of key baseline characteristics and dose on grade 3+ neutropenia based on laboratory results. Dose: dose of Rina-S. eGFR at Baseline: <60 mL / min / 1.73 m2vs >60 mL / min / 1.73 m2. Neutrophil at Baseline : <3,000 cells / pL vs >3.000 cells / pL. Platelet at Baseline: platelet count <200,000 / pL vs >200,000 / pL.

[0018] FIG. 7 is a graph illustrating best changes in target lesion (best change from baseline in sum of tumor diameter) for ovarian cancer patients and endometrial cancer patients.

[0019] FIG. 8 is a graph illustrating best changes in target lesion (best change from baseline in sum of tumor diameter) for ovarian cancer patients treated with Rina 100 mg / m2or Rina-S 120 mg / m2.

[0020] FIG. 9 is a graph illustrating treatment responses for ovarian cancer patients treated with Rina 100 mg / m2or Rina-S 120 mg / m2over time. One patient in the 120 mg / m2cohort with prior mirvetuximab soravtansine was not response-evaluable. Reasons for discontinuation included alanine aminotransferase increased (n=l; not related to treatment), neutrophil count decreased (n=l; related to treatment), small intestinal perforation (n=l; not related to treatment), and rectal hemorrhage (n=l; not related to treatment). CR: complete response, MIRV: mirvetuximab soravtansine, OC: ovarian cancer, PD: progressive disease. PR: partial response, Rina-S: rinatabart sesutecan, SD: stable disease, tx: treatment.

[0021] FIG. 10 is a graph illustrating best changes in target lesion (best change from baseline in sum of tumor diameter) for ovarian cancer patients treated with Rina-S 100 mg / m2or Rina-S 120 mg / m2by FRa PS2+ status. FRot: folate receptor, OC: ovarian cancer, PS: positive staining, SoD: sum of diameter, Rina-S: rinatabart sesutecan.DETAILED DESCRIPTION

[0022] The following description is presented to enable any person skilled in the art to make and use the present disclosure and is provided in the context of a particular application and its requirements. Various modifications to the disclosed embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the present disclosure. Thus, the present disclosure is not limited to the embodiments shown but is to be accorded the widest scope consistent with the claims.

[0023] The terminology used herein is to describe particular example embodiments only and is not intended to be limiting. As used herein, the singular forms “a,” “an,” and “the” may be intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises,” “comprising,” “includes,” and / or “including” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps,operations, elements, components, and / or groups thereof.

[0024] For convenience, certain terms in the specification, examples and claims are defined here. Unless stated otherwise, or implicit from context, the following terms and phrases have the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0025] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". Where an embodiment is set out using “comprises”, “comprising” or similar wording, the invention also provides embodiments “consisting essentially of’ what is set out. The invention also provides embodiments “consisting of’ what is set out.

[0026] The term “about”, may, for instance, allow up to 10% variation of what is set out. In some embodiments, it may allow for up to 5% variation. In some embodiments, up to 2% variation may be allowed. In some embodiments up to 1% variation may be allowed. In some embodiments, where the term “about” is used, also provided is an embodiment with exactly what is set out.

[0027] As used herein, the terms "protein" and "polypeptide" are used interchangeably herein to designate a series of amino acid residues each connected to each other by peptide bonds between the alpha-amino and carboxyl groups of adjacent residues. The terms "protein" and "polypeptide" also refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function. "Protein" and "polypeptide" are often used in reference to relatively large polypeptides, whereas the term "peptide" is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein when referring to an encoded gene product and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants,fragments, and analogs of the foregoing.

[0028] The term “tumor target” when used herein, refers to a target antigen, typically a target protein, to which an antibody can bind. Tumor targets are preferably located on the surface of a cell. The term “tumor target” when used herein includes both targets that are expressed exclusively on tumor cells as well as targets that are expressed on both tumor cells and healthy cells, but have higher expression levels on tumor cells than on healthy cells. For example, the expression on a tumor cell may be at a level that is at least 10%, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 150%, at least 200%, at least 300%, at least 400%, at least 500%, at least 750%, at least 1000%, at least 2000% or at least 5000% greater than the expression level of the antigen on non-tumor cells, such as non-tumor cells of the same tissue. Such tumor targets are generally known to the skilled person and several examples are known to be used as targets for ADCs. An “antibody that binds a tumor target” as used herein thus typically preferentially binds tumor cells as compared to healthy cells. Tumor targets include, but are not limited to, 5T4, A33, activin receptor, adrenomedullin receptors, AFP, AGS-5, ALK, annexin, AXL, B7-H3, B7-H4, BAGE proteins, BCMA, Bombesin, C33 antigen, C4.4a, C-type lectin-like(-receptor), CA19.9. CA-125. CADM1, CAIX, CanAg, CAR, carbonic anhydrase, Caveolin-1, CCK.2R, CD4, CD10, CD19, CD123, CD20, CD21, CD22, CD25, CD27, CD30. CD33. CD37. CD38. CD44, CD44v9, CD51, CD57, CD70, CD73, CD74, CD79a, CD79b, CD80, CDH6, CEA. CEACAM5, c-kit, CLDN18.2, chemokine receptors (i.e., CXCR4, CXCR5), c-Met, Cripto-1, DEC-205, Derlin-1, Desmoglein-3, Dlk-1 , DLL3, DS6, E-cadherin, E-Selectin, EAG-1 , ED-B, EpCAM, EGFR, EGFRvlll, emmprin, endothelin receptor, ErbB2 / Her2, ErbB3, ErbB4, ETV6-AML, Ephrin type-A receptor, Epiregulin, ETA, FAP-alpha, FcyR's, FGFR, FOLR1, Frizzled, Fyn3, Galectin, Ganglioside, GCC, GD2, GD3, GloboH, Glypican-3, GLUT3, GPNMB, G-protein coupled receptors (i.e., GPR49), gplOO, HER2, HER3, Hsp, HLA / B-raf, HLA-DR, HLA / k-ras, HLA MAG E-A3, HMW-MAA, hTERT, ICAM-3, IGF-R, IL-13- R, LI CAM, laminin receptor, LIV1, LMP2, LRP5, LRP6, MAGE proteins, MART-1, melanotransferrin, mesothelin, metalloproteinase, ML-IAP, MUC1. MUC18, Mud, Mud 6 (CA-125), MU Ml, N-cadherin, NAU. NaPi2b, NCAM-1, Nectin4, Notch, NP-55, NRP1,NY-BR1, NY-BR62, NY- BR85, NY-ES01, PD-1, PD-L1, PLACE PRLR, PRAME, prominin-1, PSMA (FOLH 1), PTK7. RON, ROR1, SEZ6, SLC44A4, SLITRK6, Steap-1, Steap-2. surviving, syndecan, TAG-72, Tissue Factor, TGF- beta, TMPRSS2, TMEFF2, TNFR, Tn, TROP2, TRP-1, TRP-2,TWEAKR, tyrosinase, uroplakin-3 and VEGFR.

[0029] FOLR1, or folate receptor alpha, is a cell surface protein that binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. It is also referred to as FRa. adult folate-binding protein, FBP, Folate receptor 1, Folate receptor-adult, KB cells FBP, and ovarian tumor-associated antigen M0vl8. Human FOLR1 polypeptides include, but are not limited to, those having the amino acid sequence set forth in UniProt identifier P15328-1; this sequence is incorporated by reference herein.

[0030] An antibody drug conjugate (ADC) comprises an antibody conjugated to a drug. The antibody and drug may be conjugated via any suitable means. It may be that the antibody and drug are conjugated via a linker. Alternatively, the antibody and drug may be conjugated directly to each other. The ADCs discussed herein comprise an anti-cancer drug as the drug portion of the ADC, and in particular the anti-cancer ding used in aspects of the invention is a topoisomerase 1 inhibitor.

[0031] G-CSF, or granulocyte colony- stimulating factor, also known as colony-stimulating factor 3. is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells. When used herein, the term “G-CSF” includes human G-CSF as well as modified forms thereof and non-human homologues thereof. Modifications may include modifications to increase serum half-life, such as pegylation. Human G-CSF polypeptides include, but are not limited to, those having the amino acid sequence set forth in UniProt identifier P09919; this sequence is incorporated by reference herein.

[0032] As described above, in one aspect, the invention relates to a method of treating a tumor in a human subject, the method comprising administering an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g.2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0033] Accordingly,• in some embodiments, the absolute neutrophil count (ANC) is < 3,000 cells / pL,• in some embodiments, the absolute neutrophil count (ANC) is < 3,000 cells / pL and the platelet count is < 200,000 / pL,

[0034] in some embodiments, the absolute neutrophil count (ANC) is < 3,000 cells / pL and the estimated glomerular filtration rate (eGFR) is < 60 mL / min / 1.73 m2,

[0035] in some embodiments, the absolute neutrophil count (ANC) is < 3,000 cells / pL, the platelet count is < 200,000 / pL, and the estimated glomerular filtration rate (eGFR) is < 60 mL / min / 1.73 m2,• in some embodiments, the platelet count is < 200,000 / pL,

[0036] in some embodiments, the platelet count is < 200,000 / pL and the estimated glomerular filtration rate (eGFR) is < 60 mL / min / 1.73 m2,

[0037] in some embodiments, the estimated glomerular filtration rate (eGFR) is < 60 mL / min / 1.73 m2.

[0038] When used herein, the term “baseline characteristics” has its usual meaning in the art and refers to characteristics prior to commencing the treatment of the subject, as measured for example in a sample from the subject, such as a blood, plasma, or serum sample. The baseline characteristics are typically determined within one month, e.g. within 2 weeks, preferably within one week, e.g. 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day before administering the ADC to the subject.

[0039] Methods for the determination of absolute neutrophil count, platelet count, and the estimated glomerular filtration rate (eGFR) are well-known in the art. The eGFR may, for example, be calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 method, for exampleas described in Levey et al. (2009) Ann Intern Med 2009; 150:604-12. http: / / dx.doi.org / 10.7326 / 0003-4819-150-9-200905050-00006.

[0040] In a further aspect, the invention relates to an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target for use in the treatment of a tumor, wherein the use comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3.000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0041] In a further aspect, the invention relates to G-CSF for use in the treatment of a tumor, wherein the use comprises administering an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0042] In a further aspect, the invention relates to a combination of an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target and G-CSF for use inthe treatment of a tumor, wherein the use comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0043] In a further aspect, the invention relates to the use of an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target in the manufacture of a medicament for the treatment of a tumor, wherein the treatment comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0044] In a further aspect, the invention relates to a method for reducing the risk of severe neutropenia and / or its associated complications in a human subject that is treated with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target, the method comprising administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days. e.g. 2, 3, 4, 5. or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baselinecharacteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0045] In a further aspect, the invention relates to a method of treating a tumor in a human subject, the method comprisinga) identifying a human subject eligible for treatment with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target, wherein said human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3.000 cells / pL. and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.b) administering a first dose of said ADC to the human subject, and further administering G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days. e.g. 2, 3, 4, 5. or 6 days, after the first administration of said ADC to the human subject.

[0046] In a further aspect, the invention relates to a method of treating a tumor in a human subject, the method comprisinga) selecting a human subject eligible for treatment with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target, wherein said human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2,b) administering a first dose of said ADC to the human subject, and further administering G-CSF tothe human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days. e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject.

[0047] Throughout this specification, a number of specific embodiments of the invention are described. Each of these embodiments may be an embodiment of each of the aspects mentioned herein above. Thus, where a method of treatment is set out herein, the invention also provides the corresponding product for use in the method, as well as use of the product for the manufacture of a medicament for the stated method and vice versa.

[0048] In some embodiments of the invention, the baseline characteristics of the subject include: (i) an ANC higher than 1,500 cells / pL, and / or(ii) a platelet count higher than 100,000 / pL, and / or(iii) an estimated glomerular filtration rate (eGFR) higher than 45 mL / min / 1.73 m2.

[0049] In some embodiments of the invention, the baseline characteristics are:(i) absolute neutrophil count (ANC) between 1,500 cells / pL and 3,000 cells / pL, and / or(ii) platelet count between 100,000 / pL and 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) between 45 mL / min / 1.73 m2and 60 mL / min / 1.73 m2.

[0050] In some embodiments, the baseline characteristics are:(i) absolute neutrophil count (ANC) between 1,500 cells / pL and 2,250 cells / pL, and / or(ii) platelet count between 100,000 / pLand 150,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) between 45 mL / min / 1.73 m2and 52 mL / min / 1.73 m2.

[0051] In some embodiments, the baseline characteristics are:(i) absolute neutrophil count (ANC) between 2,250 cells / pL and 3,000 cells / pL, and / or(ii) platelet count between 150,000 / pL and 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) between 52 mL / min / 1.73 m2and 60 mL / min / 1.73 m2.

[0052] In some embodiments, the human subject has no history of neutropenia-associatedcomplications in prior treatment regimens, such as prior chemotherapy regimens or prior ADC regimens. In some embodiments, the human subject would not otherwise have been eligible for prophylactic use of G-CSF according to national or local clinical practice guidelines (e.g., ASCO Guidelines (Smith et al. (2015) J Clin Oncol 33:3199-3212); NCCN Guidelines (NCCN White Blood Cell Factors Version 1.2005 ll-Oct-2024 https: / / www.nccn.org / professionals / physician_gls / pdf / growthfactors.pdf) and / or ESMO Guidelines (Crawford, J. et al. Annals of Oncology, Volume 21, v248 - v251. https: / / www.annalsofoncology.org / article / S0923-7534(19)39643-7 / fulltext), but now is eligible according to the present invention in view of the baseline characteristics identified herein.

[0053] The term “first administration” when used herein refers to the first ADC administration in an ADC treatment regimen. In preferred embodiments, this is the first time ever that the subject receives the ADC, e.g. during the first treatment with the ADC in a first cycle of a treatment that requires multiple cycles of treatment with the ADC.

[0054] While Rina-S is typically dosed based on body surface area, it was found that this could result in risks of toxicity and / or adverse effects in patients (especially patients with a high body surface area) that would receive high total amount of Rina-S per administration and thus a high exposure of drug (ac-exatecan and u-exatecan), and further aspects of the invention relate to reducing these risks by ensuring to not exceed a maximum dose of Rina-S per administration to patients. The maximum dose was determined to be 250 mg Rina-S per administration.

[0055] Accordingly, in certain aspects, the invention relates to a method of treating a tumor in a human subject, the method comprising administering Rina-S to a human subject that has the tumor, wherein the Rina-S is administered at a dosage of 100 mg / m2or 120 mg / m2, with a maximal total dose per administration of 250 mg.

