Treatment methods for CD20-expressing B-cell carcinoma

Abstract

The present invention relates to an improved method for mitigating cytokine release syndrome following interruption of an epcolitamab administration schedule for the treatment of CD20 B-cell expressing cancer.

Description

Technical Field

[0001] The present invention relates to the use of epcoritamab for the treatment of CD20 B cell cancer in the case of a delay in the dosing schedule to minimize cytokine release after restarting dosing.

Background Art

[0002] A promising approach to improving targeted antibody therapy is by specifically delivering cytotoxic cells to antigen-expressing cancer cells. This concept of using T cells to efficiently kill tumor cells is described in Staerz, et.al., 1985, Nature 314:628-631). However, the first clinical studies were somewhat disappointing due to the low potency of bispecific antibodies, severe adverse effects (cytokine storm) and immunogenicity (Muller and Kontermann, 2010, BioDrugs 24:89-98). Advances in the design and application of bispecific antibodies have partially overcome the initial barrier of cytokine storm and improved clinical efficacy without dose-limiting toxicity (Garber, 2014, Nat.Rev.Drug Discov.13:799-801; Lum and Thakur, 2011, BioDrugs 25:365-379). The absence or silencing of the Fc domain was important to overcome the initial barrier of cytokine storm described for catumaxomab (Berek et al. 2014, Int.J.Gynecol.Cancer 24(9):1583-1589; Mau-Sorensen et al. 2015, Cancer Chemother.Pharmacol.75:?1065-1073).

[0003] The CD20 molecule (also known as human B lymphocyte-restrictive differentiation antigen or Bp35) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B lymphocytes and mature B lymphocytes (Valentine et al. (1989) J. Biol. Chem. 264(19):11282-11287; and Einfield et al., (1988) EMBO J. 7(3):711-717). CD20 is found on the surface of over 90% of B cells derived from peripheral blood or lymphoid organs, is expressed during early pre-B cell development, and persists until plasma cell differentiation. CD20 is present in both normal and malignant B cells. CD20 is expressed in over 90% of B-cell non-Hodgkin lymphomas (NHL) (Anderson et al. (1984) Blood 63(6):1424-1433), but is not found in hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues (Tedder et al. (1985) J.Immunol. 135(2):973-979).

[0004] Bispecific antibodies that bind to both CD3 and CD20 may be useful in therapeutic situations where specific targeting of CD20-expressing cells and T-cell-mediated killing are desired. CD3xCD20 bispecific antibodies have been discussed in the art, for example, in Hutchings et al. (2021) Lancet 398:1157-1169; Gall et al. (2005) Experimental Hematology 33:452; Stanglmaier et al. (2008) Int.J.Cancer:123,1181; Wu et al. (2007) Nat Biotechnol.25:1290-1297; Sun et al. (2015) Science Translational Medicine As described in 7,287ra70; U.S. Patent No. 10,544,220; U.S. Patent Application Publication No. 2021 / 0371538; International Publication No. 2011014659; International Publication No. 2011090762; International Publication No. 2011028952; International Publication No. 2014047231; International Publication No. 2016 / 110576; and International Publication No. 2021 / 224499, progress has been made in mitigating cytokine release syndrome after initial administration of CD3xCD20 bispecific antibodies, but there is a need for methods to minimize cytokine release syndrome after delays in the administration schedule. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] U.S. Patent No. 10,544,220 [Patent Document 2] U.S. Patent Application Publication No. 2021 / 0371538 [Patent Document 3] International Publication No. 2011014659 [Patent Document 4] International Publication No. 2011090762 [Patent Document 5] International Publication No. 2011028952 [Patent Document 6] International Publication No. 2014047231

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Non-licensed literature

[0006] [Non-licensed document 1] Staerz, et.al.,1985,Nature 314:628-631)

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[0007] [Figure 1] An example of defining a safe repriming window is provided based on a PopPK model after missing the first full dose of EPKINLY / epcolitamab. The horizontal dotted line shows the trough concentration at the end of the priming interval. The vertical dotted line shows the time from the priming dose after missing the first full dose until the epcolitamab concentration falls below the trough concentration. [Figure 2] Definition of a safe repriming window based on the rTTE model after missing the first full dose of epcolitamab, abbreviations: CRS = cytokine release syndrome; rTTE = repeated event time. The dashed curve represents the time-dependent hazard for the reference regimen in which the first full dose was administered on schedule. The curve with an asterisk represents the time-dependent hazard for the delayed regimen in which the first full dose was delayed by one week. The curve with a circle represents the time-dependent hazard for the delayed regimen in which the first full dose was delayed by two weeks. The horizontal dotted line shows the peak instantaneous hazard from the reference regimen. [Figure 3]rTTE model-based simulation showing the length of the safe re-priming window after dose delay. Abbreviations: C1 = Cycle 1; rTTE = repeated event time. The horizontal dashed line indicates the threshold at which >95% of subjects can safely resume dosing after the delay. The vertical dashed lines (left to right) represent the switch-safe re-priming windows after missing the mid / 1st full dose, 2nd full dose, and full dose after Cycle 1, respectively. [Figure 4] Simulation PK profiles - reference (nominal dosing schedule) compared to delayed dosing (with or without re-priming) (Scenario 1). PI = prediction interval; PK = (one or more) pharmacokinetics. The solid line represents the median of the simulated individual PK profiles. The dashed line represents the geometric mean of the simulated individual PK profiles. The shaded area represents the 90% PI. [Figure 5] Simulated PK profiles - reference (nominal dosing schedule) compared to delayed dosing (with or without re-priming) (Scenario 2). PI = prediction interval; PK = (one or more) pharmacokinetics. The solid line represents the median of the simulated individual PK profiles. The dashed line represents the geometric mean of the simulated individual PK profiles. The shaded area represents the 90% PI. [Figure 6] Simulated PK profiles - reference (nominal dosing schedule) compared to delayed dosing (with or without re-priming) (Scenario 3). PI = prediction interval; PK = (one or more) pharmacokinetics. The solid line represents the median of the simulated individual PK profiles. The dashed line represents the geometric mean of the simulated individual PK profiles. The shaded area represents the 90% PI.3. [Figure 7] Simulation PK profiles - reference (nominal dosing schedule) compared to delayed dosing (with or without re-priming) (Scenario 4). PI = prediction interval; PK = (one or more) pharmacokinetics. The solid line represents the median of the simulated individual PK profiles. The dashed line represents the geometric mean of the simulated individual PK profiles. The shaded area represents the 90% PI.3. [Figure 8]Simulation PK Profile - Reference (nominal dosing schedule) compared to delayed dosing (with or without re-priming) (Scenario 5). PI = prediction interval; PK = (one or more) pharmacokinetics. Solid lines represent the median of the simulated individual PK profiles. Dashed lines represent the geometric mean of the simulated individual PK profiles. The shaded area represents 90% PI.3.

