Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Abstract

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

Conflict of interest statement

Conflict-of-interest disclosure: A.D.Z. serves on advisory committees/consults for Adaptive Biotechnologies, Amgen, Boehringer Ingelheim, Celgene, Roche-Genentech, Gilead, Hospira, NanoString Technologies, Novartis, Pharmacyclics, Portola Pharmaceuticals, and Takeda and has stock holdings in Adaptive Biotechnologies (options, not exercised); G.S. consults for Roche, Gilead, Celgene, Novartis, and Amgen, receives research funding from Roche, and receives honoraria from Roche, BMS, Merck, Servier, Gilead, Celgene, Novartis, Amgen, and Janssen; C.C. consults for Infinity, receives research funding from Celgene, and receives honoraria from Infinity; S.L.G. serves on advisory boards for Roche, Janssen, and Celgene and receives research funding from Roche and Janssen; L.H.S. consults for Roche/Genentech, Amgen, Gilead, Lundbeck, Seattle Genetics, Janssen, AbbVie, TG Therapeutics, and Celgene, and receives honoraria from Seattle Genetics, AbbVie, and TG Therapeutics; H.T. receives honoraria from Roche, BMS, and Servier and serves on advisory committees for Roche and Karyopharm; G.C. consults for Roche and Celgene and receives honoraria from Roche, Celgene, Gilead, and Janssen; M.E.D.C. serves on advisory boards for Roche, Gilead, and Celgene; A.G. consults for Celgene, Pharmacyclics/J&J, Acerta, Takeda, and Infinity, receives research funding from Celgene, Pharmacyclics/J&J, and Genentech, receives honoraria from Celgene, Takeda, Pharmacyclics/J&J, and Acerta, serves on speakers bureaus for Takeda and Pharmacyclics/J&J, and has received writing support from Takeda; C.S.T. receives honoraria from Roche and AbbVie and research funding from Roche; P.J.L. consults for Roche‐Genentech, Celgene, Jansen‐Cilag, Servier, Takeda, and Mundipharma, receives research support from Roche‐Genentech, and receives travel expenses from Roche‐Genentech; A.M.P. is an employee of AbbVie; A.S. is an employee of Roche; D. Samineni is an employee of Genentech; S.H. is an employee of Roche; E.I. is an employee of Genentech; E.S.-G. is an employee of Genentech; C.K. is an employee and equity holder of Roche; D. Sampath is an employee of Genentech; M.K. is an employee and equity holder of Roche; M.M. was an employee of Genentech and is equity holder of Roche; F.M. consults for Celgene and Gilead and receives honoraria from Celgene, Roche, Janssen, Gilead, and BMS; K.D.M. declares no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Dose-escalation cohorts (3+3 design): modified dosing schema. Four dosing cohorts received venetoclax ranging from 200 to 800 mg every day plus R-CHOP or G-CHOP. Standard CHOP chemotherapy was administered consisting of IV cyclophosphamide 750 mg/m2, IV doxorubicin 50 mg/m2, and IV vincristine 1.4 mg/m2 (with a 2.0-mg cap) on day 1, and prednisone 100 mg/day orally on days 1 to 5. A 6-week (ie, 2-cycle) observation period was allowed for evaluation of DLTs. Patients who experienced responses without excessive toxicity were allowed up to 8 cycles of CHOP at the investigator’s discretion after discussion with the Medical Monitor. D, day; W, week.

Figure 2.

Duration of disease response by PET-CT or CT. The combined response for CR/PR can be contributed by either PET-CT or CT, whichever is available. If both PET-CT and CT results were available and discordant, PET-CT results were used. *Patient continued on study therapy after PD. †Five transformed DLBCL (all CR); 1 composite lymphoma with DLBCL and FL portions (response not available); 1 Waldenström macroglobulinemia (PR); 5 marginal zone lymphoma (3 CR, response not available in 2 patients). SD, stable disease.