[0056] In one aspect, the invention relates to a method of treating a tumor in a human subject, the method comprising administering a dosage of 250 mg Rina-S to the human subject, wherein the subject has a body surface area of at least 2.084 m2, such as a body surface area of at least 2.10 m2, atleast 2.15 m2, at least 2.20 m2, or at least 2.25 m2, for example a body surface area of at least 2.5 m2. In certain embodiments, the method comprises administering a dosage of 250 mg Rina-S to a human subject that has a body surface area of at least 2.084 m2, such as a body surface area of at least 2.10 m2, at least 2.15 m2, at least 2.20 m2, or at least 2.25 m2, and that would otherwise have been treated with a dose of 120 mg / m2which would have resulted in a dosage of more than 250 mg Rina-S per administration. In certain embodiments thereof, said human subject has ovarian cancer. In alternative embodiments, the method comprises administering a dosage of 250 mg Rina-S to a human subject that has a body surface area of at least 2.51 m2, such as a body surface area of at least 2.6 m2, at least 2.75 m2, or at least 3 m2, and that would otherwise have been treated with a dose of 100 mg / m2which would have resulted in a dosage of more than 250 mg Rina-S per administration. In certain embodiments thereof, said human subject has endometrial cancer. In certain embodiments of this aspect, the body surface area of the human subject is not higher than 4.1 m2, i.e. the human subject has a body surface area from 2.084 m2to 4.1 m2.

[0057] In further aspects, the invention relates reducing the risk of severe thrombocytopenia during ADC treatment by treating the patient with platelets.

[0058] Accordingly, in a further aspect, the invention relates to a method of treating a tumor in a human subject, the method comprising administering an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target, such as Rina-S, to the human subject, and further administering platelets to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.In some embodiments, the human subject is a subject who has been monitored and been found to be susceptible to severe thrombocytopenia. In certain embodiments, the administration of platelets to the human subject is at a time of 1 to 10 days, e.g. 2 to 7 days, e.g. 3. 4, 5, 6 or 7 days, after the firstadministration of the ADC to the human subject.An tibodies and Antibody-Drug Conjugates (ADCs)

[0059] The ADC used in the present invention comprises a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target. In some embodiments, the tumor target is selected from the group consisting of: 5T4, A33, activin receptor, adrenomedullin receptors, AFP, AGS-5, ALK, annexin, AXL, B7-H3, B7-H4, BAGE proteins, BCMA, Bombesin, C33 antigen, C4.4a, C-type lectin-like(-receptor), CA19.9, CA-125, CADM1, CAIX, CanAg, CAR, carbonic anhydrase, Caveolin-1, CCK2R, CD4, CD10, CD19, CD123, CD20, CD21, CD22, CD25, CD27, CD30, CD33, CD37, CD38, CD44, CD44v9, CD51, CD57, CD70, CD73, CD74, CD79a, CD79b, CD80, CDH6, CEA, CEACAM5, c-kit, CLDN18.2, chemokine receptors (i.e„ CXCR4, CXCR5). c-Met, Cripto-1, DEC-205, Derlin-1, Desmoglein-3, Dlk-1, DLL3, DS6, E-cadherin, E-Selectin, EAG-L ED-B, EpCAM, EGFR, EGFRvlll, emmprin, endothelin receptor, ErbB2 / Her2, ErbB3, ErbB4, ETV6-AML, Ephrin type-A receptor, Epiregulin, ETA, FAP-alpha, FcyR's, FGFR, FOLR1, Frizzled, Fyn3, Galectin, Ganglioside, GCC, GD2, GD3, GloboH, Glypican-3, GLUT3, GPNMB, G-protein coupled receptors (i.e., GPR49), gplOO, HER2. HER3, Hsp, HLA / B-raf, HLA-DR, HLA / k-ras, HLA MAG E-A3. HMW-MAA. hTERT, ICAM-3, IGF-R, IL-13- R, LI CAM, laminin receptor, LIV1, LMP2, LRP5, LRP6, MAGE proteins, MART-1, melanotransferrin, mesothelin, metalloproteinase, ML-IAP, MUC1, MUC18, Mud, Mud 6 (CA-125), MU Ml, N-cadherin, NA 17, NaPi2b, NCAM-1, Nectin4, Notch, NP-55, NRP1, NY-BR1, NY-BR62, NY- BR85, NY-ES01, PD-1, PD-L1, PLAC1, PRLR, PRAME, prominin-1, PSMA (FOLH 1). PTK7. RON, RORL SEZ6, SLC44A4, SLITRK6. Steap-1. Steap-2. surviving, syndecan. TAG-72, Tissue Factor. TGF- beta, TMPRSS2, TMEFF2, TNFR, Tn, TROP2, TRP-1, TRP-2,TWEAKR, tyrosinase, uroplakin-3 and VEGFR.

[0060] In preferred embodiments, the antibody is a FOLR1 antibody. A ‘FOLR1 antibody’ as used herein is an antibody that binds to FRa. The topoisomerase 1 inhibitor may be conjugated directly to the FOLR1 antibody or indirectly via linker.

[0061] In some embodiments, the topoisomerase 1 inhibitor is a camptothecin. Exemplarycamptothecins include, for example, camptothecin, irinotecan (also referred to as CPT-11), belotecan, (7-(2-(N-isopropylamino)ethyl)camptothecin), topotecan, 10-hydroxy-CPT, SN-38, exatecan and the exatecan analog DXd (see US20150297748). Other suitable camptothecins are disclosed in WO 1996 / 021666, WO00 / 08033, US2016 / 0229862 and WO2020 / 156189. In some embodiments, the topoisomerase 1 inhibitor is selected from: MM398, rubitecan, lurtotecan, gimatecan, exatecan, sesutecan, belotecan (or derivatives thereof, including KL610023), SyntecanE, deruxtecan, Dxd, rezetecan, Ed04, HC74, adizutecan, P1021, CPT113. ZD06519, pamirtecan, P1003, samrotecan, YL0014, MF6, govitecan SN38, SHR9265, YL0010014, AMDCPT, D2102, tirumotecan, and brengitecan.

[0062] In preferred embodiments, the topoisomerase 1 inhibitor is exatecan.

[0063] In some embodiments, the FOLR1 antibody comprises a heavy chain that comprises three CDRs having the amino acid sequences of the 3 CDRs as present in SEQ ID NO: 1 (respective CDRs underlined in the sequence shown below) and a light chain that comprises three CDRs having the amino acid sequences as present in SEQ ID NO: 2 (respective CDRs underlined in the sequence shown below). In certain embodiments the Ab is an antibody that comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 2. In certain embodiments the Ab is an IgGl antibody. In certain embodiments the IgGl antibody comprises an Fc domain having the amino acid sequence set forth in SEQ ID NO: 3, or a naturally occurring human IgGl-derived Fc domain variant thereof.

[0064] In preferred embodiments, the topoisomerase 1 inhibitor is exatecan and the FOLR1 antibody comprises a heavy chain that comprises three CDRs having the amino acid sequences of the 3 CDRs as present in SEQ ID NO: 1 (respective CDRs underlined in the sequence shown below) and a light chain that comprises three CDRs having the amino acid sequences as present in SEQ ID NO: 2 (respective CDRs underlined in the sequence shown below). In certain embodiments the Ab is an antibody that comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQID NO: 2. In certain embodiments the Ab is an IgGl antibody. In certain embodiments the IgGl antibody comprises an Fc domain having the amino acid sequence set forth in SEQ ID NO: 3, or a naturally occurring human IgGl -derived Fc domain variant thereof.

[0065] In other embodiments, the FOLR1 antibody is mirvetuximab, farletuzumab, MOvl8(IgE) or luveltamab.

[0066] In some embodiments, the ADC is AZD-5335 (also referred to as “torvutatug samrotecan”, see e.g. WO 2023 / 169896; Ann Oncology. Volume 35, Supplement 2, S572-S573), ZW-191 (Cancer Res (2023) 83 (7_Supplement): 2641), MBK-103 (Cancer Res (2023) 83 (7_Supplement): 1544; also referred to as “sofetabart mipitecan” or “LY4170156”, see e.g. WO 2022 / 207699; WO 2023 / 170247; Viricel et al, 10.1158 / 1538-7445.AM2023-1544 (AACR 2023, abstract 1544), or BAT-8006 (Cancer Res (2023) 83 (5_Supplement): P4-01-12.).

[0067] In some embodiments, the ADC comprises an antibody component which comprises an Fc domain or region with one or more amino acid substitutions which diminish IgG Fc receptor (FcyR) binding (as compared to an IgGl constant region having the amino acid sequence set forth in SEQ ID NO: 3), e.g., substitutions at positions 234 and 235 of the Fc region (EU numbering of residues). In some embodiments, the substitutions are L234A and L235A (LALA), according to the EU numbering of Kabat. In some alternative forms, the Fc domain may comprise D265A and / or P329G in an Fc region derived from a human IgGl Fc region, according to the EU numbering of Kabat. In certain embodiments, the substitutions are L234A, L235A and P329G (LALA-PG) in an Fc region derived from a human IgGl Fc region, according to the EU numbering of Kabat. (See, e.g., WO 2012 / 130831 ). In some embodiments, the substitutions are L234A, L235A and D265A (LALA-DA) in an Fc region derived from a human IgGl Fc region, according to the EU number of Kabat. In certain embodiments, the Ab comprises a light chain constant region of the kappa isotype.

[0068] The ADC employed may be Rinatabart sesutecan (Rina-S; sometimes this has also been referred to as PRO 1184) as used herein is an antibody-drug conjugate (ADC) that includes an antibody to FOLR1, and exatecan drug units, each of which is connected to the antibody through a hydrophilic linker. The linker is attached to cysteine residues in the antibody. In certain embodiments, an ADCaccording to aspects of the invention comprises the following structure (structure 1):The ‘PA038’ structure (the structure between brackets) is the hydrophilic linker coupled to the drug exatecan, and this structure can be connected to an antibody (Ab) to form an ADC. In Rina-S, Ab is an IgGl antibody that comprises a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 6 (or optionally an amino acid sequence further including an additional C-terminal lysine (K), i.e. a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 4) and a light chain having an amino acid sequence as set forth in SEQ ID NO: 5. In structure 1. n is the pload, which is the average drag loading (e.g., drug to antibody ratio; or DAR). In Rina-S, n is about 8.

[0069] The term “Rina-S” as used herein includes biosimilars of Rina-S. The term "biosimilar" (e.g., of an approved reference product / biological drug) as used herein refers to a biologic product that is similar to the reference product based on data from (a) analytical studies demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of theproduct). In some embodiments, the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. In some embodiments, the route of administration, the dosage form, and / or the strength of the biological product are the same as those of the reference product. A biosimilar can be, e.g., a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification, or formulation methods. A biosimilar ADC typically is structurally highly similar to the reference product, including the antibody part, the cytotoxic payload, and the linker, but may be produced via slightly different production processes.

[0070] SEQ ID NO: 1 F131 VH amino acid sequence (wherein the three CDRs are indicated by underlining):EVQLLESGGGVVOPGRSLRLSCAASGFTFSSYGMHWVROAPGKGLEWVAVISYDGSNKYY ADSVKGRFTISRANSKNTLYLOMNSLRAEDTAVYYCARPRAYYGAYGSSFDYWGOGTQV TVSSSEQ ID NO: 2 F131 VL amino acid sequence (wherein the three CDRs are indicated by underlining): EIVMTOSPSSVSASVGDRVAITCRASOGISSWLAWYOOKPGKAPKLLIYAASSLQSGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLIFGGGTKVDIKSEQ ID NO: 3 human IgGl heavy chain constant region UniProt P01857-1:ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVS VLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQVYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGKSEQ ID NO: 4 F131 heavy chain amino acid sequence (including C-terminal K):EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYY ADSVKGRFTISRANSKNTLYLQMNSLRAEDTAVYYCARPRAYYGAYGSSFDYWGQGTQVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGKSEQ IDNO: 5 F131 light chain amino acid sequence:EIVMTQSPSSVSASVGDRVAITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVDIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 6 Fl 31 heavy chain amino acid sequence (without C-terminal K):EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYY ADSVKGRFTISRANSKNTLYLQMNSLRAEDTAVYYCARPRAYYGAYGSSFDYWGQGTQVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0071] In some embodiments, the heavy chain of the antibody component of Rina-S described herein does not contain a C-terminal lysine at the C-terminus of the CH3 region (i.e., corresponding to the C-terminal lysine at position 453 of SEQ ID NO: 4, or the C-terminal lysine at position 330 of SEQ ID NO: 3). The heavy chain of SEQ ID NO: 4 without the C-terminal lysine is provided as SEQ ID NO: 6. The C-terminal lysine may be removed, for example, by engineering the heavy chain to not contain a C-terminal lysine, or by removing the C-terminal lysine (e.g., with a carboxypeptidase, e.g. during production or processing of the antibody). Accordingly, in some embodiments, the heavy chain of the antibody component of Rina-S has the amino acid sequence of SEQ ID NO: 6. For any of the aspects and embodiments of the invention, the heavy chain of the antibody component may thus comprise either SEQ ID NO: 6 or SEQ ID NO: 4.

[0072] In some embodiments, the antibody component of Rina-S is the F131 antibody of PCT application WO / 2022 / 217022. WO / 2022 / 217022 is incorporated by reference in its entirety. WO / 2022 / 217022 is also incorporated specifically in relation to the antibodies disclosed therein and in particular in relation to F131 and related antibodies.

[0073] The average DAR (drug antibody ratio) of Rina-S is about 8. In certain embodiments, the average DAR of Rina-S is 8.

[0074] In various embodiments, the present invention concerns treatment of cancer with ADCs provided herein. In some embodiments, the ADC includes the antibody or antibody fragment that comprises VH and VL regions having amino acid sequences that are set forth in SEQ ID NO: 1 and SEQ ID NO: 2. The ADC includes drug units (for instance exatecan). The ADC may include linkers that connect the drug units to the antibody or antibody fragment. In certain embodiments, the linker includes a polar unit having the following structure (structure 2):

[0075] In some embodiments, the linker is derived from a linker compound having the following structure (structure 3):HOto which optionally one of the drug units (e.g. exatecan) is coupled via the benzylic OH. In certain embodiments the ADC comprises the PA038 linker-drug comprising a hydrophilic linker coupled to exatecan as shown in structure 1 above. In certain embodiments the ADC comprises exatecan. Exatecan has the following structure (structure 4):

[0076] In some embodiments, the ADC of the present invention has an average DAR of about 4, about 6, or about 8. In some embodiments, the ADC has an average DAR of about 8.