Summary of the Invention

Problems to be Solved by the Invention

[0008] Methods are provided herein for treating patients with CD20-expressing cancer when the dosing schedule of EPKINLY is delayed due to adverse reactions or missed doses. Resumption of the dosing schedule minimizes CRS by providing an oral or intravenous corticosteroid, such as prednisone or dexamethasone, or an equivalent, 30 to 120 minutes prior to resuming the first dose of EPKINLY and for 3 consecutive days after each of the 4 doses in the re-priming cycle.

[0009] In the methods provided according to embodiments of the present invention, a re-priming cycle is required when the dosing of epcoritamab is delayed at the specific times described below.

[0010] - If the intermediate dose (0.8 mg dose) is delayed for more than 1 day (i.e., the intermediate dose occurs more than 8 days after priming or at any intermediate dose) - If the first full dose (48 mg dose) is delayed for more than 7 days (i.e., more than 14 days from the last intermediate dose) - After the second full dose (48 mg), if the interval between a previous dose of epcoritamab and the next dose of epcoritamab exceeds 6 weeks.

[0011] Preferably, when resuming medication at a priming or intermediate dose, a 4-day series of corticosteroids should also be repeated for CRS prevention until at least one full dose is readmitted within an appropriate medication window without subsequent occurrences of CRS grade ≥ 2. This applies to both cycle 1 and repriming within the repriming cycle.

[0012] The repriming cycle preferably consists of a weekly schedule of a priming dose (0.16 mg), an intermediate dose (0.8 mg), and two full doses (48 mg each). Premedication and prophylactic steroids should be administered (as in cycle 1).

[0013] In one embodiment, a method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives 0.16 mg of epcolitamab on day 1 of cycle 1, and the timing of the next scheduled dose exceeds 8 days. a) Administer epcolitamab 0.16 mg subcutaneously to the patient. b) In the following week, administer epcolitamab 0.8 mg subcutaneously to the patient, and c) A method of resuming medication is described, which involves administering epcolitamab 48 mg subcutaneously for an additional two weeks before initiating day 1 of the subsequent cycle.

[0014] In another embodiment, a method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 0.8 mg dose of epcolitamab on day 8 of cycle 1, the time to the next scheduled dose of epcolitamab is 14 days or less, the drug is resumed with the missed dose, and subsequent drug administration is on schedule, with a 28-day drug schedule as follows: a) Administer a dose of 48 mg subcutaneously on days 1, 15, and 22 of the cycle. b) Administer a dose of 48 mg subcutaneously on days 2, 3, 1, 8, 15, and 22 of cycle. c) Administer a dose of 48 mg subcutaneously on days 1 and 15 of cycles 4-9, and d) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle. The method is described.

[0015] Another embodiment describes a method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 0.8 mg dose of epcolitamab on day 8 of cycle 1, and the time between the next scheduled dose of epcolitamab exceeds 14 days. Medication is resumed as follows: a. Administer epcolitamab 0.16 mg subcutaneously to the patient. b. The patient will be given epcolitamab 0.8 mg subcutaneously in the following week, and c. Before starting the next cycle on day 1, administer two weekly doses of 48 mg of epcolitamab subcutaneously.

[0016] Another embodiment describes a method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 48 mg dose of epcolitamab, and the time between the next scheduled dose of epcolitamab is 6 weeks or less. The missed dose is resumed, and subsequent doses are based on the following 28-day cycle: a) Administer a dose of 48 mg subcutaneously on days 1, 15, and 22 of the cycle. b) Administer a dose of 48 mg subcutaneously on days 2, 3, 1, 8, 15, and 22 of cycle. c) Administer a dose of 48 mg subcutaneously on days 1 and 15 of cycles 4-9, and d) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle.

[0017] Another embodiment describes a method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 48 mg dose of epcolitamab, and the time between the next scheduled dose of epcolitamab exceeds 6 weeks. The missed dose is resumed, and subsequent doses are based on the following 28-day dosing schedule: a) Administer a dose of 48 mg subcutaneously on days 1, 15, and 22 of the cycle. b) Administer a dose of 48 mg subcutaneously on days 2, 3, 1, 8, 15, and 22 of cycle. c) Administer a dose of 48 mg subcutaneously on days 1 and 15 of cycles 4-9, and d) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle. [Modes for carrying out the invention]

[0018] Epcolitamab: Epcolitamab, also known herein as EPINKLY, is a bispecific antibody that recognizes the T cell antigen CD3 and the B cell antigen CD20. Epcolitamab induces potent T cell-mediated killing of CD20-expressing cells. The mechanism of action of epcolitamab involves T cells as effector cells that induce the death of CD20-expressing B cells and tumor cells. This is a different mechanism of action compared to chemotherapy or conventional CD20-targeted monoclonal antibodies (mAbs) that can induce cytotoxicity via Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis, and complement-dependent cell-mediated cytotoxicity, and in some cases induce programmed cell death.

