METHODS OF REDUCING SIDE EFFECTS OF ANTI-CD30 ANTIBODY DRUG CONJUGATE THERAPY
The present disclosure, relates, in general to methods for improving adverse events in subjects having a mature T cell lymphoma and who are receiving treatment with an anti-CD30 antibody drug conjugate in combination with accompanying chemotherapy. Adverse events include peripheral neuropathy and neutropenia.
1 . A method for treating a subject having a mature T cell lymphoma that has exhibited Grade 2 or greater peripheral neuropathy after starting treatment with a combination therapy comprising an anti-CD30 antibody drug conjugate at a dose of 1.8 mg/kg every three weeks in combination with a chemotherapy consisting essentially of cyclophosphamide, doxorubicin and prednisone (CHP), comprising administering anti-CD30 antibody drug conjugate at a dose between 0.9 mg/kg to 1.2 mg/kg.
2 . The method of claim 1 wherein when the subject exhibits Grade 3 neuropathy, the administration of anti-CD30 antibody drug conjugate is withheld until peripheral neuropathy decreases to Grade 2 or less and then 0.9 to 1.2 mg/kg anti-CD30 antibody drug conjugate therapy is administered.
3 . The method of claim 1 wherein the dose of anti-CD30 antibody drug conjugate is increased to 1.8 mg/kg after the Grade 2 or Grade 3 peripheral neuropathy improves to Grade 1 or less.
4 . The method of claim 1 wherein the combination therapy is administered every three weeks.
5 . The method of claim 4 wherein the combination therapy is administered on day 1 of a 21 day cycle.
6 . The method of claim 4 wherein the combination therapy is administered for no more than six to eight cycles.
7 . (canceled)
8 . The method of claim 5 wherein the subject receives single-agent anti-CD30 antibody drug conjugate for eight to 10 additional cycles for a total of 16 cycles.
9 . (canceled)
10 . The method of claim 1 wherein the combination therapy reduces paresthesia, hypoesthesia, polyneuropathy, muscular weakness, and demyelinating polyneuropathy.
11 . The method of claim 1 wherein the neuropathy is peripheral motor neuropathy or peripheral sensory neuropathy.
12 . (canceled)
13 . The method of claim 1 wherein the anti-CD30 antibody drug conjugate is brentuximab vedotin.
14 . A method for treating a mature T cell lymphoma in a subject comprising administering a combination therapy comprising an anti-CD30 antibody drug conjugate in combination with a chemotherapy consisting essentially of cyclophosphamide, doxorubicin and prednisone (CHP) and prophylactically administering a granulopoiesis stimulating factor, wherein the granulopoiesis stimulating factor is administered with the initiation of the combination therapy.
15 . The method of claim 14 wherein the granulopoiesis stimulating factor is administered from 1 day to 7 days, or from 2 days to 5 days, after the initiation of the combination therapy.
16 . The method of claim 14 wherein the granulopoiesis stimulating factor is administered from 1 day to 7 days after a second, or subsequent, administration of the combination therapy, or wherein the granulopoiesis stimulating factor is administered from 2 days to 5 days after a second, or subsequent, administration of the combination therapy.
17 . (canceled)
18 . The method of claim 14 wherein the granulopoiesis stimulating factor is administered to a subject that has not received an anti-CD30 antibody drug conjugate therapy previously.
19 . The method of claim 14 wherein the subject has not experienced treatment-emergent grade 3-4 neutropenia after administration of the combination therapy.
20 . The method of claim 14 wherein the anti-CD30 antibody drug conjugate is brentuximab vedotin.
21 . A method for reducing the incidence of neutropenia in a subject having mature T cell lymphoma and receiving a combination therapy comprising an anti-CD30 antibody drug conjugate in combination with a chemotherapy consisting essentially of cyclophosphamide, doxorubicin and prednisone (CHP) comprising administering to the subject a granulopoiesis stimulating factor, wherein the granulopoiesis stimulating factor is administered with initiation of the combination therapy.