[0077] In various embodiments, the present invention concerns treatment of cancer with Rina-S or other ADCs noted above or disclosed in PCT applications WO2023280227 and WO2022217022. Both are disclosed in their entirety and specifically in relation to Rina-S and ADCs.

[0078] In any of the embodiments set out herein, the preferred ADC is Rina-S or a biosimilar thereof. Rina-S (or a biosimilar thereof) has the following structure:wherein Ab is an antibody that comprises a heavy chain and a light chain that have amino acid sequences that are set forth in SEQ ID NO: 6 and SEQ ID NO: 5, respectively, and wherein n is about 8, e.g. n is 8. The Ab has two such heavy chains of SEQ ID NO: 6 and two such light chains of SEQ ID NO: 5. In certain embodiments, Rina-S may instead of the heavy chain sequence set forth in SEQ ID NO: 6, comprise the heavy chain sequence set forth in SEQ ID NO: 4 (i.e. having the additional C-terminal lysine). In certain embodiments, Rina-S (or a biosimilar thereof) is formulated into a pharmaceutical composition that can be administered to the subject according to the invention, and said pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, excipients, and / or diluents.Granulocyte-Colony-Stimulating Factor ( G-CSF)

[0079] The methods and uses of the invention involve the administration of G-CSF, a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells. In some embodiments, theG-CSF used is glycosylated or non-glycosylated human G-CSF, for example filgrastim or lenograstim.

[0080] In some embodiments, the G-CSF is a non-human homologue of human G-CSF, for example a homologue having more than 80%, for example more than 90%, such as more than 95%, 96%, 97%, 98% or 99% sequence identity to human G-CSF and has G-CSF activity in a human subject.

[0081] In some embodiments, the G-CSF is a modified form of human G-CSF. Modifications may include modifications to increase serum half-life, such as pegylation. In some embodiments, G-CSF is pegfilgrastim.

[0082] G-CSF is typically used to treat neutropenia reactively, e.g. when patients develop neutropenia due to treatment with an ADC, and it was for instance also used to reactively treat patients that developed such side effects upon treatment with Rina-S. Such side effects typically occur later during treatment, e.g. after 10 days of administration of Rina-S and / or in later cycles of treatment. G-CSF was not used prophylactically to avoid or mitigate side-effects of treatment with an ADC that comprises a topoisomerase 1 inhibitor coupled to an antibody that binds to a tumor target, Rina-S, already early in treatment before side effects of the treatment with the ADC became apparent (see e.g. slide 9 of Lee et al, ESMO Congress 2024, A phase I / II study of rinatabart sesutecan (Rina-S) in patients with advanced ovarian or endometrial cancer. Annals of Oncology (2024) 35 (suppl_2): S544-S595. 10.1016 / annonc / annoncl592). Also, just taking all patients that are treated with such an ADC and treat all of them prophylactically with G-CSF early during treatment is not recommended either, since G-CSF may give rise to its own side-effects such as bone or muscle pain, back pain, fatigue, etc, and further adds to drug burden for a patient as well as to costs of treatment. The present inventors surprisingly found that a certain subpopulation of patients treated with an ADC that comprises a topoisomerase 1 inhibitor coupled to an antibody that binds to a tumor target, namely Rina-S, have an increased risk of developing side effects such as neutropenia towards the ADC, and determined previously unknown and unpredictable baseline characteristics to define this subpopulation (i.e. (i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or (ii) platelet count < 200,000 / pL, and / or (iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2), to create the possibility to start treating this specific subpopulation with G-CSF already early during treatment with the ADC, actuallybefore side effects such as neutropenia developed, i.e. already early, such as before day 10, e.g. on day 1, 2, 3, 4, 5, 6, or 7 in the first cycle of treatment with the ADC (wherein the administration of the ADC is set as day 0). This will reduce the chances of developing or the severity of the neutropenia due to the ADC treatment in at least a part of this subpopulation of patients.ADC dosages, dosage regimens, routes of administration, and patient assessmen t

[0083] In some embodiments, the dosage range of the ADCs (e.g., Rina-S) used to treat cancer (e.g.. solid tumor) in the present invention may be between 60 mg / m2and 140 mg / m2, with a maximal total dose per administration of 250 mg. In certain embodiments, the dosages may be between 80 mg / m2and 120 mg / m2, with a maximal total dose per administration of 250 mg. In certain embodiments, the dosage is about 100 mg / m2, with a maximal total dose per administration of 250 mg. In certain embodiments, the dosage is about 120 mg / m2, with a maximal total dose per administration of 250 mg. Here, “m2” (square meter) is a measurement of the patient’s body surface area (BSA). Thus, doses expressed in mg / m2are based on the BSA of the patient which may be calculated by the Mosteller’s equation (BSA in m2is (height (cm)*weight (kg) / 3600)). Such a maximum dose of 250 mg / m2is based on observed side effects of Rina-S combined with modeling and it was calculated in the work underlying this aspect of the invention that this maximum dose will limit the risk of developing side effects in patients that would otherwise receive more than this dose based on their BSA.

[0084] In some embodiments, the ADCs (e.g., Rina-S) may be given either weekly, twice weekly or every other week. The dosing schedule may include treatment cycles of two consecutive weeks of therapy followed by one, two. three or four weeks of rest, or alternating weeks of therapy and rest, or one week of therapy followed by two, three or four weeks of rest, or three weeks of therapy followed by one, two, three or four weeks of rest, or four weeks of therapy followed by one, two, three or four weeks of rest, or five weeks of therapy followed by one, two, three, four or five weeks of rest, or administration once every two weeks, once every three weeks or once a month. In some embodiments, the ADC is Rina-S and is administered to the human subject once or twice a week on a schedule with a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week oftherapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five weeks off; (vi) four weeks of therapy followed by one, two, three, four or five weeks off; (vii) five weeks of therapy followed by one, two, three, four or five weeks off; and (viii) monthly. In some embodiments, the ADC, such as Rina-S, is administered once every three weeks.

[0085] Treatment may be extended for any number of cycles, such as at least 2, at least 3, at least 4, at least 5. at least 6, at least 7, at least 8, at least 9. at least 10, at least 12, at least 16, or at least 20 cycles (e.g., 2-20 cycles, 2-16 cycles, 2-10 cycles, 2-4 cycles, 4-20 cycles, 4-16 cycles, 4-10 cycles, 6-20 cycles, 6-16 cycles, 6-10 cycles, 8-20 cycles, 8-16 cycles, 8-10 cycles, 10-20 cycles, 10-16 cycles, 12-20 cycles, 12-16 cycles, or 16-20 cycles, or more than 20 cycles). In some embodiments, the ADC dosage is administered to the human subject on Day 1 of a 21 -day treatment cycle. In some embodiments, the ADC is administered every 2 to 4 weeks. In some embodiments, the ADC is administered about every 3 weeks. In some embodiments, the ADC is administered every 3 weeks. Dosing every 3 weeks may also be referred to as Q3W. In some embodiments, the ADC is Rina-S and the Rina-S dosage is administered to the human subject in a cycle of one administration every three weeks (Q3W).

[0086] In some embodiments, the ADC dosage is administered to the human subject as a 10-minute, 20-minute, 30-minute, 40-minute, 50-minute, 60-minute intravenous (IV) infusion. In some embodiments, the ADC dosage is administered to the human subject as a 30-minute intravenous (IV) infusion.

[0087] In some embodiments, the treatment with the ADC results in a reduction in a size of the tumor, such as a solid tumor, of at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In certain embodiments, the treatment with the ADC results in a reduction in a size of the solid tumor of 15-90%, for example, 15-75%, 15-50%, 15-40%, 15-30%, 30-90%, 30-75%, 30-50%, 30-40%, 40-90%, 40-75%, 40-50%, 50-90%, or 50-75%. The person of ordinary skill will realize that a variety of factors, such as age, general health, specific organ function or weight, as well as effects of prior therapy on specific organ systems may be considered in selecting an optimal dosage of ADC,and that the dosage and / or frequency of administration may be increased or decreased during the course of therapy.

[0088] In some embodiments, the treatments of the present invention result in an improved treatment outcome for the subject. Such is especially the case when the human subject has failed a previous treatment. In certain embodiments, the improved treatment outcome is an objective response selected from stable disease, a partial response, or a complete response. In certain embodiments, the improved treatment outcome is a stable disease, indicating the progression of the solid tumor has been halted. In certain embodiments, the improved treatment outcome is a partial response. In certain embodiments, the partial response indicates that the solid tumor size has been reduced by at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. As discussed further below, the RECIST ver 1.1 criteria may be used to assess tumor size and in one embodiment, the partial response indicates that the solid tumor size has been reduced by at least 20%, at least 25%, at least 30%. at least 40%, or at least 50% according to those criteria. In certain embodiments, the improved treatment outcome is a complete response. In certain embodiments, the complete response indicates that there is no detectable cancer. In certain embodiments, the improved treatment outcome is reduced tumor burden. In certain embodiments, the reduced tumor burden indicates a reduction of the solid tumor size by at least 20%. at least 25%. at least 30%. at least 40%. or at least 50%. In certain embodiments, the improved treatment outcome is progression-free survival or disease-free survival. In certain embodiments, the progression-free survival or disease-free survival is assessed after 1, 2, 3, 4, 5, or 10 years.

[0089] Any appropriate approach may be used to assess tumors and the treatment. In some embodiments the treatment is assessed per RECIST vl.1. In embodiments, where the cancer is pleural mesothelioma treatment may be assessed using mRECIST vl.l. The RECIST ver 1.1 criteria were published by Eisenhauer et al in the European Journal of Cancer (2009) 228-247 and may be used to define the degree of response. Eisenhauer et al is incorporated in its entirety and specifically in relation to the RECIST ver 1.1 criteria. In some embodiments, Best Overall Response (BOR) may be assessed. In some embodiments, overall response rate (ORR) may be assessed. In some embodiments Disease Control Rate (DCR) may be assessed. In some embodiments, Progression Free Survival time (PFS)may be assessed. In some embodiments, Overall Survival may be assessed. In some embodiments, the Duration of Objective Response (DOR) may be assessed.

[0090] Generally, the dosage of an administered ADC (e.g., Rina-S) for human subjects can be varied depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history. As discussed above, dosages of Rina-S may vary from 60 mg / m2to 140 mg / m2, e.g. 100 mg / m2- 140 mg / m2, e.g. 100 mg / m2- 120 mg / m2, or e.g. about 80 mg / m2, about 100 mg / m2, or about 120 mg / m2, all with a maximal total dose per administration of 250 mg. In certain embodiments, Rina-S is administered intravenously on Day 1 of a 21-day cycle and may be continued until disease progression, unacceptable toxicity, or other reasons for treatment discontinuation.

[0091] In one embodiment, the present invention provides a method of treating a FOLR1 positive tumor in a human subject, the method comprising administering Rina-S to the human subject, wherein Rina-S is administered at a dosage of 100 mg / m2(maximal total dose per administration of 250 mg) administered about every three weeks (Q3W), and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said Rina-S to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / p.L, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0092] In one embodiment, the present invention provides a method of treating a FOLR1 positive tumor in a human subject, the method comprising administering Rina-S to the human subject, wherein Rina-S is administered at a dosage of 120 mg / m2(maximal total dose per administration of 250 mg) administered about every three weeks (Q3W), and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5. or 6 days, after the first administration of said Rina-S to the human subject, wherein the human subject has one or more of the following baselinecharacteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / uL, and / or(ii) platelet count < 200,000 / p.L, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0093] Such regimens may in particular be administered to a human subject having ovarian cancer. In one embodiment, they may be administered to a human subject having platinum-resistant ovarian cancer. In an alternative embodiment, they may be administered to a human subject having platinumsensitive ovarian cancer. In further embodiments, they may be administered to a human subject having endometrial cancer. In yet further embodiments, they may be administered to a human subject having breast cancer, non-small-cell lung carcinoma (NSCLC) or mesothelioma.

[0094] In one embodiment, the present invention provides a method of treating a FOLR1 positive ovarian cancer in a human subject, the method comprising administering Rina-S to the human subject, wherein Rina-S is administered at a dosage of 100 mg / m2(optionally at a maximal total dose per administration of 250 mg) administered about every three weeks (Q3W), and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days. e.g. 2, 3. 4, 5, or 6 days, after the first administration of said Rina-S to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0095] In one embodiment, the present invention provides a method of treating a FOLR1 positive ovarian cancer in a human subject, the method comprising administering Rina-S to the human subject, wherein Rina-S is administered at a dosage of 120 mg / m2(optionally at a maximal total dose per administration of 250 mg) administered about every three weeks (Q3W), and further administering a G-CSF to the human subject on the same day as the first administration of said ADC. or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, afterthe first administration of said Rina-S to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0096] In one embodiment, the present invention provides a method of treating a FOLR1 positive endometrial cancer in a human subject, the method comprising administering Rina-S to the human subject, wherein Rina-S is administered at a dosage of 100 mg / m2(optionally at a maximal total dose per administration of 250 mg) administered about every three weeks (Q3W), and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days. e.g. 2, 3. 4, 5, or 6 days, after the first administration of said Rina-S to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0097] In one embodiment, the present invention provides a method of treating a FOLR1 positive endometrial cancer in a human subject, the method comprising administering Rina-S to the human subject, wherein Rina-S is administered at a dosage of 120 mg / m2(optionally at a maximal total dose per administration of 250 mg) administered about every three weeks (Q3W), and further administering a G-CSF to the human subject on the same day as the first administration of said ADC. or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said Rina-S to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.G-CSF dosages, dosage regimens, routes of administration

[0098] The methods and uses of the invention involve the administration of G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of the ADC to the human subject, i.e. in the first cycle of ADC treatment. It is to be understood that said administration of G-CSF refers to the first administration of G-CSF in the ADC treatment regimen. G-CSF administration may be continued thereafter for multiple days.

[0099] In one embodiment, G-CSF is administered 1 day after the first administration of the ADC.

[0100] In one embodiment, G-CSF is administered 2 days after the first administration of the ADC.

[0101] In one embodiment, G-CSF is administered 3 days after the first administration of the ADC.

[0102] In one embodiment, G-CSF is administered 4 days after the first administration of the ADC.

[0103] In one embodiment, G-CSF is administered 5 days after the first administration of the ADC.

[0104] In one embodiment, G-CSF is administered 6 days after the first administration of the ADC.

[0105] In one embodiment, G-CSF is administered 7 days after the first administration of the ADC.

[0106] In one embodiment, G-CSF is administered 8 days after the first administration of the ADC.

[0107] In one embodiment, G-CSF is administered 9 days after the first administration of the ADC.