[0019] Epcolitamab is produced using Genmab's DuoBody® technology (Labrijn et al., 2013; Labrijn et al., 2014). The DuoBody molecule is a bispecific antibody with a regular IgG1 structure and biochemical characteristics typical of human IgG1. Therefore, the DuoBody molecule exhibits normal binding to the neonatal Fc receptor (FcRn), resulting in a relatively long plasma half-life typical of the IgG1 molecule. The Fc domain of epcolitamab has been modified to silence Fc-mediated effector function, ensuring that epcolitamab does not activate T cells via FcγR-mediated CD3 crosslinking. FcRn binding is conserved.

[0020] The terms “epcolitamab” or “EPKINLY®” refer to an IgG1 bispecific CD3×CD20 antibody comprising a first heavy-chain and light-chain pair defined by SEQ ID NOs. 1 and 2, respectively, and a second heavy-chain and light-chain pair defined by SEQ ID NOs. 3 and 4. The first heavy-chain and light-chain pair comprises a region that binds to human CD3ε (epsilon), and the second heavy-chain and light-chain pair comprises a region that binds to human CD20. The first binding region comprises VH and VL sequences defined by SEQ ID NOs. 5 and 6, and the second binding region comprises VH and VL sequences defined by SEQ ID NOs. 7 and 8. This bispecific antibody can be prepared as described in International Publication No. 2016 / 110576.

[0021] As used herein, epcolitamab is used to treat CD20 B-cell carcinoma. CD20 B-cell carcinoma refers to malignant lymphoma characterized by the malignant transformation of cells from lymphoid tissue. Historically, lymphomas have been classified into Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Malignant lymphomas originate from B cells in over 90% of cases, T cells in less than 10%, and NK cells in rare cases. The World Health Organization (WHO) has classified many types of mature B-cell neoplasms, including lymphomas, over the past 20 years, with the most recent update in 2016 (Swerdlow et al., 2016). The majority of mature B-cell neoplasms are thought to belong to NHL. The prognosis for these malignancies depends on the type of lymphoma and the stage of the disease.

[0022] Clinically, NHL is classified into low-grade (slow-growing) lymphoma and invasive (rapid-growing) lymphoma. The most common types of lymphoma are diffuse large B-cell lymphoma (DLBCL), which accounts for approximately 33% of NHL cases; follicular lymphoma (FL), which accounts for 25% of NHL cases; and mantle cell lymphoma (MCL), which accounts for 10% of NHL cases. Clinical safety data available from the ongoing EPCORE NHL-1 study (GCT3013-01; NCT03625037) have shown that epcolitamab induces cytokine release syndrome (CRS) as a high-frequency adverse event (AE) in 51% of patients treated to date (see Example 1). Typical cytokine release symptoms include chills, fever, and hypotension. To mitigate the potential serious AEs due to cytokine release in individual patients treated with epcolitamab, several safety precautions may be implemented, including: • A priming dose as the first dose, i.e., a dose lower than subsequent doses; • Premedication to reduce CRS during the first four doses (i.e., during Cycle 1) and possibly for subsequent doses. In certain embodiments, prophylactic corticosteroids such as dexamethasone, prednisolone or equivalents are administered for four consecutive days (pre-administration on the day of administration) for the first four weekly doses (i.e., during Cycle 1); for Cycle 2 and beyond, only if CRS ≥ Grade 2 occurs after the second full dose of Cycle 1 or the fourth dose of epcolitamab (C1D22) (or in any repriming cycle); and Hospitalization is recommended for monitoring the patient during Cycle 1 (and any repriming cycles).

[0023] In some embodiments, the dexamethasone equivalent is selected from the following: [Table 1]

[0024] Preferably, the equivalent is administered in the approximate equivalent dose provided in the table.

[0025] Indications: In some embodiments, EPKINLY can be used to treat patients with unspecified relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy, including DLBCL arising from low-grade lymphoma and high-grade B-cell lymphoma.

[0026] In other embodiments, Epkinly can be used to treat patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more systemic therapies, including diffuse large B-cell lymphoma (DLBCL), transformed from low-grade lymphoma, high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL Gr 3B).

[0027] In further embodiments, EPKINLY can be used to treat relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, CD20-positive relapsed or refractory diffuse large B-cell lymphoma, and relapsed or refractory follicular lymphoma.

[0028] Medication schedule and premedication schedule: Table 1 shows the subcutaneous administration schedule for EPKINLY. As shown in Table 1, EPKINLY is administered in 28-day cycles until disease progression or unacceptable toxicity occurs. [Table 2]

[0029] During Cycle 1, the premedications shown in Table 2 are administered to reduce the risk of cytokine release syndrome (CRS). In some embodiments, if the patient is at risk of CRS, these premedications may be administered in subsequent cycles.

[0030] [Table 3]

[0031] In some embodiments, the epcolitamab administration cycle may be delayed to manage adverse events or because the patient has missed the next dose in the cycle. If a delay in administration occurs, epcolitamab administration may be resumed as described in Table 3.

[0032] [Table 4]

[0033] Dosage adjustments and management of adverse reactions: Cytokine release syndrome (CRS) If CRS is diagnosed or suspected, refrain from emergency medication until the CRS resolves. Manage as described in Table 4 and consider further management in accordance with current practice guidelines. Provide supportive care for CRS, which may include intensive care for severe or life-threatening CRS.

