Bispecific antibody against cd3 and cd20 in combination therapy for treating diffuse large b-cell lymphoma

Abstract

Provided are methods of clinical treatment of diffuse large B-cell lymphoma (DLBCL) (e.g., previously untreated, high-risk DLBCL) in human subjects using a bispecific antibody which binds to CD3 and CD20 in combination with standard of care regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

1 . A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a combination of (a) epcoritamab or a biosimilar thereof (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, (e) vincristine and (f) prednisone, in 21-day cycles, wherein
 (a) epcoritamab or a biosimilar thereof is administered subcutaneously, wherein
 (i) a priming dose is administered on day 1 of the first 21-day cycle, an intermediate dose is administered on day 8 of the first 21-day cycle, and a full dose of 24 or 48 mg on day 15 of the first 21-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose, 
 (ii) a full dose of 24 or 48 mg on days 1, 8 and 15 of the second, third and fourth 21-day cycles; 
 (iii) a full dose of 24 or 48 mg is administered once every three weeks on day 1 of two to four subsequent 21-day cycles; and 
 (iv) a full dose of 24 or 48 mg is subsequently administered one every four weeks on day 1 in 28-day cycles: 
   (b) rituximab is administered intravenously at a dose of 375 mg/m 2  once every three weeks;   (c) cyclophosphamide is administered intravenously at a dose of 750 mg/m 2  once every three weeks;   (d) doxorubicin is administered intravenously at a dose of 50 mg/m 2  once every three weeks;   (e) vincristine is administered intravenously weeks at a dose of 1.4 mg/m 2  once every three; and   (f) prednisone is administered orally or intravenously at a dose of 100 mg once a day from day 1 to day 5 of each 21 day cycle;   
       wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs. 
     
     
         2 . The method of  claim 1 , wherein epcoritamab or a biosimilar thereof is administered at a full dose of 24 mg. 
     
     
         3 . The method of  claim 1 , wherein epcoritamab or a biosimilar thereof is administered at a full dose of 48 mg. 
     
     
         4 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the priming dose is 0.16 mg. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the intermediate dose is 0.8 mg. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the administration of rituximab once every three weeks is performed for six or eight 21-day cycles. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the administration of cyclophosphamide once every three weeks is performed for six or eight 21-day cycles. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the administration of doxorubicin once every three weeks is performed for six or eight 21-day cycles. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the administration of vincristine once every three weeks is performed for six or eight 21-day cycles. 
     
     
         27 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein prednisone is administered for six or eight 21-day cycles. 
     
     
         30 - 32 . (canceled) 
     
     
         33 . The method of  claim 1  wherein:
 (a) epcoritamab or a biosimilar thereof is administered as follows:
 (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; 
 (ii) in cycles 2-4, a full dose of 24 mg is administered on days 1, 8, and 15; 
 (iii) in cycles 5 and 6, a full dose of 24 mg is administered on day 1; 
 
 (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and 
 (c) prednisone is administered on days 1-5 in cycles 1-6. 
 
     
     
         34 . The method of  claim 1 , wherein:
 (a) epcoritamab or a biosimilar thereof is administered as follows:
 (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; 
 (ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; 
 (iii) in cycles 5 and 6, a dose of 48 mg is administered on day 1; 
   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and   (c) prednisone is administered on days 1-5 in cycles 1-6.   
     
     
         35 . The method of  claim 33 , wherein epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 7. 
     
     
         36 . The method of  claim 1 , wherein:
 (a) epcoritamab or a biosimilar thereof is administered as follows:
 (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; 
 (ii) in cycles 2-4, a dose of 24 mg is administered on days 1, 8, and 15; 
 (iii) in cycles 5-8, a dose of 24 mg is administered on day 1; 
   (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and   (c) prednisone is administered on days 1-5 in cycles 1-8.   
     
     
         37 . The method of  claim 1  wherein:
 (a) epcoritamab or a biosimilar thereof is administered as follows:
 (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; 
 (ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; 
 (iii) in cycles 5-8, a dose of 48 mg is administered on day 1; 
 
 (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and 
 (c) prednisone is administered on days 1-5 in cycles 1-8. 
 
     
     
         38 . The method of  claim 36 , wherein epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 9. 
     
     
         39 - 44 . (canceled) 
     
     
         45 . The method of  claim 1 , wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered sequentially. 
     
     
         46 . The method of  claim 1 , wherein prednisone is administered first, rituximab is administered second, cyclophosphamide is administered third, doxorubicin is administered fourth, vincristine is administered fifth, and epcoritamab or a biosimilar thereof is administered last if rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered on the same day. 
     
     
         47 . The method of  claim 1 , wherein the DLBCL is double-hit or triple-hit DLBCL. 
     
     
         48 . The method of  claim 1 , wherein the DLBCL is follicular lymphoma Grade 3B. 
     
     
         49 . The method of  claim 1 , wherein the subject has an International Prognostic Index (IPI) score or Revised-IPI score ≥3. 
     
     
         50 . The method of  claim 1 , wherein the subject has not received prior therapy for DLBCL or follicular lymphoma Grade 3B. 
     
     
         51 - 63 . (canceled) 
     
     
         64 . The method of  claim 1 , wherein the method comprises administering a biosimilar of epcoritamab comprising a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 26 and 27, respectively. 
     
     
         65 . The method of  claim 1 , wherein the method comprises administration of epcoritamab. 
     
     
         66 . The method of  claim 34 , wherein epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 7. 
     
     
         67 . The method of  claim 37 , wherein epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 9.