[0108] In one embodiment, G-CSF is administered 10 days after the first administration of the ADC.

[0109] In certain embodiments, G-CSF is not only administered after the first administration of the ADC, but also after one or more subsequent ADC administrations, for example after two or more administrations. In some embodiments, G-CSF is administered after each administration of the ADC. preferably between 1 and 7 days, e.g. 2, 3. 4, 5, or 6 days, after each administration of the ADC, i.e. in each cycle of ADC treatment. Preferably, when G-CSF is administered after each administration of the ADC, the G-CSF administration starts on the same day in each cycle, e.g. on day 3, 4 or 5.

[0110] The G-CSF dosage and dosage regimen may follow the prescribed regimen for the treatment or prevention of cytopenia, such as neutropenia, for the particular form of G-CSF used. Information about dosage and timing of G-CSF treatment after treatment of a human subject with a chemotherapydrug, or analogously with an ADC, can be found in the label of the G-CSF preparation, as is known to the skilled person. Preferably G-CSF is administered at least 24 hours after treatment with the chemotherapy drug or ADC.

[0111] G-CSF is in certain embodiments administered multiple times in each ADC cycle with intervals of 1 day (daily dosing). In some embodiments, G-CSF is administered daily until the neutrophil count has recovered to the normal range, typically up to 14 days, such as for 2, 3, 4, 5, 6, 7, 8. 9, 10, 11, 12 13 or 14 days, but if needed this may even take longer, e.g. up to about 20 days.

[0112] In one embodiment, the G-CSF dose is 5 micrograms / kg / day. In one embodiment, the G-CSF is filgrastim and the dose is 5 micrograms / kg / day.

[0113] In other embodiments, in particular when the form of G-CSF used has a longer serum halflife, only one dose is administered per ADC cycle, e.g. a dose of 6 mg. In one embodiment, the G-CSF is pegfilgrastim and the dose per cycle is 6 mg.

[0114] In some embodiments, G-CSF is administered subcutaneously.Patients and cancer types

[0115] In some embodiments, the method of the present invention can be used to treat a tumor. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a hematological tumor.

[0116] In some embodiments, the subject has a plurality of solid tumors. In some embodiments, the subject has a plurality of solid tumors because the cancer has metastasized. In some embodiments, the solid tumor is a primary tumor. In some embodiments, the solid tumor is a secondary tumor. In some embodiments, the subject has a plurality of solid tumors with both the primary solid tumor and secondary solid tumor(s) present. In certain embodiments, the solid tumor is present in a human subject having a cancer selected from the group consisting of: ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. In certain embodiments, the solid tumor is ovarian cancer. In certain embodiments, the solid tumor is ovarian cancer and the subject is treated with Rina-S at a dosage of 120 mg / m2per administration (optionally at a maximal total dose per administrationof 250 mg). In certain embodiments, the solid tumor is platinum-resistant ovarian cancer (PROC). In certain embodiments, the solid tumor is platinum- sensitive ovarian cancer (PSOC). In certain embodiments, the solid tumor may be ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the solid tumor may be a primary peritoneal carcinoma. In some embodiments, the solid tumor may be a fallopian tube cancer. In certain embodiments, the solid tumor may be endometrial cancer. In certain embodiments, the solid tumor is endometrial cancer and the subject is treated with Rina-S at a dosage of 100 mg / m2per administration (optionally at a maximal total dose per administration of 250 mg). In certain embodiments, the solid tumor may be lung cancer, such as non-small-cell lung cancer (NSCLC). In certain embodiments, the solid tumor may be breast cancer, including HER2-negative breast cancer. In some embodiments, the solid tumor may be a mesothelioma. In certain embodiments, the solid tumor may be pleural mesothelioma or peritoneal mesothelioma. In some embodiments, the methods of the present invention can be used to treat cancer (e.g., solid tumor) that is FOLR1 positive. As used herein, the tumor being “FOLR1 positive” means that at least a portion of the tumor cells are expressing the FOLR1 protein that can be detected by standard methods such as immunohistochemistry (IHC); a cell being “FOLR1 positive” means that the cell is expressing the FOLR1 protein that can be detected by standard methods such as IHC. In certain embodiments, FOLR1 expression in a tumor is determined by applying a regulatory approved test (e.g. an FDA approved Ventana FOLR1-2.1 RxDx Assay, or a local equivalent thereof) on a tumor sample. In some embodiments, at least 10%, 15%, 20%, 25%, 30%, 40%, or at least 50% of the cells in a sample from the tumor are FOLR1 positive. In certain embodiments, in a sample from the solid tumor of the human subject, at least 25% of cancer cells are FOLR1 positive. In certain embodiments, in a sample from the solid tumor of the human subject, at least 75% of cancer cells are FOLR1 positive. In certain embodiments, in a sample from the solid tumor of the human subject, less than 75% of cancer cells are FOLR1 positive. In certain embodiments, in a sample from the solid tumor of the human subject, less than 25% of cancer cells are FOLR1 positive. In certain embodiments the tumor in the human subject has high FOLR1 expression, identified as FRa membrane staining intensity >2+ (“PS2+”) in >75% of tumor cells in an IHC assay such as the Ventana FOLR1 (FOLR1-2.1) RxDxAssay. In certain embodiments the tumor in the human subject has medium FOLR1 expression, identified as FRot membrane staining intensity >1+ (“PS 1+”) in >25% of tumor cells and PS2+ in <75% of tumor cells in an IHC assay such as the Ventana FOLR1 (FOLR1-2.1) RxDx Assay. In certain embodiments the tumor in the human subject has low FOLR1 expression, identified as PS 1+ in <25% of tumor cells in an IHC assay such as the Ventana FOLR1 (FOLR1-2.1) RxDx Assay. In certain embodiments, the human subject is treated with Rina-S according to the invention at a time where there has not been a determination of the percentage of cancer cells which are FOLR1 positive in a sample of the solid tumor of the human subject; in certain embodiments thereof, the human subject has an ovarian cancer.

[0117] In some embodiments, the methods of the present invention can be used to treat cancer (e.g., solid tumor) that is localized. In some embodiments, the method of the present invention can be used to treat cancer (e.g., solid tumor) that is metastatic. In some embodiments the patient has an advanced solid tumor. In some embodiments, the patient has a locally advanced tumor. In some embodiments the tumor has spread so that the patient has secondary solid tumors in addition to the primary tumor. In some embodiments, the tumor cannot be removed by surgery, i.e. the tumor is unresectable. In some embodiments, the tumor has both spread (the cancer is metastatic) and at least one solid tumor is present which is unresectable. In some embodiments, the tumor is refractory or recurrent.

[0118] In some embodiments, the subject may have high-grade epithelial ovarian cancer. In some embodiments, the subject may have a high-grade serous ovarian cancer.

[0119] In certain of the embodiments set out herein, the subject may have a tumor that is a platinum-resistant tumor. In some embodiments, the subject may have high-grade serous or endometrioid EOC (epithelial ovarian cancer), primary peritoneal cancer, or fallopian tube cancer, resistant to platinum chemotherapy. In one embodiment, the subject has platinum-resistant ovarian cancer. Alternatively, the subject may have a tumor that is platinum- sensitive. In some embodiments, the subject may have platinum-sensitive ovarian cancer.

[0120] In some embodiments, the subject to be treated has a histologically or cytologically confirmed metastatic or unresectable solid malignancy. In some embodiments, the subject has ovariancancer and also epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the subject has endometrial cancer. In some embodiments, the subject has non-small cell lung cancer (NSCLC). In some embodiments, the subject has EGFR-mutated NSCLC. In some embodiments, the subject has breast cancer. In some embodiments, the subject has hormone receptorpositive, HER2-negative or triple-negative breast cancer. In some embodiments the subject has mesothelioma. In one embodiment, the cancer is selected from histologically or cytologically confirmed metastatic or unresectable solid malignancy including ovarian cancer (must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer), endometrial cancer, non-small cell lung cancer, epidermal growth factor receptor (EGFR) -mutated NSCLC, breast cancer (hormone receptor-positive, HER2-negative and triple-negative), uterine cancer, and mesothelioma.

[0121] In one embodiment, the patient has already had their FRa expression status determined, for instance using the Ventana FOLR1-2.1 RxDx Assay. In one embodiment, the patient has high FRa expression (ie, FRa expression >75% PS2+), for instance as measured using the Ventana FOLR1-2.1 RxDx Assay. In another embodiment, the patient does not have high FRa expression, and in particular has a FRa expression <75% PS2+, for instance as measured using the Ventana FOLR1-2.1 RxDx Assay. In further embodiments, the patient has a FRa expression <25% PS2+, for instance as measured using the Ventana FOLR1-2.1 RxDx Assay. In certain embodiments, the patient has not already had their FRa expression status determined. In such embodiments the patient may be treated with Rina-S according to the invention absent predetermination of FRa expression status, e.g. in patients having ovarian cancer.

[0122] In some embodiments, a method of the present invention may comprise a step of determining whether or not the tumor expresses FOLR1. In further embodiments, it may comprise the step of determining the level of expression of FOLR1. In other embodiments, it may not comprise either of those steps. In certain embodiments thereof, the human subject has ovarian cancer. In certain embodiments, the patients have been pretreated with other therapies against the tumor, e.g. with at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the patients are treated with the ADC. in particular Rina-S, at a dose level of 100 mg / m2. In certain embodiments, the patients are treatedwith the ADC, in particular Rina-S, at a dose level of or 120 mg / m2. In certain embodiments, the dosage is administered to the patients about every three weeks (Q3W). In certain embodiments, the administration of the ADC, in particular Rina-S, is via intravenous administration.

[0123] In some embodiments, whether or not there is FOLR1 expression is not determined beyond determining the presence or absence of any expression of FOLR1. In some embodiments, the level of FOLR1 expression in the solid tumor is not determined at all prior to treatment. For instance, as a large majority of ovarian cancers display FOLR1 expression it may be that a subject with ovarian cancer is simply treated according to the invention without determining the presence, or absence, or level of FOLR1 expression, because of the high chance the tumor will express FOLR1 and also because the exact level of FOLR1 expression may be less important for Rina-S than for other cancer drugs.

[0124] In one embodiment, a patient with one of the recited cancer types herein is treated without any determination of whether or not the solid tumor displays FOLR1 expression. In certain embodiments thereof, the human subject has ovarian cancer. In certain embodiments, the human subjects have been pretreated with other therapies against the tumor, e.g. with at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the human subjects are treated with ADC. in particular Rina-S, at a dose level of 100 mg / m2. In certain embodiments, the human subjects are treated with the ADC, in particular Rina-S, at a dose level of or 120 mg / m2. In certain embodiments, the dosage is administered to the human subjects about every three weeks (Q3W). In certain embodiments, the administration of the ADC, in particular Rina-S, is via intravenous administration.Combination therapies

[0125] In some embodiments of the methods of the present invention, the ADC may be used as a combination therapy with one or more therapeutic modalities selected from the group consisting of unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, localized radiation therapy, surgery and interference RNA therapy.

[0126] In one embodiment, where the ADC is used in combination with another anti-cancer drug it may be that they are administered simultaneously, it may be that ADC and further drug are given simultaneously, separately, or sequentially. In one embodiment, they may be given in the same pharmaceutical composition. In an alternative embodiment, the ADC and further drug may be given in separate compositions. In one embodiment, although the ADC and further drug are administered separately, it may be that they are packaged together, for instance in the form of a kit comprising both. In one embodiment, an ADC for use in a method as set out herein is provided. In an alternative embodiment, the invention provides the further drug for use in a method as set out herein wherein the ADC is also administered. Various regimens are set out herein involving administration of an ADC as described herein and the invention provides such regimens where the second drug is administered as part of the regimen. It may be, for instance, that the second drug is administered at the same time as the ADC. Alternatively, the further drug may be administered according to the standard regimen for that drug. The present invention also provides regimens which alternate administration of the ADC with the further drug.

[0127] In some embodiments, the ADC may be used in combination with a platinum-based chemotherapy drug. Examples of such drugs include cisplatin, carboplatin, and oxaliplatin. In some embodiments, the ADC may be used in combination with carboplatin.

[0128] In some embodiments, the ADC may be used in combination with a drug that is a VEGF inhibitor. In some embodiments, the ADC is used in combination with bevacizumab.

[0129] In some embodiments, the ADC may be used in combination with an immuno-oncology therapy agent. In some embodiments, the ADC may be used in combination with an immune checkpoint inhibitor, such as a drug that inhibits the functional interaction between PD-1 and PD-L1, such as a PD-1 binding antibody or a PD-L1 binding antibody. Non-limiting examples of a drug that inhibits PD-1 include pembrolizumab, nivolumab, nofazinlimab, and cemiplimab. In some embodiments, the ADC may be used in combination with pembrolizumab. In some embodiments, the ADC may be used in combination with nofazinlimab. In some embodiments, the ADC may be used in combination with pembrolizumab. In some embodiments, the ADC may be used in combinationwith a drug that inhibits PD-L1. Non-limiting examples of a drug that inhibits PD-1 include atezolizumab, avelumab, and durvalumab.

[0130] In some embodiments, the ADC may be used in combination with a drug that is a PARP inhibitor. In some embodiments, the ADC is used in combination with olaparib.

[0131] In some embodiments, the method or use of the invention further comprises administering platelets to the subject.

[0132] In preferred embodiments, the ADC may be of use for treatment of cancers for which standard therapies are not effective, such as ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. More preferably, the combination of ADC and other therapeutic modality is more efficacious than either alone, or the sum of the effects of individual treatments. In one embodiment, a combination is synergistic. Patent application PCT / US2024 / 048613, incorporated by reference herein, discloses successful combinations of Rina-S with either one of: (i) a platinum-based chemotherapy, (ii) an anti-angiogenic agent, (iii) a PARP inhibitor, and (iv) an immune checkpoint inhibitor, and demonstrates potentiation of antiproliferative or anti-tumor effects of those combinations in in vivo models. An ADC according to the invention, such as Rina-S, used in treatment regimens in such combination treatments with other anti-cancer drugs can also benefit from the instant invention, i.e. a human subject treated with such combination treatments in certain embodiments of the instant invention is further administered G-CSF starting at a time between days 1 -10, preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of the ADC, such as Rina-S, to the human subject.Patient groups and histories

[0133] The human subject may have previously been treated with at least one anti-cancer therapy. In one embodiment, the subject may previously have been treated with at least one anti-cancer therapy that was not effective in treating the cancer. In one embodiment, the subject may previously have been treated with at least one anti-cancer therapy that was initially effective, but which now has reduced or no efficacy. In some embodiments, the subject may have become resistant to the previous therapywhen it is administered on its own.