[0034] [Table 5] TIFF2026516281000006.tif61166

[0035] Immunoeffector cell-associated neurotoxicity syndrome (ICANS) Patients should be monitored for signs and symptoms of ICANS. At the first signs of ICANS, avoid epikinesthesia and perform a neurological evaluation to rule out other causes of neurological symptoms. Provide supportive care, which may include intensive care. ICANS can be managed as described in Table 5 and current clinical guidelines.

[0036] [Table 6] TIFF2026516281000008.tif233165

[0037] Other adverse reactions: In some embodiments, prophylactic antibiotics, antiviral therapy, and antifungal therapy are recommended for patients at high risk of these infections. For example, prophylactic antiviral therapy is essential for patients with a history of recurrent herpesvirus infection, herpes infection during prior antilymphoma therapy, neutropenia, and / or low CD4+ cell count (less than 200 cells / μL), for example, acyclovir 400 mg orally three times daily.

[0038] As another example, prophylaxis against Pneumocystis jirovecii, such as oral trimethoprim / sulfamethoxazole 160 mg / 800 mg every other day, is essential in patients who have been receiving corticosteroids for more than four consecutive days (e.g., during CRS prophylaxis or adverse event (AE) management), as well as in patients considered to be at high risk, such as those with low CD4+ cell counts (less than 350 cells / μL).

[0039] In other embodiments, whole blood counts are used throughout treatment to monitor cytopenia. Based on the severity of cytopenia, EPKINLY may be temporarily withdrawn or permanently discontinued. Prophylactic granulocyte colony-stimulating factor administration should be used if applicable.

[0040] Table 6 lists the changes in EPKINLY dosage for other adverse reactions. [Table 7]

[0041] In preferred embodiments, epcolitamab is provided for subcutaneous use in a sterile, preservative-free, clear to slightly milky white, colorless to slightly yellowish solution, free of visible particles. For priming doses, epcolitamab is provided as a single-dose 4 mg / 0.8 mL vial containing epcolitamab (4 mg), acetate (0.19 mg), polysorbate 80 (0.32 mg), sodium acetate (1.7 mg), sorbitol (21.9 mg), and water for injection (USP). The pH is 5.5.

[0042] For a complete dose cycle, epcolitamab is supplied as a single-dose 48 mg / 0.8 mL vial containing epcolitamab (48 mg), acetate (0.19 mg), polysorbate 80 (0.32 mg), sodium acetate (1.7 mg), sorbitol (21.9 mg), and water for injection (USP). The pH is 5.5.

[0043] [Examples] Example 1: Safety findings from the EPCORE NHL-1 study (GCT3013-01; NCT03625037) Cytokine release syndrome: Cytokine release syndrome (CRS) occurred in 51% of patients receiving EPKINLY at the recommended dose in clinical trials, with Grade 1 CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5%. Recurrent CRS occurred in 16% of patients. Almost all (92%) of all CRS events occurred during Cycle 1. In Cycle 1, 9% of CRS events occurred after the 0.16 mg dose on Day 1, 16% after the 0.8 mg dose on Day 8, 61% after the 48 mg dose on Day 15, and 6% after the 48 mg dose on Day 22.

[0044] The median time to onset of CRS from the last administered EPKINLY dose across all doses was 24 hours (range: 0–10 days). The median time to onset after the first complete 48 mg dose was 21 hours (range: 0–7 days). CRS resolved in 98% of patients, and the median duration of the CRS event was 2 days (range: 1–27 days).

[0045] In patients who experienced CRS, signs and symptoms included fever, hypotension, hypoxia, dyspnea, chills, and tachycardia. Concurrent neurological adverse reactions associated with CRS occurred in 2.5% of patients and included headache, confusion, tremor, dizziness, and ataxia.

[0046] Initiate treatment according to the EPKINLY dosing schedule (see Table 1). Administer pre-treatment medications to reduce the risk of CRS, and monitor the patient for potential CRS after EPKINLY accordingly (see Table 2). After the first 48 mg dose, the patient must be hospitalized for 24 hours. Immediately assess the patient for hospitalization at the first signs or symptoms of CRS, manage them according to current clinical guidelines, and provide supportive care as needed. Withhold or discontinue EPKINLY based on the severity of CRS (see Table 4).

[0047] Immunoeffector cell-associated neurotoxicity syndrome (ICANS) Immunoeffector cell-associated neurotoxic syndrome (ICANS) occurred in 6% (10 / 157) of patients treated with EPKINLY at the recommended dose in clinical trials, with 4.5% experiencing grade 1 ICANS and 1.3% experiencing grade 2 ICANS. One fatal ICANS event occurred (0.6%). Of the 10 ICANS events, 9 occurred within cycle 1 of EPKINLY treatment, and the median time to ICANS was 16.5 days (range: 8–141 days) from the start of treatment. Compared to the most recent dose of EPKINLY, the median time to ICANS was 3 days (range: 1–13 days). The median duration of ICANS was 4 days (range: 0–8 days), and ICANS resolved in 90% of patients who received supportive care. Clinical symptoms of ICANS included, but were not limited to, confusion, lethargy, tremor, dysgraphia, aphasia, and nonconvulsive status epilepticus. ICANS may develop after the resolution of CRS, or in the absence of CRS, or concurrently with CRS.

[0048] Immediately assess the patient at the first sign or symptom of ICANS and provide supportive care based on severity. Withhold or discontinue EPKINLY as indicated in Table 5, and consider further management according to current clinical guidelines.

[0049] infectious disease Among patients treated with the recommended dose of EPKINLY, 15% reported serious infections, including opportunistic infections, with 14% experiencing grade 3 or 4 infections and 1.3% experiencing fatal infections. The most common grade 3 or higher infections were sepsis, COVID-19, urinary tract infections, pneumonia, and upper respiratory tract infections. Infections can be managed as described in Table 6.

