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US-20260124300-A1 - COMBINATION TREATMENT OF AN ANTI-CD20/ANTI-CD3 BISPECIFIC ANTIBODY AND CHEMOTHERAPY

US20260124300A1US 20260124300 A1US20260124300 A1US 20260124300A1US-20260124300-A1

Abstract

The present invention relates to methods of treating B-cell lymphomas, e.g., primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL), by administering an anti-CD20/anti-CD3 bispecific antibody (e.g., glofitamab) and in combination with one or more anti-CD20 antibodies (e.g., obinutuzumab and/or rituximab) and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide.

Inventors

  • Mark Francis DIXON
  • Maria FILIPPOU-FRYE
  • Ritika Hari JAGTIANI
  • Linda Maria Lundberg
  • Stephen James SIMKO, III

Assignees

  • HOFFMANN-LA ROCHE INC.
  • GENENTECH, INC.

Dates

Publication Date
20260507
Application Date
20251029

Claims (20)

  1. 1 . A method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human individual in need thereof, comprising administering to the human individual an effective amount of glofitamab, rituximab, ifosfamide, carboplatin, and etoposide, wherein administering such treatment to a plurality of human individuals results in: (a) an improvement in complete response (CR) rate of a plurality of human individuals as compared to a reference CR rate, wherein the reference CR rate is the CR rate of a plurality of human individuals who have received a control treatment comprising rituximab, ifosfamide, carboplatin, and etoposide in the absence of glofitamab; (b) a CR rate of between 45% and 83%, or about 66%, 67%, or 69%; (c) an improvement in overall response (OR) rate of a plurality of human individuals as compared to a reference OR rate, wherein the reference OR rate is the OR rate of a plurality of human individuals who have received a control treatment comprising rituximab, ifosfamide, carboplatin, and etoposide in the absence of glofitamab; and/or (d) an OR rate of between 56% and 90%, or about 76%, 78%, or 83%.
  2. 2 . The method of claim 1 , wherein: (a) the improvement in CR rate is; (i) between 8% and 44%, or about 28%; and/or (ii) statistically significant; or (b) the improvement in OR rate is: (i) between 1% and 29%, or about 15%; and/or (ii) statistically significant.
  3. 3 - 6 . (canceled)
  4. 7 . The method of claim 1 , wherein the CR rate is the proportion of individuals whose best overall response is a CR as determined by positron emission tomography-computed tomography (PET-CT) or positron emission tomography-magnetic resonance imaging (PET-MRI); and/or the OR rate is the proportion of individuals whose best overall response is a partial response (PR) or a CR.
  5. 8 - 14 . (canceled)
  6. 15 . The method of claim 1 , wherein the treatment comprises administering glofitamab, rituximab, ifosfamide, carboplatin, and etoposide according to a dosing regimen comprising a first and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1) of about 2.5 mg of the glofitamab and a second dose (C1D2) of about 10 mg of the glofitamab, and the second dosing cycle comprises a single dose (C2D1) of about 30 mg of the glofitamab; and (b) the first dosing cycle comprises a single dose (C1D1) of ifosfamide; a single dose (C1D1) of carboplatin; and a first dose (C1D1) of etoposide, a second dose (C1D2) of etoposide, and a third dose (C1D3) of etoposide; and wherein the second cycle comprises a single dose (C2D1) of ifosfamide; a single dose (C2D1) of carboplatin; and a first dose (C2D1) of etoposide, a second dose (C2D2) of etoposide, and a third dose (C2D3) of etoposide.
  7. 16 . The method of claim 15 , wherein; (a) the C1D1 and the C1D2 of the glofitamab are administered to the individual on Days 8 and 15, respectively, of the first dosing cycle; (b) the C2D1 of the glofitamab is administered to the individual on Day 8 of the second dosing cycle; (c) the first dosing cycle comprises a single dose (C1D1) of obinutuzumab; (d) the second dosing cycle comprises a single dose (C2D1) of rituximab; and/or (e) the first and second dosing cycles are each 21-day dosing cycles.
  8. 17 - 18 . (canceled)