[0134] In some embodiments, the human subject has previously been treated with 1 to 4 anticancer therapies. In some embodiments, the at least one anti-cancer therapy includes treatment with a chemotherapeutic agent. In some embodiments, the human subject has previously been treated with at least one anti-cancer therapy selected from the group consisting of:(a) platinum-based chemotherapy, such as carboplatin;(b) a VEGF antagonist-based therapy, optionally bevacizumab;(c) poly-ADP ribose polymerase inhibitor (PARPi) therapy;(d) FOLR1 -targeted therapy, such as mirvetuximab soravtansine; and(e) treatment with an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, for example pembrolizumab.

[0135] In some embodiments, the at least one anti-cancer therapy includes treatment with at least one anti-cancer therapy selected from the group consisting of platinum chemotherapy, bevacizumab, poly ADP-ribose polymerase (PARP) inhibitor, and mirvetuximab soravtansine. The human subject may have failed to respond to the at least one anti-cancer therapy prior to treatment of the ADC.

[0136] In some embodiments, the subject to be treated is selected from one with high-grade serious ovarian cancer, primary peritoneal cancer or fallopian tube cancer. In some embodiments, the subject is selected from a subject with such a solid tumor and the subject has received 1 to 3 lines of therapy with a different anti-cancer therapy (prior induction plus maintenance is considered 1 line of therapy, even if parts of the treatment regimen, induction or maintenance, are interrupted and / or resumed at a later date, in the absence of disease progression while on active treatment - a switch / change in regimen due solely to toxicity or participant preference, and not disease progression is not considered a separate line of therapy). In some embodiments, where the cancer is ovarian cancer, it is platinum-resistant / refractory ovarian cancer. In some embodiments, the subject has received prior bevacizumab. In some embodiments, the subject has breast cancer with known or suspected deleterious germline or somatic BRCA mutations (e.g. as determined by an FDA-approved test) and has been treated with a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the subject has an FRa statusbased on an FDA approved test (e.g. the Ventana FOLR1 RxDx Assay) - subjects who are FRa positive may have previously received mirvetuximab soravtansine, (MIRV), hr some embodiments, the subjects are FRa positive but not eligible for treatment by MIRV, e.g. because the FRa expression is too low. In some embodiments, the subject is treated according to the invention when the FRa expression level of the tumor in the subject has not been determined by a regulatory (e.g. FDA-) approved test. In some embodiments, whether or not the tumor expresses FRa is not determined. For example, it may be that a high proportion of that cancer will express FRa so it is not considered necessary to determine the presence of FRa or at least it is not considered necessary to determine the level of FRa expression. In one embodiment, the cancer in such embodiments is ovarian cancer.

[0137] In some embodiments, the subject has platinum-sensitive ovarian cancer (PSOC) and has received 1 to 3 prior lines of therapy, in particular where the prior lines of therapy are with a platinumbased chemotherapeutic agent.

[0138] In some embodiments, the subject has platinum-resistant or platinum-refractory cancer. In some embodiments, the subject will have high grade serous or endometrioid EOC, primary peritoneal cancer, or fallopian tube cancer, resistant to platinum chemotherapy. In some embodiments, the subject will have platinum-resistant or platinum-refractory cancer, wherein the subject has received prior platinum chemotherapy drug-based therapy. In some embodiments, the subject will have received 1 to 2 prior lines of such therapy. In some embodiments, the subject will have endometrial cancer and in particular any subtype of endometrial cancer excluding sarcoma. In some embodiments, the subject will have such endometrial cancer and have received prior platinum-based chemotherapy for recurrent or advanced disease. In some embodiments, for any of the subjects mentioned in this paragraph they will not have any of the following: (i) another malignancy within 3 years; (ii) Active central nervous system (CNS) metastases (treated, stable CNS metastases are allowed); (iii) Uncontrolled Grade 3 or greater infection within 2 weeks of commencing treatment; (iv) testing positive for hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV); (v) a history of (non-infectious) interstitial lung disease (ILD) / pneumonitis that required steroids within the past 2 years, has current ILD / pneumonitis, or where suspected ILD / pneumonitiscannot be ruled out by imaging at screening; (v) use of a strong CYP3A inhibitor within 14 days (dose escalation only); or (vi) Prior therapy with a topoisomerase 1 inhibitor-based antibody drug conjugate.

[0139] In one embodiment, the subject will have histologically or cytologically confirmed highgrade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In one embodiment, such a subject will have received 1 to 4 prior lines of therapy. In one preferred embodiment the patient will have received at least one of:a) Platinum chemotherapyb) Bevacizumab, unless the patient has a documented contraindicationc) A poly ADP-ribose polymerase (PARP) inhibitor (for patients with known or suspected deleterious germline or somatic BRCA mutations)d) Mirvetuximab soravtansine, if:i. Mirvetuximab soravtansine is available in the region, andii. the patient is eligible based on positive FRa expression per an FDA-approved (or local equivalent) test, andiii. the patient does not have a documented medical exception, including chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment / monitoring, such as uncontrolled glaucoma, wet age- related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and / or monocular vision.

[0140] In some embodiments, the subjects that are treated with the ADC according to the present invention have previously been treated with other lines of therapy, e.g. 1, 2, 3, 4, 5, 6, or 7 prior other cancer therapies. In certain embodiments, a subject having ovarian cancer that is treated with the ADC according to the present invention has been previously treated with one or more of bevacizumab, PARP inhibitor, platinum-based chemotherapy (e.g. cisplatin, carboplatin, oxaliplatin), and / or mirvetuximab soravtansine. In certain embodiments, a subject having endometrial cancer that is treated with the ADC according to the present invention has been previously treated with a PD- 1inhibitor (e.g. pembrolizumab).

[0141] In one embodiment, a subject that has only had one line of platinum-based therapy will have received at least 4 cycles of platinum therapy, and must have either had a response (complete response [CR] or partial response [PR]) or had non-measurable disease at the start of platinum-based therapy, and then progressed between > 91 days and < 183 days after the date of the last dose of platinum. In a further embodiment, patients who have received 2 to 4 lines of platinum-based therapy will have progressed on or within 183 days after the date of the last dose of platinum.

[0142] In one embodiment, the subject will not have one or more of the following exclusion criteria (particularly where the subject is being treated for PROC):• Prior therapy with an antibody-drug conjugate containing a topoisomerase 1 inhibitor. • Have primary platinum-refractory disease, defined as ovarian cancer that did not respond (CR or PR) to or progressed < 91 days after the last dose of a first-line platinum- containing regimen.• History of another malignancy within 3 years before the first dose of Rina-S, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS >90%), including, but not limited to, adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, ductal carcinoma in situ, or Stage I uterine cancer.• Known active central nervous system metastases or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids and anticonvulsants prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. Patients with suspected brain metastases at screening may undergo a computed tomography (CT) / magnetic resonance imaging (MRI) of the brain prior to study entry.• Hospitalization or clinical symptoms due to gastrointestinal obstruction within the past 91 days or radiographic evidence of gastrointestinal obstruction at the time of screening. Enrollment of patients who currently require parenteral nutrition must be discussed with the study medical monitor to determine eligibility.• Ascites requiring frequent paracentesis (more often than approximately every 4 weeks) for symptomatic management. Enrollment of patients with an indwelling peritoneal catheter must be discussed with the medical monitor to determine eligibility.

[0143] In one embodiment, the subject may have a particular level of FRa expression, for instance as measured by the Ventana FOLR1-2.1 RxDx Assay. In one embodiment, the subject has a tumor that does not have high FRa expression per the Ventana FOLR1-2.1 RxDx Assay (or local equivalent test), for instance the patient may have a FRa expression of <75% PS2+. In one embodiment, the subject has an FRa expression of <25% PS2+. In one embodiment, the subject has a tumor that does have high FRa expression per the Ventana FOLR1-2.1 RxDx Assay and in particular a FRa expression level of >75% PS2+. In one embodiment, the subject has a FRa expression level of > 75% PS2+ per the Ventana FOLR1-2.1 RxDx Assay and not have previously received mirvetuximab soravtansine.

[0144] In one embodiment, the subject has a tumor with FRa expression and is further defined by whether the subject has been previously treated with mirvetuximab soravtansine. In one embodiment, the subject is mirvetuximab soravtansine naive and FRa expression non-high [ie, <75% PS2+], In one embodiment, the subject is mirvetuximab soravtansine naive and FRa expression high [i.e., 3= 75% PS2+], In one embodiment, the subject has been mirvetuximab soravtansine-treated previously.

[0145] In one embodiment, the subject will have received 1 to 4 prior lines of therapy, which must include platinum-based chemotherapy, bevacizumab, and / or mirvetuximab soravtansine.

[0146] In certain embodiments, the human subject that is treated or eligible for treatment according to the invention is an adult human subject, e.g. a human subject that is 18 years or older, e.g. 18-100 years old, 18-85 years old, 18-80 years old, 18-75 years old, 18-70 years old, 18-65 old, or 18-60years old. In certain embodiments, the human subject is 50 years or older, 55 years or older, 60 years or older, 65 years or older, e.g. 50-100 years old. 50-90 years old, 50-85 years old, 50-80 years old.55-100 years old, 55-90 years old, 55-85 years old, 55-80 years old, 60-100 years old, 60-90 years old, 60-85 years old, 60-80 years old, 65-100 years old, 65-90 years old, 65-85 years old, or 65-80 years old.