[0050] Cytopenia In clinical trials, among patients receiving the recommended dosage, 32% experienced grade 3 or 4 decreased neutrophils, 12% experienced decreased hemoglobin, and 12% experienced decreased platelets. Febrile neutropenia occurred in 2.5% of patients. Cytopenia can be managed as described in Table 6.

[0051] Drug interactions For certain CYP substrates, even minimal changes in concentration can lead to serious adverse reactions. When administered concurrently with EPKINLY, monitor the toxicity or drug concentration of such CYP substrates.

[0052] Epcolitamab induces the release of cytokines (see Example 3, Clinical Pharmacology) that can suppress the activity of CYP enzymes, thereby increasing exposure to CYP substrates. Increased exposure to CYP substrates is likely to occur after the first dose of EPKINLY on day 1 of cycle 1, and for up to 14 days after the first 48 mg dose on day 15 of cycle 1, as well as during and after the CRS.

[0053] Example 2: Clinical trial experience The safety of EPKINLY was evaluated in EPCORE NHL-1, a single-arm trial in patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including unspecified DLBCL, DLBCL arising from low-grade lymphoma, high-grade B-cell lymphoma, and other B-cell lymphomas. A total of 157 patients received EPKINLY by subcutaneous injection according to the following 28-day cycle schedule until disease progression or unacceptable toxicity occurred: Cycle 1: EPKINLY 0.16 mg on day 1, 0.8 mg on day 8, and 48 mg on days 15 and 22. • Cycles 2-3: EPKINLY 48mg on days 1, 8, 15, and 22 • Cycles 4-9: EPKINLY 48mg on days 1 and 15 • Cycle 10 or longer: EPKINLY 48mg on day 1

[0054] Of the 157 patients treated, the median age was 64 years (range: 20–83 years), 60% were male, and 97% had an ECOG performance status of 0 or 1. Race was reported for 133 patients (85%); of these patients, 61% were Caucasian, 19% were Asian, and 0.6% were Native Hawaiian or other Pacific Islander. As reported, there were no Black or African American, Hispanic, or Latino patients treated in the clinical trial. The median number of prior treatments was 3 (range: 2–11). This study excluded patients with CNS involvement in lymphoma, allogeneic HSCT or solid organ transplantation, ongoing active infection, and any patients with known T-cell immunodeficiency.

[0055] The median exposure duration for patients receiving EPKINLY was 5 cycles (range: 1–20 cycles).

[0056] Serious adverse reactions occurred in 54% of patients who received EPKINLY. Serious adverse reactions in 2% or more of patients included CRS, infections (including sepsis, COVID-19, pneumonia, and upper respiratory tract infections), pleural effusion, febrile neutropenia, fever, and ICANS. Fatal adverse reactions occurred in 3.8% of patients who received EPKINLY, including COVID-19 (1.3%), hepatotoxicity (0.6%), ICANS (0.6%), myocardial infarction (0.6%), and pulmonary embolism (0.6%).

[0057] Permanent discontinuation of EPKINLY due to adverse reactions occurred in 3.8% of patients. Adverse reactions leading to permanent discontinuation of EPKINLY included COVID-19, CRS, ICANS, pleural effusion, and fatigue.

[0058] Discontinuation of EPKINLY due to adverse reactions occurred in 34% of patients receiving EPKINLY. Adverse reactions requiring discontinuation in 3% or more patients included CRS, neutropenia, sepsis, and thrombocytopenia.

[0059] The most common adverse reactions (≥20%) were CRS, fatigue, musculoskeletal pain, injection site reactions, fever, abdominal pain, nausea, and diarrhea. The most common grade 3–4 clinical laboratory abnormalities (≥10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelet count.

[0060] Table 7 summarizes the adverse reactions in EPCORE NHL-1. [Table 8]

[0061] Clinically relevant adverse reactions in less than 10% of patients receiving EPKINLY included ICANS, sepsis, pleural effusion, COVID-19, pneumonia (including pneumonia and COVID-19 pneumonia), tumor flare, febrile neutropenia, upper respiratory tract infection, and oncolytic syndrome.

[0062] Table 8 summarizes the clinical laboratory abnormalities associated with EPCORE NHL-1. [Table 9]

[0063] The efficacy population included 148 patients with DLBCL, not specified (NOS), including DLBCL and high-grade B-cell lymphoma arising from low-grade lymphoma. Of the 148 patients, the median age was 65 years (range: 22–83), 62% were male, 97% had an ECOG performance status of 0 or 1, and 3% had an ECOG performance status of 2. Race was reported for 125 patients (84%); of these patients, 61% were Caucasian, 20% were Asian, and 0.7% were Native Hawaiian or other Pacific Islander. As reported, there were no Black or African American, Hispanic, or Latino patients treated in the clinical trial. Diagnoses were DLBCL NOS in 86%, DLBCL transformed from slowly progressive lymphoma in 27%, and high-grade B-cell lymphoma in 14%. The median number of prior treatments was 3 (range: 2–11), with 30% receiving two prior treatments, 30% receiving three, and 40% receiving four or more. 18 percent had received prior autologous HSCT, and 39% had received prior chimeric antigen receptor (CAR) T-cell therapy. 82 percent of patients had disease refractory to their last treatment, and 29% were refractory to CAR-T-cell therapy.

[0064] Efficacy was established based on the overall response rate (ORR) and duration of response, as determined by the Lugano 2014 criteria, evaluated by an independent review committee (IRC). The efficacy results are summarized in Table 10.

[0065] [Table 10]

[0066] The median time to response was 1.4 months (range: 1–8.4 months). Among those who responded, the median follow-up period for DOR was 9.8 months (range: 0.0–17.3 months).

[0067] Example 3: Clinical Pharmacology Pharmacodynamics: Circulating B cell number In patients who had detectable B cells at the start of treatment by day 15 of cycle 1, circulating B cells decreased to undetectable levels (less than 10 cells / microliter) after administration of the approved recommended dose of EPKINLY (after the first full dose of 48 mg), and depletion persisted while the patient continued treatment.