  9. 19 . The method of claim 16 , wherein; (a) the C1D1 of obinutuzumab is about 1000 mg and/or is administered on Day 1 of the first dosing cycle; (b) the C2D1 of rituximab is about 375 mg/m 2 and/or is administered on Day 1 of the second dosing cycle; and/or (c) ifosfamide is administered at a dose of about 5000 mg/m 2 , carboplatin is administered at a dose in mg to target area under the curve (AUC) of about 5 mg/mL/min with maximum dose of about 750 mg, and etoposide is administered at a dose of about 100 mg/m 2 for each dose of etoposide; and/or ifosfamide and carboplatin are administered on Day 2 of the first and second dosing cycles and the C1D1-C1D3 and C2D1-C2D3 of etoposide are administered on Days 1, 2, and 3, respectively, of each of the first and second dosing cycles.
  10. 20 - 27 . (canceled)
  11. 28 . The method of claim 15 , wherein the dosing regimen comprises one or more additional dosing cycles.
  12. 29 . The method of claim 28 , wherein; (a) the one or more additional dosing cycles are each 21-day dosing cycles; (b) the dosing regimen comprises three, four, or five dosing cycles in total; and/or (c) the one or more additional dosing cycles comprises a third dosing cycle, and wherein the third dosing cycle comprises: (i) an additional single dose of glofitamab; (ii) an additional single dose of rituximab; and (iii) an additional single dose of ifosfamide; an additional single dose of carboplatin; and an additional first dose, an additional second dose, and an additional third dose of etoposide.
  13. 30 - 32 . (canceled)
  14. 33 . The method of claim 2 , wherein; (a) the additional single dose of glofitamab is about 30 mg; and/or is administered to the individual on Day 8 of the third dosing cycle; (b) the additional single dose of rituximab is about 375 mg/m 2 ; and/or is administered on Day 1 of each of the third dosing cycle; and/or (c) the additional single dose of ifosfamide is about 5000 mg/m 2 , the additional single dose of carboplatin is about 5 mg/mL/min in mg to target area under the curve (AUC) with maximum dose of about 750 mg, and the additional single dose of etoposide is about 100 mg/m 2 for each of the additional first dose, the additional second dose, and the additional third dose of etoposide; and/or the additional single dose of ifosfamide and the additional single dose of carboplatin are administered on Day 2 of the third dosing cycle and the additional first dose, the additional second dose, and the additional third dose of etoposide are administered on Days 1, 2, and 3, respectively, of the third dosing cycle.
  15. 34 - 38 . (canceled)
  16. 39 . The method of claim 28 , wherein the one or more additional dosing cycles comprises a fourth dosing cycle or a fourth and a fifth dosing cycle, and wherein the fourth or fifth dosing cycle each comprises an additional single dose of glofitamab, wherein the single dose of glofitamab is about 30 mg and/or is administered on Day 1 of the fourth or fifth dosing cycle.
  17. 40 - 41 . (canceled)
  18. 42 . The method of claim 1 , wherein the control treatment comprises administering a single dose of rituximab, a single dose of ifosfamide, a single dose of carboplatin, and a first dose, a second dose, and a third dose of etoposide according to a dosing regimen comprising three 21-day dosing cycles, wherein rituximab is administered at a dose of about 375 ma/m 2 on Day 1 of each dosing cycle; ifosfamide is administered at a dose of about 5000 ma/m 2 on Day 2 of each dosing cycle; and carboplatin is administered at a dose in ma to target area under the curve (AUC) of about 5 mg/mL/min with maximum dose of about 800 mg on Day 2 of each dosing cycle, and wherein etoposide is administered at a dose of about 100 mg/m 2 each on Days 1, 2, and 3, respectively, of each dosing cycle.
  19. 43 - 44 . (canceled)
  20. 45 . The method of claim 1 , wherein: (a) the individual has received one prior systemic therapy; (b) the individual is transplant or CAR-T cell therapy eligible; (c) the DLBCL is not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBCL); (d) the individual has extranodal disease; and/or (e) the individual is aged 18 years or older.