[0147] The invention can also be applied analogously outside the field of ADCs, e.g. to chemotherapy treatment with topoisomerase 1 inhibitors. Accordingly, in further aspects, the invention relates reducing the risk of severe neutropenia and / or its associated complications upon treatment with a topoisomerase 1 inhibitor, including topoisomerase 1 inhibitor in an unconjugated form, i.e. not linked or conjugated to an antibody. Accordingly, in a further aspect, the invention relates to a method of treating a tumor in a human subject, the method comprising administering a topoisomerase 1 inhibitor to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.Embodiments of this aspect of the invention with respect to identity of topoisomerase 1 inhibitors, administration (e.g. dosages, timing) of G-CSF, eligible human subjects, determination of baseline characteristics, combination treatments, etc. are analogous to the embodiments for ADCs, and thus the invention also provides such embodiments according to this aspect of the invention.Further numbered embodimentsThe following represent numbered embodiments of the invention:1. A method of treating a tumor in a human subject, the method comprising administering a topoisomerase 1 inhibitor to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.2. A method of treating a tumor in a human subject, the method comprising administering an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3. 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.3. An ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target for use in the treatment of a tumor, wherein the use comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baselinecharacteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.4. G-CSF for use in the treatment of a tumor, wherein the use comprises administering an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3.000 cells / pL, and / or(ii) platelet count < 200.000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.5. A combination of (i) an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target and (ii) G-CSF for use in the treatment of a tumor, wherein the use comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3.000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.6. Use of an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target in the manufacture of a medicament for the treatment of a tumor, wherein the treatment comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.7. A method for reducing the risk of severe neutropenia and / or its associated complications in a human subject that is treated with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target, the method comprising administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC. or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g.2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / p.L, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.A method of treating a tumor in a human subject, the method comprisinga. identifying or selecting a human subject eligible for treatment with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target, wherein said human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or (ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2, b. administering a first dose of said ADC to the human subject, and further administering G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject.9. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-8. wherein the tumor target is FOLR1.10. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9, wherein the tumor is a solid tumor.11. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9, wherein the tumor is ovarian cancer.12. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9. wherein the tumor is endometrial cancer.13. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9, wherein the tumor is breast cancer.14. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9, wherein the tumor is lung cancer, such as non-small-cell lung cancer.15. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1 -9, wherein the tumor is mesothelioma.16. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9, wherein the tumor is ovarian epithelial cancer.17. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9. wherein the tumor is primary peritoneal cancer.18. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-9. wherein the tumor is fallopian tube cancer.19. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-18, wherein the tumor is a platinum-resistant tumor.20. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to embodiment 19, wherein the tumor is high grade serous or endometrioid epithelial ovarian carcinoma, primary peritoneal cancer, or fallopian tube cancer, resistant to platinum chemotherapy.21. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-18. wherein the tumor is a platinum- sensitive ovarian cancer.22. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-21, wherein the human subject has previously been treated with at least one anti-cancer therapy.23. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to embodiment 22, wherein the at least one anti-cancer therapy includes treatment with a chemotherapeutic agent.24. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 22-23. wherein the human subject has failed to respond to the at least one anti-cancer therapy prior to treatment with said ADC.25. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-24, wherein the human subject has previously been treated with platinum-based chemotherapy.26. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use orthe use of an ADC in the manufacture of a medicament according to any one of embodiments 1-25, wherein the human subject has previously been treated with carboplatin.27. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-26, wherein the human subject has previously been treated with a VEGF antagonist-based therapy.28. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-27. wherein the human subject has previously been treated with bevacizumab.29. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-28, wherein the human subject has previously been treated with poly-ADP ribose polymerase inhibitor (PARPi) therapy.30. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-29, wherein the human subject has previously been treated with FOLRl-targeted therapy.31. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-30, wherein the human subject has previously been treated with mirvetuximab soravtansine.32. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-31, wherein the human subject has previously been treated with an immune checkpoint inhibitor.33. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-32, wherein the human subject has previously been treated with a PD-1 inhibitor.34. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-33. wherein the human subject has previously been treated with a PD-L1 inhibitor.35. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-34, wherein the human subject has previously been treated with pembrolizumab.36. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-35, wherein the topoisomerase 1 inhibitor is exatecan.37. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to embodiment 36, wherein the ADC comprises linker-drug PA038 set forth in structure 1.38. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-37. wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain that comprises three CDRs having the amino acid sequences of the 3 CDRs as present in SEQ ID NO: 1 (respective CDRs underlined in the sequence shown) and a light chain that comprises three CDRs having the amino acid sequences as present in SEQ ID NO: 2 (respective CDRs underlined in the sequence shown).39. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-38, wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 2.40. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-39, wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain comprising SEQ ID NO: 6 and a light chain comprising SEQ ID NO: 5.41. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-39,wherein the antibody is a F0LR1 antibody and wherein the FOLR1 antibody comprises a heavy chain comprising SEQ ID NO: 4 and a light chain comprising SEQ ID NO: 5.42. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-39, wherein the ADC is rinatabart sesutecan (Rina-S).43. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-42, wherein the ADC is administered at a dosage of between 60 mg / m2and 140 mg / m2, with a maximal total dose per administration of 250 mg.44. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-42, wherein the ADC is administered at a dosage of between 80 mg / m2and 120 mg / m2, with a maximal total dose per administration of 250 mg.45. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-42, wherein the ADC is administered at a dosage of 100 mg / m2, with a maximal total dose per administration of 250 mg.46. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-42, wherein the ADC is administered at a dosage of 120 mg / m2, with a maximal total dose per administration of 250 mg.47. The method, the ADC for use, the G-CSF for use. the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-46, wherein the ADC is administered to the human subject in a cycle of one administration every three weeks (Q3W).48. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to embodiment 47, wherein thecycle is repeated multiple times, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, or more times.49. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48, wherein the G-CSF is human G-CSF.50. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48, wherein the G-CSF is recombinant human G-CSF.51. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48, wherein the G-CSF is filgrastim.52. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48. wherein the G-CSF is lenograstim.53. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48, wherein the G-CSF is pegylated human G-CSF.54. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48, wherein the G-CSF is pegfilgrastim.55. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-48. wherein G-CSF is further administered after one or more or each of the subsequent administrations of the ADC.56. The method, the ADC for use, the G-CSF for use, the combination of ADC and G-CSF for use or the use of an ADC in the manufacture of a medicament according to any one of embodiments 1-55, further comprising administering platelets to the subject.57. A method of treating a tumor in a human subject, the method comprising administering Rina-S toa human subject that has the tumor, wherein the Rina-S is administered at a dosage of 100 mg / m2, with a maximal total dose per administration of 250 mg.58. A method of treating a tumor in a human subject, the method comprising administering Rina-S to a human subject that has the tumor, wherein the Rina-S is administered at a dosage of 120 mg / m2, with a maximal total dose per administration of 250 mg.59. A method of treating a tumor in a human subject, the method comprising administering a dosage of 250 mg Rina-S to the human subject, wherein the subject has a body surface area of at least 2.084 m2.60. Rina-S for use in the treatment of a tumor in a human subject, wherein the Rina-S is administered at a dosage of 100 mg / m2, with a maximal total dose per administration of 250 mg.61. Rina-S for use in the treatment of a tumor in a human subject, wherein the Rina-S is administered at a dosage of 120 mg / m2, with a maximal total dose per administration of 250 mg.62. Rina-S for use in the treatment of a tumor in a human subject, wherein the Rina-S is administered at a dosage of 250 mg, wherein the subject has a body surface area of at least 2.084 m2.63. Use of Rina-S in the manufacture of a medicament for the treatment of a tumor in a human subject, wherein the treatment comprises administering Rina-S at a dosage of 100 mg / m2, with a maximal total dose per administration of 250 mg.64. Use of Rina-S in the manufacture of a medicament for the treatment of a tumor in a human subject, wherein the treatment comprises administering Rina-S at a dosage of 120 mg / m2, with a maximal total dose per administration of 250 mg.65. Use of Rina-S in the manufacture of a medicament for the treatment of a tumor in a human subject, wherein the treatment comprises administering Rina-S at a dosage of 250 mg, wherein the subject has a body surface area of at least 2.084 m2.66. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-65, wherein the subject has a body surface area of at least 2.25 m2. 67. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-65, wherein the subject has a body surface area of at least 2.51 m2.68. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is a solid tumor.69. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is ovarian cancer.70. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is endometrial cancer.71. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is breast cancer.72. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is lung cancer.73. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is non-small-cell lung cancer.74. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is mesothelioma.75. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is ovarian epithelial cancer.76. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is primary peritoneal cancer.77. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is fallopian tube cancer.78. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-67, wherein the tumor is a platinum-resistant tumor.79. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to embodiment 78, wherein the tumor is high grade serous or endometrioid epithelial ovarian carcinoma, primary peritoneal cancer, or fallopian tube cancer, resistant to platinum chemotherapy.80. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-79, wherein the tumor is a platinum- sensitive ovarian cancer.81. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-80, wherein the human subject has previously been treated with at least one anti-cancer therapy.82. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to of embodiment 81, wherein the at least one anti-cancer therapy includes treatment with a chemotherapeutic agent.83. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 81-82, wherein the human subject has failed to respond to the at least one anti-cancer therapy prior to treatment with said ADC.84. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-83, wherein the human subject has previously been treated with platinum-based chemotherapy.85. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-84, wherein the human subject has previously been treated with carboplatin.86. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-85, wherein the human subject has previously been treated with a VEGF antagonist-based therapy.87. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-86, wherein the human subject has previously been treated with bevacizumab.88. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-87, wherein the human subject has previously been treated with poly-ADP ribose polymerase inhibitor (PARPi) therapy.89. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-88, wherein the human subject has previously been treated with FOLR1- targeted therapy.90. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-89, wherein the human subject has previously been treated with mirvetuximab soravtansine.91. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-90, wherein the human subject has previously been treated with an immune checkpoint inhibitor.92. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-91, wherein the human subject has previously been treated with a PD-1 inhibitor.93. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-92, wherein the human subject has previously been treated with a PD-L1 inhibitor.94. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-93, wherein the human subject has previously been treated with pembrolizumab.95. The method. Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-94, wherein Rina-S is administered to the human subject in a cycle of one administration every three weeks (Q3W).96. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-95, wherein the cycle is repeated multiple times, such as 2, 3, 4, 5, 6, 7, 8. 9, 10, 12, 16, 20, or more times.97. The method, Rina-S for use or the use of Rina-S in the manufacture of a medicament according to any one of embodiments 57-96, further comprising administering platelets to the subject.98. A method of treating a tumor in a human subject, the method comprising administering an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds a tumor target, such as Rina-S, to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, and further administering platelets to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.99. The method according to embodiment 98, wherein the antibody is a FOLR1 antibody.100. The method according to embodiment 98 or 99, wherein the tumor is a solid tumor.101. The method according to any one of embodiments 98-100, wherein the tumor is ovarian cancer.102. The method according to any one of embodiments 98-100, wherein the tumor is endometrial cancer.103. The method according to any one of embodiments 98-100, wherein the tumor is breast cancer.104. The method according to any one of embodiments 98-100, wherein the tumor is lung cancer, such as non- small-cell lung cancer.105. The method according to any one of embodiments 98-100, wherein the tumor is mesothelioma.106. The method according to any one of embodiments 98-100. wherein the tumor is ovarian epithelial cancer.107. The method according to any one of embodiments 98-100, wherein the tumor is primary peritoneal cancer.108. The method according to any one of embodiments 98-100, wherein the tumor is fallopian tube cancer.109. The method according to any one of embodiments 98-108, wherein the tumor is a platinum-resistant tumor.110. The method according to embodiment 109, wherein the tumor is high grade serous or endometrioid epithelial ovarian carcinoma, primary peritoneal cancer, or fallopian tube cancer, resistant to platinum chemotherapy.111. The method according to any one of embodiments 98-100, wherein the tumor is a platinum-sensitive ovarian cancer.112. The method according to any one of embodiments 98-111, wherein the human subject has previously been treated with at least one anti-cancer therapy.113. The method according to according to embodiment 112, wherein the at least one anti-cancer therapy includes treatment with a chemotherapeutic agent.114. The method according to any one of embodiments 112-113, wherein the human subject has failed to respond to the at least one anti-cancer therapy prior to treatment with said ADC.115. The method according to any one of embodiments 98-114, wherein the human subject has previously been treated with platinum-based chemotherapy.116. The method according to any one of embodiments 98-115, wherein the human subject has previously been treated with carboplatin.117. The method according to any one of embodiments 98-116, wherein the human subject has previously been treated with a VEGF antagonist-based therapy.118. The method according to any one of embodiments 98-117, wherein the human subject has previously been treated with bevacizumab.119. The method according to any one of embodiments 98-118, wherein the human subject has previously been treated with poly-ADP ribose polymerase inhibitor (PARPi) therapy.120. The method according to any one of embodiments 98-119, wherein the human subject has previously been treated with FOLR1 -targeted therapy.121. The method according to any one of embodiments 98-120, wherein the human subject has previously been treated with mirvetuximab soravtansine.122. The method according to any one of embodiments 98-121, wherein the human subject has previously been treated with an immune checkpoint inhibitor.123. The method according to any one of embodiments 98-122, wherein the human subject has previously been treated with a PD-1 inhibitor.124. The method according to any one of embodiments 98-123, wherein the human subject has previously been treated with a PD-L1 inhibitor.125. The method according to any one of embodiments 98-124, wherein the human subject has previously been treated with pembrolizumab.126. The method according to any one of embodiments 98-125. wherein the topoisomerase 1 inhibitor is exatecan.127. The method according to embodiment 126, wherein the ADC comprises linker-drug PA038 as shown in structure 1.128. The method according to any one of embodiments 98-127, wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain that comprises three CDRs having the amino acid sequences of the 3 CDRs as present in SEQ ID NO: 1 (respective CDRs underlined in the sequence shown) and a light chain that comprises three CDRs having the amino acid sequences as present in SEQ ID NO: 2 (respective CDRs underlined in the sequence shown).129. The method according to any one of embodiments 98-128, wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 1 and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 2.130. The method according to any one of embodiments 98-129, wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain comprising SEQ ID NO: 6 and a light chain comprising SEQ ID NO: 5.131. The method according to any one of embodiments 98-129, wherein the antibody is a FOLR1 antibody and wherein the FOLR1 antibody comprises a heavy chain comprising SEQ ID NO: 4 and a light chain comprising SEQ ID NO: 5.132. The method according to any one of embodiments 98-131, wherein the ADC is rinatabart sesutecan (Rina-S).133. The method according to any one of embodiments 98-132, wherein the ADC is administered at a dosage of between 60 mg / m2and 140 mg / m2, with a maximal total dose per administration of 250 mg.134. The method according to any one of embodiments 98-133, wherein the ADC is administered ata dosage of between 80 mg / m2and 120 mg / m2, with a maximal total dose per administration of 250 mg.135. The method according to any one of embodiments 98-134, wherein the ADC is administered at a dosage of 100 mg / m2, with a maximal total dose per administration of 250 mg.136. The method according to any one of embodiments 98-134, wherein the ADC is administered at a dosage of 120 mg / m2, with a maximal total dose per administration of 250 mg.137. The method according to any one of embodiments 98-136, wherein the ADC is administered to the human subject in a cycle of one administration every three weeks (Q3W).138. The method according to embodiment 137, wherein the cycle is repeated multiple times, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, or more times.139. A method of treating a tumor in a human subject, the method comprising administering a topoisomerase 1 inhibitor to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(iii) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(iv) platelet count < 200,000 / p.L, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.140. A method for reducing the risk of severe neutropenia and / or its associated complications in a human subject that is treated with a topoisomerase 1 inhibitor, the method comprising administering said topoisomerase 1 inhibitor to the human subject and further administering G-CSF on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.141. A topoisomerase 1 inhibitor for use in the treatment of a tumor, wherein the use comprises administering said topoisomerase 1 inhibitor to the human subject and further administering G-CSF on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.142. G-CSF for use in the treatment of a tumor, wherein the use comprises administering a topoisomerase 1 inhibitor to the human subject and further administering G-CSF on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.143. A combination of a topoisomerase 1 inhibitor and G-CSF for use in the treatment of a tumor, wherein the use comprises administering said topoisomerase 1 inhibitor to the human subject and further administering G-CSF on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g.2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.144. Use of a topoisomerase 1 inhibitor in the manufacture of a medicament for the treatment of a tumor, wherein the treatment comprises administering said topoisomerase 1 inhibitor to the human subject and further administering G-CSF on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200.000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.145. A method of treating a tumor in a human subject, the method comprisinga) identifying a human subject eligible for treatment with a topoisomerase 1 inhibitor, wherein said human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3.000 cells / pL. and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.b) administering a first dose of said topoisomerase 1 inhibitor to the human subject, and further administering G-CSF to the human subject on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject.146. A method of treating a tumor in a human subject, the method comprisinga) selecting a human subject eligible for treatment with a topoisomerase 1 inhibitor, wherein said human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL. and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2,b) administering a first dose of said topoisomerase 1 inhibitor to the human subject, and further administering G-CSF to the human subject on the same day as the first administration of said topoisomerase 1 inhibitor, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said topoisomerase 1 inhibitor to the human subject.EXAMPLESAbbreviations

[0148] CNS: central nervous system

[0149] HIV: human immunodeficiency virus

[0150] IHC: immunohistochemistry

[0151] EOC: epithelial ovarian cancer

[0152] FRa: folate receptor a (also “FOLR1”)

[0153] HER2: human epidermal growth factor receptor 2

[0154] HR: hormone receptor

[0155] NSCEC: non-small cell lung cancer

[0156] RECIST: response evaluation criteria in solid tumors

[0157] TRAE: treatment related adverse event

[0158] ECOG: Eastern Cooperative Oncology GroupExample 1: Study 1: Safety, tolerability and anti-tumor activity testing of Rina- S

[0159] The goal of this study 1 is to determine the safety, tolerability and maximum tolerated dose (MTD) of rinatabart sesutecan (Rina-S; PRO 1184). FIG. 1 shows the study 1 design for the drug dosage schedule. Part A (dose escalation) included five tumor types. Part B (dose expansion) included four tumor specific cohorts and one basket cohort. Incremental doses of Rina-S were administered to 5 different cancer patients over 21 days, ranging from 60 mg / m2, to 180 mg / m2at the end of the maximum therapeutic dose. Four tumor-specific cohorts and one basket cohort (ovarian cancer) were included in the study 1.

[0160] Safety assessments include physical examination, vital signs and body measurements, standard clinical laboratory assessments such as hematology, blood biochemistry, and monitoring of adverse events and serious adverse events. Rina-S was well tolerated at least up to 120 mg / m2, with common adverse events including hematologic cytopenias, gastrointestinal adverse events and fatigue.

[0161] Anti-tumor activity was determined. FIG. 2 shows the best change from baseline in targetlesion tumor burden for fifteen patients: ovarian and endometrial cancer. FIG. 3 shows the percentage change in tumor size over time: ovarian and endometrial cancer. FIG. 4 shows the reduction in CA-125 levels.