[0068] Cytokine concentration Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured. Transient increases in circulating cytokines were observed at dose levels of 0.04 mg or higher. Following administration of the approved recommended dose of EPKINLY, cytokine levels increased within 24 hours after the first dose on day 1 of cycle 1, reached peak levels after the first 48 mg dose on day 15 of cycle 1, and returned to baseline before the next full dose of 48 mg on day 22 of cycle 1.

[0069] Example 4: Defining a safe repriming window The recommendation for repriming is based on population PK (PopPK) modeling and is supported by observed clinical data. The PopPK model-based approach assumed that repriming was necessary when the EPKINLY concentration fell below the trough concentration (Ctrough) after the first priming dose (see Figure 1). The EPKINLY concentration profiles of individual subjects were simulated using individual post-hoc PK parameters after missing the planned first full dose of EPKINLY, after missing the second full dose, or after missing the full dose after cycle 1. The time required for each subject's EPKINLY concentration to fall below Ctrough after the priming dose was defined as the safe repriming window. The safe repriming windows calculated from all subjects were summarized. After missing the planned first full dose, the safe repriming window (5th percentile; 95% coverage and only 5% of subjects with their corresponding Ctrough concentrations after the priming dose) was 4.76 weeks. After missing the planned second full dose, the safe repriming window (5th percentile) was 18.4 weeks. After missing the planned full dose after cycle 1, the safe repriming window (5th percentile) was 25.1 weeks. Because the safe repriming concentration threshold was defined as the Ctrough after the priming dose, the repriming time window after missing the intermediate dose could not be calculated using a population PK-based approach. Therefore, delays in the intermediate dose result in the EPKINLY concentration falling below the defined threshold. Thus, a conservative repriming strategy was proposed for a 1-day delay in the intermediate dose (i.e., more than 8 days between the priming dose (0.16 mg) and the intermediate dose (0.8 mg)). Similarly, repeated event time (rTTE) modeling methods were investigated and similar results were obtained (see below).

[0070] We used more conservative values ​​from popPK model-based simulations to determine the repriming window. For the delayed intermediate dose, we selected a 1-day repriming window (8 days after the priming dose). For the delayed first full dose, we selected a 7-day repriming window (14 days after the intermediate dose). For the second full dose and the delayed full dose after cycle 1, we selected a conservative 6-week window.

[0071] To further support these repriming windows, we simulated individual predictive PK profiles for EPKINLY. These are described below.

[0072] ●Reference (Nominal medication schedule) ○ Cohort 1 (Nominal Medication Schedule): Post-hoc simulation based on medication administered according to schedule (baseline) ●Scenario 1 (Delayed / re-priming after priming dose of 0.16 mg epcolitamab) ○Cohort 2 (delayed dosing, no repriming required): Post-hoc simulation where the intermediate dose is administered 8 days after the priming dose (does not meet the repriming threshold; delayed by 1 day from the planned intermediate dose), followed by the planned dose. ○Cohort 3 (requiring delayed dosing and repriming): Post-hoc simulation where repriming is performed 9 days after the priming dose (meeting the repriming threshold; 2-day delay from the planned intermediate dose), followed by the planned dose. ●Scenario 2 (Delayed / repriming after an intermediate dose of epcolitamab 0.8 mg) ○ Cohort 2 (delayed dosing, no repriming required): Post-hoc simulation of administering the first full dose 14 days after the intermediate dose (does not meet the repriming threshold; 7-day delay from the planned first full dose), followed by the planned dose. ○Cohort 3 (Delayed dosing, repriming required): Post-hoc simulation in which repriming is performed 21 days after the intermediate dose (meeting the repriming threshold; 14 days delayed from the planned first full dose), followed by the planned dose. ●Scenario 3 (Delayed / repriming after full quarterly dose of 48 mg epcolitamab) ○ Cohort 2 (delayed dosing, no repriming required): Post-hoc simulation of administering the second complete dose 6 weeks after the first complete dose (no repriming threshold met for more than 6 weeks between complete doses; 5-week delay from the planned QW dose [second complete dose]), followed by the planned dose. ○Cohort 3 (requiring delayed dosing and repriming): Post-hoc simulation in which repriming is performed 7 weeks after the first complete dose (meeting the repriming threshold of more than 6 weeks between complete doses; 6 weeks delay from the planned QW dose [second complete dose]), followed by the planned dose. ●Scenario 4 (Delayed / repriming after full Q2W dose of 48mg epcolitamab): ○Cohort 2 (delayed dosing, no repriming required): Post-hoc simulation in which the full dose is administered 6 weeks after the full dose in C9D1 (repriming threshold not met for more than 6 weeks between full doses; 4-week delay from the planned Q2W dose), followed by the planned dose. ○Cohort 3 (requiring delayed dosing and repriming): Post-hoc simulation in which repriming is performed 8 weeks after the full dose of C9D1 (meeting the repriming threshold for more than 6 weeks between full doses, with a 6-week delay from the planned Q2W dose), followed by the planned dose. ●Scenario 5 (Delayed / repriming after full dose of 48 mg epcolitamab Q4W): ○Cohort 2 (delayed dosing, no repriming required): Post-hoc simulation in which the dose is administered 6 weeks after the full dose in C12D1 (repriming threshold not met for more than 6 weeks between full doses; 2-week delay from the planned Q4W dose), followed by the planned dose. ○Cohort 3 (requiring delayed dosing and repriming): Post-hoc simulation in which repriming is performed 10 weeks after the full dose of C9D1 (meeting the repriming threshold for more than 6 weeks between full doses, and 6 weeks delayed from the planned Q4W dose), followed by the planned dose.

