Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma
Salles, Gilles; Gopal, Ajay K; Minnema, Monique C; Wakamiya, Karen; Feng, Huaibao; Schecter, Jordan M; Wang, Michael
(2019) Clinical Lymphoma, Myeloma and Leukemia, volume 19, issue 5, pp. 275 - 284
(Article)
Abstract
BACKGROUND: Daratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL). PATIENTS AND METHODS: This was
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a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489). RESULTS: The trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4). CONCLUSION: In NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.
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Keywords: CD38, DLBCL, FL, MCL, Non-Hodgkin lymphoma, Journal Article
ISSN: 2152-2650
Publisher: Cancer Media Group
Note: Funding Information: The assay was verified on panels of commercially obtained formalin-fixed, paraffin-embedded lymphoma specimens; specimens were provided by Janssen, the Indiana University School of Medicine Simon Cancer Center, and the Cooperative Human Tissue Network (funded by the National Cancer Institute). The CD38 IHC assay was based on the EnVision Flex visualization technology and used the CD38 primary antibody, clone DAK-CD38 (Agilent Technologies, Carpinteria, CA).11 The assay staining protocol was developed for the Dako PT Link and Autostainer Link 48 automated IHC platform. After incubation with the CD38 antibody or the negative control reagent, specimens were incubated with a ready-to-use visualization reagent consisting of secondary antibody molecules and horseradish peroxidase molecules coupled to a dextran polymer backbone. The enzymatic conversion of the subsequently added diaminobenzidine chromogen resulted in precipitation of a visible reaction product localized to the antigen. Stained slides were then interpreted using a light microscope. For determination of CD38-positive staining, partial and/or complete linear circumferential membrane staining of neoplastic lymphocytes was included. Normal hematopoietic and necrotic cells were excluded from scoring. The total percentage of CD38-positive tumor cells was determined by qualitative assessment by a board-certified hematopathologist.G.S. reports grants, personal fees, and nonfinancial support from Celgene and grants and personal fees from Roche during the conduct of the study in addition to personal fees from Janssen, Gilead, Celgene, Novartis, Amgen, Servier, Bristol-Myers Squibb, Merck, MorphoSys, Roche, Acerta, and Pfizer outside the submitted work. A.K.G. reports grants and nonfinancial support from Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, and Effector; research support from Frank and Betty Vandermeer and Sonya and Tom Campion; grants, personal fees, and nonfinancial support from Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, and Incyte; and personal fees from Aptevo, BRIM Bio, and Sanofi outside the submitted work. M.C.M. received research support from Celgene; served on the Advisory Board for Janssen, Amgen, Takeda, Celgene, and Servier; and received nonfinancial support from Celgene. K.W. is an employee of Agilent Technologies and holds stock in Agilent Technologies and Amgen. H.F. is an employee of Janssen. J.S. is an employee of Janssen and holds stock and/or stock options in J&J. MW reports grants and/or personal fees from Pharmacyclics, Janssen, Novartis, AstraZeneca, Kite Pharmaceuticals, Juno, and Acerta Pharma.Sponsored by Janssen Research & Development LLC, which designed the study, collected and analyzed the data, and interpreted the data. Editorial and medical writing support were provided by MedErgy and were funded by Janssen Global Services LLC. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.The authors thank the patients who participated in this study, the staff members at the study sites, the data and safety monitoring committee, staff members who were involved in data collection and analyses, and the remaining investigators who enrolled patients onto this study (including Dr Martine Chamuleau and Dr Elly Lugtenburg). The authors also thank Dr Preetesh Jain for providing comments. Editorial and medical writing support was provided by Kimberly Carmony, PhD, of MedErgy, and were funded by Janssen Global Services LLC. Funding Information: Sponsored by Janssen Research & Development LLC, which designed the study, collected and analyzed the data, and interpreted the data. Editorial and medical writing support were provided by MedErgy and were funded by Janssen Global Services LLC . The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency . As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu . Funding Information: The assay was verified on panels of commercially obtained formalin-fixed, paraffin-embedded lymphoma specimens; specimens were provided by Janssen, the Indiana University School of Medicine Simon Cancer Center, and the Cooperative Human Tissue Network (funded by the National Cancer Institute). The CD38 IHC assay was based on the EnVision Flex visualization technology and used the CD38 primary antibody, clone DAK-CD38 (Agilent Technologies, Carpinteria, CA).11 The assay staining protocol was developed for the Dako PT Link and Autostainer Link 48 automated IHC platform. After incubation with the CD38 antibody or the negative control reagent, specimens were incubated with a ready-to-use visualization reagent consisting of secondary antibody molecules and horseradish peroxidase molecules coupled to a dextran polymer backbone. The enzymatic conversion of the subsequently added diaminobenzidine chromogen resulted in precipitation of a visible reaction product localized to the antigen. Stained slides were then interpreted using a light microscope. For determination of CD38-positive staining, partial and/or complete linear circumferential membrane staining of neoplastic lymphocytes was included. Normal hematopoietic and necrotic cells were excluded from scoring. The total percentage of CD38-positive tumor cells was determined by qualitative assessment by a board-certified hematopathologist.G.S. reports grants, personal fees, and nonfinancial support from Celgene and grants and personal fees from Roche during the conduct of the study in addition to personal fees from Janssen, Gilead, Celgene, Novartis, Amgen, Servier, Bristol-Myers Squibb, Merck, MorphoSys, Roche, Acerta, and Pfizer outside the submitted work. A.K.G. reports grants and nonfinancial support from Teva, Bristol-Myers Squibb, Merck, Takeda, TG Therapeutics, and Effector; research support from Frank and Betty Vandermeer and Sonya and Tom Campion; grants, personal fees, and nonfinancial support from Seattle Genetics, Pfizer, Janssen, Gilead, Spectrum, and Incyte; and personal fees from Aptevo, BRIM Bio, and Sanofi outside the submitted work. M.C.M. received research support from Celgene; served on the Advisory Board for Janssen, Amgen, Takeda, Celgene, and Servier; and received nonfinancial support from Celgene. K.W. is an employee of Agilent Technologies and holds stock in Agilent Technologies and Amgen. H.F. is an employee of Janssen. J.S. is an employee of Janssen and holds stock and/or stock options in J&J. MW reports grants and/or personal fees from Pharmacyclics, Janssen, Novartis, AstraZeneca, Kite Pharmaceuticals, Juno, and Acerta Pharma.Sponsored by Janssen Research & Development LLC, which designed the study, collected and analyzed the data, and interpreted the data. Editorial and medical writing support were provided by MedErgy and were funded by Janssen Global Services LLC. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. The authors thank the patients who participated in this study, the staff members at the study sites, the data and safety monitoring committee, staff members who were involved in data collection and analyses, and the remaining investigators who enrolled patients onto this study (including Dr Martine Chamuleau and Dr Elly Lugtenburg). The authors also thank Dr Preetesh Jain for providing comments. Editorial and medical writing support was provided by Kimberly Carmony, PhD, of MedErgy, and were funded by Janssen Global Services LLC. Publisher Copyright: © 2018
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