[0162] Rina-S showed encouraging antitumor activity across FOLR1 expression levels in this heavily pretreated patient population and most patients had a reduction in target lesion.Example 2: Dose escalation and dose expansion of the Study 1

[0163] As continuation of the Study 1, the patients with ovarian cancer in Part B (cohort Bl, ovarian cancer dose expansion) were randomized 1:1 to Rina-S 100 mg / m2or Rina-S 120 mg / m2. The inclusion criteria for cohort B 1 are as shown below.a) Histologically or cytologically confirmed ovarian cancer (OC) (must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer) b) Prior treatment (1-3 lines for PROC or 4 lines regardless of platinum-sensitivity status)c) ECOG PS 0-1d) Measurable disease per RECIST vl.le) Adequate hematologic, hepatic, renal, and cardiac function

[0164] Table 1 shows patient demographics and disease characteristics in cohort Bl.Table 1: Ovarian Cancer Dose Expansion - Patient Demographics and Disease Characteristics Rina-S Rina-S100 mg / m2120 mg / m2Cohort Bl: OC Dose Expansion n = 22 n = 20Age, median (range), years 62.5 (42-82) 64.5 (37-83) Prior lines of therapy, median (range) 3 (1-5) 3 (1-4) Bevacizumab, n (%) 20 (90.9) 18 (90.0) PARPi, n (%) 15 (68.2) 12 (60.0) Mirvetuximab soravtansine, n (%) 4 (18.2) 4 (20.0)Platinum sensitivity status, n (%)Resistant 21 (96) 18 (90.0) Sensitive 1 (4.5) 2 (10.0)Example 3: Overall safety of Rina-S

[0165] Table 2 shows overall safety of cohort Bl. OC Dose Expansion at 100 and 120 mg / m2: TEAEs of any grade and grade 3-4 were reported in 100% and 65%-72.7% of patients, respectively; TEAEs leading to dose reductions occurred in 22.7%-50% of patients; safety profdes were similar between cohorts. As can be seen in Fig. 5, cytopenias, including neutropenia, were the most common Grade 3 / 4 TEAEs.Table 2: Overall Safety of Cohort Bl: OC Dose ExpansionCohort Bl: OC Dose ExpansionRina-S Rina-SOverall Safety, % 100 mg / m2, n = 22 120 mg / m2, n = 20Any- grade TEAE 100 100Grade 3 / 4b 72.7 65.0TEAEs leading to dose reductions 22.7 25.0Prophylactic G-CSF use36.4 55(not permitted in cycle 1)

[0166] No ocular toxicity, neuropathy, or interstitial lung disease was observed. The emerging safety profile of Rina-S in Part B is consistent with Part A.

[0167] Prophylactic G-CSF use was not permitted in cycle 1.

[0168] Exploratory Multivariate analyses (MVA) were conducted on data from all 100 mg / m2and 120 mg / m2patients (including patients with ovarian cancer, endometrial cancer and other tumor types) to the potential impact of dose, baseline demographic and baseline laboratory parameters on any grade >3 TEAE and / or SAEs (serious adverse events). Rina-S dose as well as the patient baselinecharacteristics including tumor type, ECOG, prior radiotherapy (yes or no), eGFR status, hemoglobin count, neutrophil count, and platelet count were assessed in the MVA. The general trends based on laboratory data corroborated with the TEAE of grade >3 and / or SAEs on certain parameters, and the cut-points for eGFR, HgB, ANC and platelets were refined through additional univariate and multivariate analyses.

[0169] Analysis of post-treatment risk of severe neutropenia indicated that the lower baseline ANC (< 3,000 cells / pL), eGFR (< 60 mL / min / 1.73 m2) and platelets (< 200,000 / pL) are associated with increased risk (Fig. 6).

[0170] Furthermore, exposure -response analysis showed that the probability of grade >3 hematological TEAEs (eg, grade >3 neutropenia and grade >3 thrombocytopenia) is higher with increasing exposure (ac-exatecan). PK simulation results showed that Cmax of ac-exatecan and u-exatecan in high BSA subjects (>2.2 m2) were approximately 7% and 60% higher relative to that in the overall population. With capping the dose at 250 mg, the exposures (ie, ac-exatecan) in subjects with high BSA are predicted to be approximately similar to the overall population.Example 4: Determination of anti-tumor activity of Rina-S in the Study 1

[0171] As continuation of the Study 1, the antitumor activity of Rina-S was evaluated in dose escalation and dose expansion.

[0172] In Part A (dose escalation), Rina-S showed encouraging antitumor activity in heavily pretreated patients with OC and endometrial cancer (EC). Table 3 shows the results of antitumor activity for Part A. Fig. 7 shows the best change in target lesion for OC and EC dose escalation.Table 3: Part A: OC and EC Dose EscalationRina-S (100 mg / m2and 120 mg / m2), n = 26aConfirmed ORR,b% (95% CI) 30.8 (14.3-51.8)Best overall response,bn (%)PR 8 (30.8)SD 15 (57.7)PD 3 (11.5)DCR, % (95% CI) 88.5 (69.8-97.6)Median DOR, weeks (95% CI) 35.3 (20.14-NE)“Response-evaluable population. The response evaluable population set includes all treated patients who had a baseline and at least 1 evaluable postbaseline tumor assessment, or who had documented progression of disease at any time after the first dose of Rina-S. Response assessment per RECIST vl.l.bBased on investigator assessment.PR: partial response; SD: stable disease; PD: disease progression; DCR: disease control rate; DOR: duration of response

[0173] In Part B, Rina-S showed encouraging antitumor activity at 120 mg / m2, including a complete response, in heavily pretreated patients with OC. Table 4 shows the results of antitumor activity for cohort B 1 of Part B. The Treatment duration range was 3.0-42.0+ weeks. The Median on-study followup was 24 weeks. Fig. 8 shows the best change in target lesion for OC dose expansion.Table 4: Cohort Bl: OC Dose Expansion0Rina-S Rina-S(100 mg / m2), n = 22b(120 mg / m2), n = 18bConfirmed ORR,b22.7 55.6Best overall response,bn (%)CR 1 (4.5) 2 (11.1)PR 4 (18.2) 8 (44.4)SD 14 (63.6) 6 (33.3)PD 3 (13.6) 1 (5.6)Not evaluable 0 1 (5.6)86.4 88.9DCR, % (95% CI)(65.1-97.1) (65.3-98.6)Median DOR (95% CI) NR (NR-NR)“Based on investigator assessment.bResponse-evaluable population.cOne patient in the 120 mg / m2cohort with prior mirvetuximab soravtansine was not response-evaluable.

[0174] As shown in Fig. 9, most responses with Rina-S 120 mg / m2were observed early (at week 6) and all confirmed responses with 120 mg / m2were ongoing at the time of data cutoff in patients with heavily pretreated OC. As shown in Fig. 10. responses in patients with OC were observed across all FRa expression levels.Example 5: Recruitment of patients for the study 2

[0175] Approximately 530 patients with platinum resistant ovarian cancer (PROC) across global sites are randomized. The inclusion and exclusion criteria for subjects are as shown below.

[0176] Key Inclusion Criteria• Patients must have histologically or cytologically confirmed high grade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.• Patients must have received 1 to 4 prior lines of therapy.• Patients must have received prior treatment with at least 1 of the following therapies:o Platinum chemotherapyo Bevacizumab, unless the patient has a documented contraindicationo Patients with known or suspected deleterious germline or somatic BRCA mutations must have been treated with a poly ADP-ribose polymerase (PARP) inhibitoro Mirvetuximab soravtansine, if:■ Mirvetuximab soravtansine is available in the enrollment region, and ■ The patient is eligible based on positive FRa expression per an FDA-approved (or local equivalent) test, and■ The patient does not have a documented medical exception, including chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment / monitoring, such as uncontrolled glaucoma, wet age- related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and / or monocular vision.Diagnostic testing (e.g., for FRa and BRCA) is performed in a laboratory certified by Clinical Laboratory Improvement Amendments (CLIA; or local equivalent) using a test approved by the relevant regulatory body (FDA or local equivalent).• Patients must have platinum-resistant disease:o Patients who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum therapy, and must have either had a response (complete response [CR] or partial response [PR]) or had non-measurable disease at the start of platinum-based therapy, and then progressed between > 91 days and < 183 days after the date of the last dose of platinum.o Patients who have received 2 to 4 lines of platinum-based therapy must have progressed on or within 183 days after the date of the last dose of platinum.

[0177] Key Exclusion Criteria• Prior therapy with an antibody-drug conjugate containing a topoisomerase 1 inhibitor.• Have primary platinum-refractory disease, defined as ovarian cancer that did not respond (CR or PR) to or progressed < 91 days after the last dose of a first-line platinum-containing regimen. • History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS >90%), including, but not limited to, adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ, or Stage I uterine cancer.• Known active central nervous system metastases or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids and anticonvulsants prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. Patients with suspected brain metastases at screening should undergo a computed tomography (CT) / magnetic resonance imaging (MRI) of the brain prior to study entry.• Hospitalization or clinical symptoms due to gastrointestinal obstruction within the past 91 days or radiographic evidence of gastrointestinal obstruction at the time of screening. Enrollment of patients who currently require parenteral nutrition must be discussed with the study medical monitor to determine eligibility.• Ascites requiring frequent paracentesis (more often than approximately every 4 weeks) for symptomatic management. Enrollment of patients with an indwelling peritoneal catheter must be discussed with the medical monitor to determine eligibility.

[0178] The 530 patients with PROC consists of: approximately 420 patients, including: patientswhose tumors do not have high FRa expression per the Ventana FOLR1-2.1 RxDx Assay (or local equivalent test) (i.e., FRa expression <75% PS2+), patients previously treated with mirvetuximab soravtansine, and patients who are not candidates for mirvetuximab soravtansine due to medical conditions; and approximately 110 patients with high FRa expression (i.e., FRa expression >75% PS2+) who have not previously received mirvetuximab soravtansine, but are enrolled in regions where mirvetuximab soravtansine is not available therapy.Example 6: Test Product, Dose, and Mode of Administration of the study 2

[0179] Patients are randomized in a 1:1 ratio to receive treatment with Rina-S vs Investigator’s Choice (IC) (paclitaxel, topotecan, PLD, or gemcitabine).

[0180] Rinatabart Sesutecan (Rina-S): A dose of 120 mg / m2Rina-S is administered on Day 1 of a 21-day treatment cycle. Rina-S is administered as a 30-minute intravenous (IV) infusion. The total maximum administered dose of Rina-S should not exceed 250 mg, regardless of BSA.

[0181] Investigator’s Choice (IC) Therapies: Patients will receive one of the following chemotherapies on a 4- week cycle at the discretion of the investigator: Paclitaxel 80 mg / m2as a 1-hour IV infusion on Days 1. 8, and 15 every 4 weeks (Q4W); Topotecan 4 mg / m2as a 30-minute IV infusion on Days 1, 8 and 15 Q4W, or 1.25 mg / m2as a 30minute IV infusion on Days 1-5 Q3W; Pegylated liposomal doxorubicin (PLD) 40 mg / m2as a 1 mg / min IV infusion on Day 1 Q4W. After Cycle 1, the drug can be delivered as a 1-hour infusion; and Gemcitabine 1000 mg / m2, or 800 mg / m2at investigator’s discretion, as a 30-minute IV infusion on Days 1, 8, and 15 Q4W.

[0182] Required Concomitant Therapy:

[0183] Initiate G-CSF prophylactic growth factor in cycle 1 with close monitoring for patients who may be susceptible to severe neutropenia:(i) baseline ANC < 3,000 cells / pL and / or(ii) baseline platelets < 200,000 cells / pL and / or(iii) baseline eGFR < 60 mL / min / 1.73 m2and / or(iv) history of neutropenia- associated complications in prior chemotherapy regimens.G-CSF administration is initiated in such eligible patients at least one day after administration of Rina-S, e.g. on day 2, 3, 4, 5, 6, 7 or 8 of treatment (considering the day of administration of Rina-S as day 1 of the cycle).

[0184] Prophylactic use of growth factors for all other patients at potential risk of neutropenia is required in accordance with national or local clinical practice guidelines (e.g., ASCO Guidelines, ESMO Guidelines).

[0185] Close monitoring and platelet transfusion, in accordance with national or local clinical practice guidelines (e.g., ASCO Guidelines, ESMO Guidelines), are strongly recommended for patients who may be more susceptible to severe thrombocytopenia (baseline ANC < 3,000 cells / pL and / or baseline platelets < 200,000 cells / pL and / or eGFR < 60 mL / min / 1.73 m2).

[0186] There is an estimated 4- to 6-month treatment period (the duration of treatment is expected to vary for each patient). Patients continue to receive study drug until the first instance of disease progression, unacceptable toxicity, investigator decision, consent withdrawal, pregnancy, death, or premature study termination by the sponsor. Patients who present equivocal findings of progression may be allowed to continue the study drug with approval of the medical monitor and if, in the opinion of the investigator, the patient is clinically stable. If progression is confirmed unequivocally on the next response assessment, study drug is discontinued.Example 7: Determination of anti-tumor activity of Rina-S in the study 2Efficacy AnalysisPrimary Endpoint: PFS per Investigator Assessment

[0187] This study is designed to evaluate PFS in patients with PROC receiving either Rina-S or IC, with the hypothesis that Rina-S is superior to IC in PFS. The study is considered to have met this objective if Rina-S is superior to IC in PFS at the final analysis of PFS.

[0188] PFS is defined as the time from randomization to the first documentation of disease progression (PD) per RECIST vl.l according to investigator assessment, or to death due to any cause, whichever comes first.PFS is calculated as follows:PFS (days) = (date of first documented PD or death - date of randomization) + 1 Key Secondary Endpoints:Overall Survival

[0189] OS is defined as the time from randomization to death due to any cause. OS is calculated as follows:OS (days) = (date of death - date of randomization + 1).Ob jective Response Rate

[0190] ORR is defined as the percentage of the patients who have a best response of confirmed CR or PR using RECIST vl.l. Responses per investigator will be used as the primary analysis of ORR and responses based on blinded independent central review (BICR), incorporating status of CA-125 normalization for CR, will be used as a sensitivity analysis.Adverse events

[0191] Investigators and study personnel report all adverse events (AEs) and SAEs whether elicited during patient questioning, discovered during physical examination, laboratory testing and / or other means by recording them in EDC and / or the SAE form, as appropriate.

[0192] When documenting hematological findings, each affected cell lineage is reported individually (eg, red blood cells, neutrophils, platelets) rather than reporting pancytopenia as a single entity. Thus, instead of reporting pancytopenia, the following is reported:Anemia (if hemoglobin is decreased),Neutropenia (if neutrophil counts are decreased), orThrombocytopenia (if platelet counts are decreased).Example 8: Recruitment of patients for the study 3

[0193] A phase 3 randomized, open-label study of rinatabart sesutecan (Rina-s) versus treatment of investigator’s choice in patients with endometrial cancer (EC) after platinum-based chemotherapy andPD(L)-1 therapy.

[0194] Approximately 544 patients with advanced, recurrent, or metastatic EC are randomized.