22 . The method of claim 14 wherein the granulopoiesis stimulating factor is a granulocyte-colony stimulating factor (GCSF).
23 . The method of claim 22 wherein the GCSF is a long-acting GCSF or a non long-acting GCSF.
24 . The method of claim 22 ,
wherein the GCSF is long-acting GCSF, and is administered 1 day or 2 days after the initiation of the combination therapy, or
wherein the GCSF is not long acting, and is administered 1, 2, 3, 4, 5, 6 or 7 days after the initiation of the combination therapy.
25 . (canceled)
26 . The method of claim 14 wherein the combination therapy is administered every 3 weeks or every 2 weeks.
27 . (canceled)
28 . The method of claim 14 wherein the combination therapy is administered on day 1 of a 21 day cycle.
29 . The method of claim 28 wherein the combination therapy is administered for no more than six to eight cycles.
30 - 31 . (canceled)
32 . The method of claim 1 wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises
i) a heavy chain CDR1 set out in SEQ ID NO: 4, a heavy chain CDR2 set out in SEQ ID NO: 6, a heavy chain CDR3 set out in SEQ ID NO: 8; and
ii) a light chain CDR1 set out in SEQ ID NO: 12, a light chain CDR2 set out in SEQ ID NO: 14, and a light chain CDR13 set out in SEQ ID NO: 16.
33 . The method of claim 1 wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises
i) an amino acid sequence at least 85% identical to a heavy chain variable region set out in SEQ ID NO: 2 and
ii) an amino acid sequence at least 85% identical to a light chain variable region set out in SEQ ID NO: 10.
34 . The method of claim 1 wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a monoclonal anti-CD30 antibody, optionally wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a chimeric AC10 antibody.
35 . (canceled)
36 . The method of claim 1 wherein the antibody drug conjugate comprises monomethyl auristatin E and a protease-cleavable linker.
37 . The method of claim 36 wherein i) the protease cleavable linker comprises a thiolreactive spacer and a dipeptide; and/or ii) the protease cleavable linker consists of a thiolreactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer.
38 . (canceled)
39 . The method of claim 14 wherein the anti-CD30 antibody drug conjugate is brentuximab vedotin.
40 . The method of claim 39 wherein the anti-CD30 antibody drug conjugate is brentuximab vedotin and is administered at 1.8 mg/kg, cyclophosphamide is administered at 750 mg/m 2 , doxorubicin is administered at 50 mg/m 2 , and prednisone is administered at 100 mg on days 1 to 5 of a 21 day cycle.
41 . The method of claim 14 wherein the granulopoiesis stimulating factor is administered in a dose range from 5 to 10 mcg/kg/day, or 300 to 600 mcg/day, or 6 mg/dose.
42 - 43 . (canceled)
44 . The method of claim 1 wherein the subject is suffering from a mature T cell lymphoma selected from the group consisting of peripheral T cell lymphoma (PTCL), PTCL entities typically manifesting as nodal involvement, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphomas, peripheral T-cell lymphoma-not otherwise specified, subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma, enteropathy-type intestinal T-cell lymphoma, and extranodal T-cell lymphoma-nasal type.
45 . (canceled)
46 . The method of claim 44 wherein the PTCL is selected from the group consisting of systemic anaplastic large cell lymphoma (sALCL), angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), Adult T-Cell Leukemia/Lymphoma (ATLL), Enteropathy-associated T-cell lymphoma (EATL) and Hepatosplenic T-cell lymphoma; or
wherein the PTCL is selected from the group consisting of angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS), Adult T-Cell Leukemia/Lymphoma (ATLL), Enteropathy-associated T-cell lymphoma (EATL) and Hepatosplenic T-cell lymphoma.
47 . (canceled)
48 . The method of claim 46 wherein the sALCL is selected from the group consisting of anaplastic lymphoma kinase positive (ALK+) sALCL and anaplastic lymphoma kinase negative (ALK−) sALCL.