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Oct. 1, 2025, is named 51177-061003_Sequence_Listing_10_125.xml and is 52,557 bytes in size. FIELD OF THE INVENTION The present invention relates to methods of treating B-cell lymphomas, e.g., primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL), by administering an anti-CD20/anti-CD3 bispecific antibody (e.g., glofitamab) in combination with one or more anti-CD20 antibodies (e.g., obinutuzumab and/or rituximab) and chemotherapeutic agents (e.g., ifosfamide, carboplatin, and etoposide). BACKGROUND OF THE INVENTION Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world (Bray et al. 2018). The most common subtype of NHL of B-cell origin (Sun et al. Am. J. Clin. Pathol. 138:429-434, 2012; Al-Hamadani et al. Am. J. Hematol. 24:4785-4797, 2015), DLBCL is an aggressive NHL with a median survival of <1 year in untreated patients (Rovira et al. Ann. Hematol. 94:803-812, 2015). Despite its aggressive disease course, approximately 50%-70% of patients may be cured with the current standard-of-care treatment that consists of rituximab, a monoclonal antibody targeting CD20, in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy (Flowers et al. C A Cancer J. Clin. 60:393-408 2010; Tilly et al. Ann. Oncol. 26(Suppl 5):v116-125 2015; NCCN Clinical Practice Guidelines in Oncology, 2020). Nevertheless, R-CHOP is found to be inadequate in 30%-50% of patients because of either primary refractoriness, defined as failure to achieve a complete response (CR) after first-line therapy with rituximab plus an anthracycline (Vardhana et al. Br. J. Haematol. 176:591-599, 2017), or relapse after achieving a CR. For patients who are not cured by first-line therapy and who are medically able to tolerate intensive therapy, high-dose salvage chemoimmunotherapy followed by ASCT offers a second chance for long-term remission. Approximately half of patients with relapsed DLBCL are refractory to salvage chemoimmunotherapy (Gisselbrecht et al. J. Clin. Oncol. 28:4184-4190, 2010) and are thus unable to proceed to ASCT. In addition, for a subgroup of patients with DLBCL, CAR-T therapy is an available treatment option, particularly for patients that have primary refractory disease, or have relapsed within 12 months of initial chemoimmunotherapy (Kamdar et al. 2022, Lancet 399, 2294-2308; Locke et al. 2022, N Engl J Med 386, 640-54). Given that the median EFS observed in both studies was less than 1 year, continued opportunity for optimization of therapeutic regimens involving CAR-T therapy remains. Therefore, a significant clinical need exists for improved salvage immunochemotherapy regimens for patients with relapsed or refractory (R/R) DLBCL. SUMMARY OF THE INVENTION The invention features methods for treating an individual having a diffuse-large B-cell lymphoma (DLBCL) (e.g., a relapsed and/or refractory DLBCL; e.g., a diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), Epstein-Barr virus [EBV]+ DLBCL, High-grade B-cell lymphoma (HGBCL), High-grade B-cell lymphoma (HGBCL) with MYC and B-cell lymphoma 2 and/or B-cell lymphoma 6 rearrangements, or HGBCL, NOS; e.g., R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), R/R Epstein-Barr virus [EBV]+ DLBCL, R/R High-grade B-cell lymphoma (HGBCL), R/R High-grade B-cell lymphoma (HGBCL) with MYC and B-cell lymphoma 2 and/or B-cell lymphoma 6 rearrangements, or R/R HGBCL, NOS)) by administering to the individual a treatment comprising glofitamab in combination with rituximab, ifosfamide, carboplatin and etoposide (i.e., glofit-R-ICE). In one aspect, the invention features a method for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a human individual in need thereof, comprising administering to the human individual an effective amount of glofitamab, rituximab, ifosfamide, carboplatin, and etoposide, wherein administering such treatment to a plurality of human individuals results in an improvement in complete response (CR) rate of a plurality of human individuals as compared to a reference CR rate, wherein the reference CR rate is the CR rate of a plurality of human individuals who have received a control treatment comprising rituximab, ifosfamide, carboplatin, and etoposide in the absence of glofitamab. In some embodiments, the improvement in CR rate is between 8% and 44% (e.g., between 8% and 40%, between 8% and 30%, between 8% and 20%, between 10% and 44%, between 20% and 44%, between 30% and 44%, between 20% and 30%, between 10% and 40%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, between 30% and 35%, or between 35% and 40%; about 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 44%). In some embodiments, the improvem