[0073] Concentrations were generally maintained for delayed doses within the proposed time window. When the second full dose was administered 6 weeks after the first full dose, concentrations decreased (Scenario 2 / Cohort 2 in Figure 5), but concentrations remained sufficiently higher than after the initial priming and intermediate doses. However, when the full dose was administered within 6 weeks between the Q2W and Q4W dosing schedules, no substantial decrease in concentration was observed (Scenario 4 / Cohort 2 in Figure 7, Scenario 5 / Cohort 2 in Figure 8). Based on PK simulations, the repriming window was appropriate.

[0074] Iterative Event Time (rTTE) Modeling Techniques for CRS The PK-CRS model was developed to describe CRS risk. Long-term exposure-CRS relationships based on extensive data and priming / intermediate dose combinations from the GCT3013-01 (NCT03625037) and GCT3013-04 (NCT04542824) clinical trials were described using the rTTE model. Recorded times for Grade 2 or higher CRS events were used as event times, and data were right-censored at the end of observation. The hazard function for repeated CRS events was modeled as the effect of epcolitamab plasma concentration. To describe the development of tolerability to CRS hazards after repeated dosing, inhibitory effects on the hazard were included in a turnover model in which the inhibition rate is stimulated by epcolitamab plasma concentration. Random effects were included for the inhibitory components.

[0075] Based on the rTTE PK-CRS model, the instantaneous hazard time profile for each subject was simulated. The tolerability effect decreases as the delay time from the last dose administration increases. Therefore, longer delays in drug administration will result in a higher hazard for CRS, depending on the tolerability function and hazard function dynamics of each individual subject. The safe repriming window is defined as follows (see Figure 2).

[0076] ●During the step-up dosing phase (i.e., intermediate dose and first full dose), repriming was assumed to be necessary if the peak instantaneous CRS hazard from the delayed intermediate dose or first full dose was greater than the peak from the corresponding planned priming / intermediate regimen or priming / intermediate / first full dose regimen (reference schedule). Therefore, the duration of delay was considered safe as long as the peak hazard from the delayed intermediate dose or the delayed first full dose was less than or equal to the peak hazard from the reference, planned priming / intermediate regimen, or priming / intermediate / first full dose regimen, respectively.

[0077] ●Because the CRS risk after the second full dose is low, it was assumed that repriming was necessary if the peak instantaneous CRS hazard from the delayed full dose was greater than the maximum CRS hazard from both the initial priming dose and the planned dose (second full dose or a specific full dose after cycle 1), i.e., if the reference CRS hazard was a higher peak hazard value from either the initial priming dose or the planned dose (second full dose or a specific full dose after cycle 1). The delay duration was considered safe as long as the peak hazard from the delayed full dose was less than or equal to the reference hazard.

[0078] We simulated scenarios involving delayed intermediate dose, delayed first full dose, delayed second full dose, and delayed full dose after cycle 1. For each of these scenarios, we simulated delays of 1 to 28 weeks. Figure 3 shows the percentage of subjects who were able to safely resume medication (as defined above) at each specified delay for each scenario.

[0079] Based on simulation results using the CRS rTTE model, a delay of less than one week after missing the planned intermediate dose was considered safe (i.e., more than 95% of simulated subjects were able to safely resume the planned intermediate dose without increased CRS risk). Similarly, a delay of less than one week after missing the planned first full dose may be considered safe. After missing the planned second full dose and the full dose after cycle 1, safe repriming windows were predicted to be 14 weeks and 20 weeks, respectively.

[0080] Example 5: Identification of dose delay in EPCORE NHL-1 The EPCORE NHL-1 study (GCT3013-01; NCT03625037) identified dose delays requiring repriming that were longer than the cutoff period proposed above. The data are shown in Table 10.

[0081] [Table 11]

[0082] The evaluation of CRS events after dose delay without repriming did not show an increased risk of CRS after dose delay below the proposed cutoff for repriming, compared to the overall CRS risk observed in EPCORE NHL-1.

[0083] [Table 12] TIFF2026516281000015.tif78166

Claims

1. A method for treating CD20-expressing B-cell cancer in human patients, comprising administering epcolitamab in a 28-day priming cycle, comprising a single 0.16 mg dose administered on day 1, a single 0.8 mg dose of epcolitamab administered on day 7, a first 48 mg dose administered on day 15, and a second 48 mg dose of epcolitamab administered on day 22, followed by weekly or bi-weekly doses of 48 mg doses thereafter, where, If the aforementioned 0.8 mg dose is not administered by the 8th day at the latest, another 0.16 mg dose is administered, followed by a 0.8 mg dose within 7 days, and / or the administration of the first and second 48 mg doses follows. If the first 48 mg dose is not administered within 14 days of the 0.8 mg dose, another 0.16 mg dose is administered, followed by another 0.8 mg dose within 7 days, and thereafter the first and second 48 mg doses are administered, and / or A method wherein, when either the second 48 mg dose or the weekly or bi-weekly 48 mg dose is administered six weeks after the last preceding 48 mg dose, the priming cycle is repeated before the weekly or bi-weekly 48 mg dose is administered.

2. The method according to claim 1, wherein if the 0.8 mg dose is administered no later than the 7th or 8th day, the 0.8 mg dose of epcolitamab is administered on the 7th day, the first 48 mg dose is administered on the 14th day, and the second 48 mg dose is administered on the 21st day.

3. The method according to claim 1 or 2, wherein if the first 48 mg dose is administered within 14 days of the administration of the 0.8 mg dose, the second 48 mg dose is administered 7 days later.

4. The method according to any one of claims 1 to 3, wherein if either the second 48 mg dose or the 48 mg dose administered weekly or bi-weekly is administered not according to schedule but within six weeks of the last preceding 48 mg dose, the subsequent dose is administered weekly or bi-weekly according to schedule.