49 - 53 . (canceled)
54 . The method of claim 44 , wherein the subject has an International Prognostic Index (IPI) score≥2.
55 . The method of claim 44 , wherein the subject has not previously been treated for a hematologic cancer or wherein the subject has previously been treated for a hematologic cancer and the cancer has relapsed or is refractory.
56 . (canceled)
57 . The method of claim 44 , wherein the PTCL
i) is a stage III or stage IV PTCL;
ii) is a CD30-expressing PTCL; and/or
iii) is a CD30-expressing PTCL.
58 - 60 . (canceled)
61 . The method of claim 44 wherein
i) a when the mature T cell lymphoma is PTCL, and wherein if the subject is diagnosed with Grade 2 or greater peripheral motor neuropathy after starting treatment with a combination therapy comprising an anti-CD30 antibody drug conjugate at a dose of 1.8 mg/kg every three weeks in combination with a chemotherapy consisting essentially of cyclophosphamide, doxorubicin and prednisone (CHP), the dose of anti-CD30 antibody drug conjugate is reduced to 1.2 mg/kg; or
ii) when the mature T cell lymphoma is PTCL, and wherein if the subject is diagnosed with Grade 3 or greater peripheral sensory neuropathy after starting treatment with a combination therapy comprising an anti-CD30 antibody drug conjugate at a dose of 1.8 mg/kg every three weeks in combination with a chemotherapy consisting essentially of cyclophosphamide, doxorubicin and prednisone (CHP), the dose of anti-CD30 antibody drug conjugate is reduced to 1.2 mg/kg.
62 . (canceled)
63 . A method for decreasing the incidence of infection in a subject having mature T cell lymphoma and receiving a combination therapy comprising an anti-CD30 antibody drug conjugate in combination with a chemotherapy consisting essentially of cyclophosphamide, doxorubicin and prednisone (CHP) comprising administering to the subject a granulopoiesis stimulating factor in an amount effective to reduce infections, wherein the granulopoiesis stimulating factor is administered with the initiation of the combination therapy.
64 . The method of claim 63 wherein the granulopoiesis stimulating factor is administered from 1 day to 7 days after, or from 2 days to 5 days, after the initiation of the combination therapy.
65 . The method of claim 63 wherein the granulopoiesis stimulating factor is administered from 1 day to 7 days after a second, or subsequent, administration of the combination therapy or wherein the granulopoiesis stimulating factor is administered from 2 days to 5 days after the a second, or subsequent, administration of the combination therapy.
66 - 68 . (canceled)
69 . The method of claim 63 wherein the granulopoiesis stimulating factor is a granulocyte-colony stimulating factor GCSF.
70 - 78 . (canceled)
79 . The method of claim 63 wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises
i) a heavy chain CDR1 set out in SEQ ID NO: 4, a heavy chain CDR2 set out in SEQ ID NO: 6, a heavy chain CDR3 set out in SEQ ID NO: 8; and
ii) a light chain CDR1 set out in SEQ ID NO: 12, a light chain CDR2 set out in SEQ ID NO: 14, and a light chain CDR13 set out in SEQ ID NO: 16.
80 . The method of claim 63 wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises
i) an amino acid sequence at least 85% identical to a heavy chain variable region set out in SEQ ID NO: 2 and
ii) an amino acid sequence at least 85% identical to a light chain variable region set out in SEQ ID NO: 10.
81 . The method of claim 63 wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a monoclonal anti-CD30 antibody, optionally wherein the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a chimeric AC10 antibody.
82 . (canceled)
83 . The method of claim 63 wherein the antibody drug conjugate comprises monomethyl auristatin E and a protease-cleavable linker.
84 - 85 . (canceled)
86 . The method of claim 63 wherein the anti-CD30 antibody drug conjugate is brentuximab vedotin.
87 - 107 . (canceled)
108 . The method of claim 87 , wherein the granulopoiesis stimulating factor is administered from 1 to 8 days after initiation of the combination therapy.