[0195] Key Inclusion Criteria• Patients must have histologically or cytologically confirmed advanced, recurrent, metastatic, or primary unresectable endometrial cancer (EC; any subtype excluding neuroendocrine tumors, carcinosarcoma, or endometrial sarcoma).• Patients must have received at least 1, but not more than 3. prior lines of therapy:o Patients must have received prior platinum-based chemotherapy and a PD(L)-1 inhibitor, either separately or in combinationo If the tumor recurred more than 12 months after completion of platinum-based chemotherapy administered with curative intent or in the adjuvant setting, additional platinum-based chemotherapy must be administered for recurrent or metastatic disease, if eligible, for rechallenge as determined by the investigatoro Prior induction plus maintenance is considered 1 line of therapyo Hormonal therapy alone (ie, without chemotherapy) will not be counted as a separate line of therapy.

[0196] Key Exclusion Criteria• Prior therapy with an antibody-drug conjugate containing a topoisomerase 1 inhibitor.• Has a past or current malignancy other than the inclusion diagnosis before the planned first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5- year OS >90%), including, but not limited to, adequately treated cervical carcinoma of Stage IB or less, noninvasive basal cell or squamous cell skin carcinoma, noninvasive superficial bladder cancer, ductal carcinoma in situ, or any past malignancy considered cured for >3 years (ie, eligible patients must have complete response of >3 years duration).• Known active central nervous system metastases or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for atleast 4 weeks prior to study entry after completion of brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids and anticonvulsants prescribed for symptoms associated with brain metastases for at least 7 days prior to the planned first dose of study drug. Patients with suspected brain metastases at screening should undergo a computed tomography (CT) / magnetic resonance imaging (MRI) of the brain prior to study entry.• Hospitalization or clinical symptoms due to gastrointestinal obstruction within the past 91 days or radiographic evidence of gastrointestinal obstruction at the time of screening. Enrollment of patients who currently require parenteral nutrition must be discussed with the study medical monitor to determine eligibility.Example 9: Test Product, Dose, and Mode of Administration of the study 3

[0197] Patients are randomized in a 1:1 ratio to receive treatment with Rina-S vs IC (paclitaxel or doxorubicin).

[0198] Rinatabart Sesutecan (Rina-S): Rina-S is administered on Day 1 of a 21 -day treatment cycle at a dose of 100 mg / m2. Rina-S will be administered as a 30-minute intravenous (IV) infusion. The total maximum administered dose of Rina-S should not exceed 250 mg, regardless of BSA.

[0199] Investigator’s Choice Therapies: Patients will receive one of the following chemotherapies at the discretion of the investigator:(i) Paclitaxel 80 mg / m2as a 1-hour IV infusion on Days 1, 8, and 15 every 4 weeks (Q4W), or (ii) Doxorubicin 60 mg / m2as a 1 mg / min IV infusion on Day 1 every 3 weeks (Q3W). After Cycle 1. doxorubicin can be delivered as a 1-hour infusion Q3W.

[0200] Required Concomitant Therapy for Rina-S :

[0201] For patients randomized to Rina-S treatment, initiate G-CSF prophylactic growth factor in cycle 1 with close monitoring for patients who may be susceptible to severe neutropenia:(i) baseline ANC < 3.000 cells / pL and / or(ii) baseline platelets < 200,000 cells / pL and / or(iii) baseline eGFR < 60 mL / min / 1.73 m2and / or(iv) history of neutropenia-associated complications in prior chemotherapy regimens.G-CSF administration is initiated in such eligible patients at least one day after administration of Rina-S, e.g. on day 2, 3, 4, 5, 6, 7 or 8 of treatment (considering the day of administration of Rina- S as day 1 of the cycle).

[0202] Prophylactic use of growth factors for all other patients (regardless of Rina-S / IC treatment) at potential risk of neutropenia is required in accordance with national or local clinical practice guidelines (e.g., ASCO Guidelines, ESMO Guidelines).

[0203] Patients continue to receive study drug until the first instance of disease progression, unacceptable toxicity, investigator decision, consent withdrawal, pregnancy, death, or premature study termination by the sponsor. Patients who present equivocal findings of progression may be allowed to continue the study drug with approval of the medical monitor and if, in the opinion of the investigator, the patient is clinically stable. If progression is confirmed unequivocally on the next response assessment, study drug is discontinued.Example 10: Determination of anti-tumor activity of Rina-S in the study 3Efficacy Analysis

[0204] This study is designed to evaluate PFS and OS in patients with advanced, recurrent, or metastatic EC receiving either Rina-S or IC, with the hypotheses that Rina-S is superior to IC in PFS and OS. The study is considered to have met its objective if Rina-S is superior to IC in PFS and / or OS. The key secondary endpoint is ORR, with the hypothesis that Rina-S is superior to IC in ORR. Dual Primary Endpoints: PFS per Investigator Assessment and OSPFS

[0205] PFS is defined as the time from randomization to the first documentation of disease progression (PD) per RECIST vl.l according to investigator assessment, or to death due to any cause, whichever comes first.OS

[0206] OS is defined as the time from randomization to death due to any cause.Adverse events

[0207] Investigators and study personnel will report all AEs and SAEs whether elicited during patient questioning, discovered during physical examination, laboratory testing and / or other means by recording them in EDC (electronic data capture) and / or the SAE form, as appropriate.

[0208] When documenting hematological findings, each affected cell lineage is reported individually (eg, red blood cells, neutrophils, platelets) rather than reporting pancytopenia as a single entity. Thus, instead of reporting pancytopenia, the following is reported:• Anemia (if hemoglobin is decreased),• Neutropenia (if neutrophil counts are decreased), or• Thrombocytopenia (if platelet counts are decreased).Example 11: Clinical Evaluation of Rinatabart Sesutecan with Risk Mitigation Measures

[0209] Rina-S was administered intravenously every three weeks (Q3W) at doses of 100 mg / m2or 120 mg / m2to human subjects with ovarian or endometrial cancer. Enhanced risk mitigation measures were implemented across the clinical program from a certain time point onwards. These measures included:a) prophylactic administration (starting one to a few days after the first administration of Rina-S, i.e. in the first cycle) of granulocyte colony-stimulating factor (G-CSF) with close monitoring starting from Cycle 1 for subjects who may be more susceptible to severe neutropenia (i.e. subjects with: baseline ANC <3,000 cells / pL, and / orbaseline platelets <200,000 cells / pL, and / orbaseline eGFR <60 mL / min / 1.73 m2, and / orhistory of neutropenia-associated complications in prior chemotherapy regimens);b) prophylactic use of G-CSF according to national or local clinical practice guidelines (e.g.ASCO or ESMO Guidelines) in other subjects at potential risk of neutropenia;c) following dose modification and management guidelines in protocols for hematologic AEs(i.e., neutropenia, neutropenic fever, thrombocytopenia, and anemia); andd) a maximum total dose of 250 mg of Rina-S to limit exposure in subjects with high body surface area.

[0210] Hematologic toxicides, including neutropenia, anemia, thrombocytopenia, and febrile neutropenia, were assessed. These hematologic toxicity TEAEs occurred predominantly early during treatment. For example, across all 175 subjects with ovarian cancer who received Rina-S at 120 mg / m2in study 1, the median time to first onset of each individual hematologic toxicity TEAE was less than 1 month, ranging from 14 days to 29.5 days. Across all 92 subjects with endometrial cancer who received Rina-S at 100 mg / m2in study 1, the median time to first onset for each individual hematologic toxicity TEAE was approximately 1 month or less, ranging from 11 days to 31 days.

[0211] In subjects with ovarian cancer treated at 120 mg / m2, implementation of the risk mitigation measures resulted in a reduction in the incidence of any-grade hematologic treatment-emergent adverse events (TEAEs) from 82.3% (N=62) to 54.0% (N=l 13). Reductions were observed across individual cytopenias, including neutropenia (74.2% to 35.4%), thrombocytopenia (48.4% to 26.5%), and anemia (67.7% to 44.2%). Grade >3 hematologic TEAEs decreased from 61.3% to 34.5%, and hematologic serious adverse events decreased from 14.5% to 5.3%. Dose reductions and dose delays or interruptions were also reduced (24.2% to 17.7% and 37.1% to 15.9%, respectively), and no treatment discontinuations due to hematologic toxicity were observed following implementation.

[0212] In subjects with endometrial cancer treated at 100 mg / m2, the risk mitigation measures resulted in reductions in neutropenia (56.0% [N=25] to 22.4% [N=67]) and anemia (56.0% to 40.3%) for any-grade events, and a reduction in Grade >3 hematologic TEAEs from 64.0% to 32.8%. Dose modifications due to hematologic toxicity were also reduced (52.0% to 19.4%).

[0213] Taken together, the available data suggest a positive trend of improved outcomes with the risk mitigation strategy implemented across the Rina-S clinical program. The data demonstrated that the application of prophylactic growth factor support, structured monitoring, and controlled dosing reduces both the incidence and severity of hematologic toxicities associated with Rina-S, whilemaintaining therapeutic activity, thereby providing an improved and clinically manageable safety profile.

[0214] Having thus described the basic concepts, it may be rather apparent to those skilled in the art after reading this detailed disclosure that the foregoing detailed disclosure is intended to be presented by way of example only and is not limiting. Various alterations, improvements, and modifications may occur and are intended to those skilled in the art, though not expressly stated herein. These alterations, improvements, and modifications are intended to be suggested by this disclosure and are within the spirit and scope of the exemplary embodiments of this disclosure.

[0215] Moreover, certain terminology has been used to describe embodiments of the present disclosure. For example, the terms “one embodiment,” “an embodiment.” and “some embodiments” mean that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Therefore, it is emphasized and should be appreciated that two or more references to “an embodiment” or “one embodiment” or “an alternative embodiment” in various portions of this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined as suitable in one or more embodiments of the present disclosure.

Claims

1.WHAT IS CLAIMED IS:1) A method of treating a tumor in a human subject, the method comprising administering an antibody-drug conjugate (ADC) comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target to the human subject, and further administering a G-CSF to the human subject on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.2) The method of claim 1, wherein the antibody that binds to a tumor target is a FOLR1 antibody.3) The method of claim 1 or 2, wherein the tumor is a solid tumor, preferably selected from the group consisting of:a) ovarian cancer,b) endometrial cancer,c) breast cancer,d) lung cancer, such as non-small-cell lung cancer, ande) mesothelioma.4) The method of any one of claims 1-3, wherein the tumor is ovarian cancer, such as ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.5) The method of any one of claims 1-3, wherein the tumor is endometrial cancer.6) The method of any one of claims 1-4, wherein the tumor is a platinum-resistant tumor, optionally a high grade serous or endometrioid epithelial ovarian carcinoma, primary peritoneal cancer, or fallopian tube cancer, resistant to platinum chemotherapy.7) The method of any one of claims 1-4 or 6, wherein the tumor is platinum-resistant ovarian cancer.8) The method of any one of claims 1-4, wherein the tumor is platinum-sensitive ovarian cancer.9) The method of any one of the preceding claims, wherein the human subject has previously been treated with at least one anti-cancer therapy, optionally wherein(a) the at least one anti-cancer therapy includes treatment with a chemotherapeutic agent, and / or (b) wherein the human subject has failed to respond to the at least one anti-cancer therapy prior to treatment with said ADC.10) The method of any one of the preceding claims, wherein the human subject has previously been treated with at least one anti-cancer therapy selected from the group consisting of:(a) platinum-based chemotherapy, such as carboplatin;(b) a VEGF antagonist-based therapy, optionally bevacizumab;(c) poly-ADP ribose polymerase inhibitor (PARPi) therapy;(d) FOLR1 -targeted therapy, such as mirvetuximab soravtansine; and(e) treatment with an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, for example pembrolizumab.11) The method of any one of the preceding claims, wherein the topoisomerase 1 inhibitor is exatecan, for instance wherein the ADC comprises the linker-drug PA038 as set forth in structure 1.12) The method of any one of the preceding claims, wherein the ADC is rinatabart sesutecan (Rina-S).13) The method of claim 12, wherein Rina-S is administered at a dosage of between 60 mg / m2and 140 mg / m2, for example a dosage of between 80 mg / m2and 120 mg / m2, with a maximal total dose per administration of 250 mg.14) The method of claim 13, wherein Rina-S is administered at a dosage of 100 mg / m2, with a maximal total dose per administration of 250 mg.15) The method of claim 13, wherein Rina-S is administered at a dosage of 120 mg / m2, with a maximal total dose per administration of 250 mg.16) The method of any one of the preceding claims, wherein the ADC is administered to the human subject in a cycle of administrations, for instance one administration every three weeks (Q3W).17) The method of claim 16, wherein the cycle is repeated multiple times, such as 2, 3. 4, 5, 6. 7, 8, 9.10, 12, 16, 20, or more times.18) The method of any one of the preceding claims, wherein the G-CSF is human G-CSF, such as recombinant human G-CSF, for example filgrastim or lenograstim, optionally modified, such as pegylated, for example pegfilgrastim.19) The method of any one of the preceding claims, wherein G-CSF is also administered after one or more or each subsequent administration(s) of the ADC.20) The method of any one of the preceding claims, further comprising administering platelets to the subject.21) An ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target for use in the treatment of a tumor, wherein the use comprises administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL. and / or(ii) platelet count < 200,000 / pL, and / or(iii) baseline estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.22) A method for reducing the risk of severe neutropenia and / or its associated complications in a human subject that is treated with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target, the method comprising administering said ADC to the human subject and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject, wherein the human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL, and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.23) A method of treating a tumor in a human subject, the method comprisinga) identifying a human subject eligible for treatment with an ADC comprising a topoisomerase 1 inhibitor conjugated to an antibody that binds to a tumor target, wherein said human subject has one or more of the following baseline characteristics:(i) absolute neutrophil count (ANC) < 3,000 cells / pL. and / or(ii) platelet count < 200,000 / pL, and / or(iii) estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2,b) administering a first dose of said ADC to the eligible human subject identified in step (a), and further administering G-CSF on the same day as the first administration of said ADC, or, preferably, to the human subject at a time between 1 and 10 days, more preferably between 1 and 7 days, e.g. 2, 3, 4, 5, or 6 days, after the first administration of said ADC to the human subject.24) A method of treating a tumor in a human subject, the method comprising administering Rina-S to a human subject that has the tumor, wherein the Rina-S is administered at a dosage of 100 mg / m2or 120 mg / m2, with a maximal total dose per administration of 250 mg.25) A method of treating a tumor in a human subject, the method comprising administering a dosage of 250 mg Rina-S to the human subject, wherein the subject has a body surface area of at least 2.084 m2, e.g at least 2.1 m2, e.g. at least 2.2 m2, e.g. at least 2.51 m2.

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