5. The method according to any one of claims 1 to 4, wherein the epcolitamab is administered subcutaneously.

6. The aforementioned 48 mg dose, administered weekly or bi-weekly, a) Administer epcolitamab on days 1, 8, 15, and 22 for two 28-day cycles, followed by... b) Administer epcolitamab on days 1 and 15 of cycles 4-9 for 6 cycles, and c) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle. The method according to any one of claims 1 to 5, administered in a drug regimen including the following:

7. A method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 0.16 mg dose of epcolitamab on day 1 of cycle 1, and the next scheduled timing is delayed by more than 8 days. a. Administer epcolitamab 0.16 mg subcutaneously to the patient. b. The patient shall be given epcolitamab 0.8 mg subcutaneously in the following week, and c. Before initiating day 1 of the subsequent cycle, administer 48 mg of epcolitamab subcutaneously for an additional two weeks. A method for resuming medication.

8. A method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 0.8 mg dose of epcolitamab on day 1, 8 of cycle, and the next scheduled dose of epcolitamab is restarted by subcutaneous administration of a delayed 48 mg dose of epcolitamab when the time to the next scheduled dose is 14 days or less, and then the subsequent scheduled doses are continued, with the recommended 28-day treatment schedule being as follows: a) Administer a dose of 48 mg subcutaneously on days 1, 15, and 22 of the cycle. b) Administer a dose of 48 mg subcutaneously on days 2, 3, 1, 8, 15, and 22 of cycle. c) Administer a dose of 48 mg subcutaneously on days 1 and 15 of cycles 4-9, and d) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle. The method.

9. A method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 0.8 mg dose of epcolitamab on day 1, 8 of the cycle, and the time between the next scheduled dose of epcolitamab exceeds 14 days. a. Administer 0.16 mg of epcolitamab subcutaneously to the patient. b. The patient shall be given 0.8 mg of epcolitamab subcutaneously in the following week, and c. Before starting the next cycle on day 1, administer two weekly doses of 48 mg of epcolitamab subcutaneously. A method for resuming medication.

10. A method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 48 mg dose of epcolitamab on day 15 of cycle 1, and the time to the next scheduled dose of epcolitamab is 6 weeks or less, and the drug is restarted by subcutaneous administration of a delayed 48 mg dose of epcolitamab, and then the subsequent scheduled doses are continued. The 28-day medication schedule is as follows: a) Administer a dose of 48 mg subcutaneously on days 1, 15, and 22 of the cycle. b) Administer a dose of 48 mg subcutaneously on days 2, 3, 1, 8, 15, and 22 of cycle. c) Administer a dose of 48 mg subcutaneously on days 1 and 15 of cycles 4-9, and d) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle. The method.

11. A method for treating CD20-expressing B-cell cancer in a human patient, wherein the patient receives a 48 mg dose of epcolitamab, the time to the next scheduled dose of epcolitamab is 6 weeks or less, and the drug is restarted with the missed dose, with subsequent doses being administered according to schedule. The 28-day medication schedule is as follows: a) Administer a dose of 48 mg subcutaneously on days 1, 15, and 22 of the cycle. b) Administer a dose of 48 mg subcutaneously on days 2, 3, 1, 8, 15, and 22 of cycle. c) Administer a dose of 48 mg subcutaneously on days 1 and 15 of cycles 4-9, and d) Administer a dose of 48 mg subcutaneously on day 1 of every subsequent cycle. The method.

12. The method according to any one of claims 1 to 11, comprising administering an oral or intravenous corticosteroid to the patient for four consecutive days in relation to each dose of epcolitamab.

13. The method according to claim 12, wherein the corticosteroid is administered in relation to each dose of epcolitamab until at least two consecutive doses of 48 mg epcolitamab have been administered.

14. The method according to claim 12 or 13, wherein the corticosteroid is administered on the day the epcolitamab is administered and for three days thereafter.

15. The method according to any one of claims 12 to 14, comprising administering an oral or intravenous corticosteroid to the patient 30 to 120 minutes before each dose of epcolitamab, for example, before each of the four doses of epcolitamab in the priming cycle.

16. The method according to any one of claims 12 to 15, wherein the corticosteroid is selected from the group consisting of 100 mg of oral or intravenous prednisolone, 15 mg of oral or intravenous dexamethasone, or equivalents.

17. The method according to any one of claims 11 to 16, further comprising administering diphenhydramine or acetaminophen orally or intravenously to the patient 30 to 120 minutes before each of the four epcolitamab doses in the priming cycle.

18. A method for treating CD20-expressing B-cell carcinoma in human patients, wherein the patient is considered to be at risk of antifungal or antiviral infection. The method comprises administering antibiotic therapy, antiviral therapy, or antifungal therapy prophylactically before initiating treatment with epcolitamab.

19. The method according to claim 18, wherein the patient is at risk of an antifungal infection caused by Pneumocystis jirovecii, and the patient receives corticosteroids for four or more consecutive days, comprising orally administering trimethoprim / sulfamethoxazole 160 mg / 800 mg every other day.

20. The method according to claim 18, wherein the patient is at risk of recurrent antiviral infection and is administered antiviral therapy such as acyclovir for recurrent herpesvirus infection, or a nucleoside / nucleotide analog such as tenofovir disoproxil fumarate, tenofovir alafenamide, or entecavir for chronic hepatitis B virus infection.

21. The method according to any one of claims 1 to 20, wherein epcolitamab comprises (i) a CD3 binding arm comprising the heavy chain sequence shown in SEQ ID NO: 1 and the light chain sequence shown in SEQ ID NO: 2, and (ii) a CD20 binding arm comprising the heavy chain sequence shown in SEQ ID NO: 3 and the light chain sequence shown in SEQ ID NO: 4.

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