Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Abstract

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

Conflict of interest statement

Conflict-of-interest disclosure: I.W.F. has received research funding for his institution from AbbVie, Acerta, Agios, ArQule, Beigene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead, Incyte, Infinity, Janssen, KITE, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Seattle Genetics, Takeda, TG Therapeutics, Trillium, and Verastem. J.G.G. has received honoraria from Roche, AbbVie, Pharmacyclics, Celgene, and Janssen; has held a consulting or advisory role for Roche, Acerta, AbbVie, Pharmacyclics, Celgene, and Janssen; and has received research funding from Celgene, Acerta, and Janssen. M.J.S.D. has received honoraria from, and has held a consulting or advisory role for, AbbVie and Roche, and has received travel, accommodation, or expenses from AbbVie; his institution has received research funding from Roche. W.W. has received travel, accommodation, or expenses from AbbVie, Genentech/Roche, Janssen, Pharmacyclics, Gilead, and Pfizer; his institution has received research funding from GlaxoSmithKline/Novartis, AbbVie, Genentech, Karyopharm, Pharmacyclics LLC, Acerta, Gilead Sciences, Juno Therapeutics, KITE Pharma, Sunesis, Miragen, Oncternal Therapeutics, Inc, Cyclacel, Loxo Oncology, Janssen, and Xencor. R.R.F. has received honoraria from Janssen and Genentech; has held a consulting or advisory role for AbbVie, Genentech, Gilead, Janssen, Acerta/AstraZeneca, Pharmacyclics, Sunesis, Loxo Oncology, TG Therapeutics, and Verastem; has received research funding from Acerta and TG Therapeutics; and has served on a data safety monitoring board for Incyte. P.H. has received honoraria from, and participated in speakers’ bureaus for, Janssen, AbbVie, and Gilead, and has received travel, accommodation, or expenses from Janssen and AbbVie; his institution has received research funding from Pharmacyclics, Janssen, AbbVie, Gilead, and Roche. K.A.R. has held a consulting or advisory role for Acerta and has received research funding from Genentech. S.P.I. has held a consulting or advisory role for Genentech, Takeda, and Bristol-Myers Squibb, and has received research funding from Genentech, Takeda, Spectrum Pharmaceuticals, Seattle Genetics, Bristol-Myers Squibb, Amgen, and Rhizem. A.Q.-M. has received research funding from Roche and Glycart. L.Y. has held a consulting or advisory role for Janssen, Roche, Gilead, and AbbVie, and has received research funding from Roche and Janssen. H.S.W. has received honoraria from Gilead and AbbVie; has held a consulting or advisory role for AbbVie; and has received travel, accommodation, or expenses from AbbVie and Gilead. M.V. is an employee of AbbVie. C.K. and an immediate family member of C.K. are employees of Roche and own Roche stock; C.K. also has a patent or intellectual property interest to declare from Roche. H.H. is an employee of Roche. Y.J. is an employee of Genentech and owns Roche stock. G.L. has research funding to disclose from Genentech, Boehringer Ingelheim, Stemline, Celgene, and BC Pharma. D.S.P. and K.H. are employees of Roche and own Roche stock. M.M. is an employee of Genentech and holds Roche stock. T.J.K. is an employee of UC San Diego Health and Moores Cancer Center; has held a consulting or advisory role for Gilead, Celgene, Roche/Genentech, AbbVie, and Pharmacyclics; has received honoraria from Gilead, AbbVie, Pharmacyclics, Janssen, and Verastem; and has received research funding from Roche/Genentech, AbbVie, Pharmacyclics, and Oncternal. M.B.M. declares no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Dosing schedule. Schedule A, Venetoclax followed by obinutuzumab. Schedule B, Obinutuzumab followed by venetoclax. For both the R/R and 1L populations, schedule A was examined prior to schedule B. Data from schedule A provided safety guidance for subsequent dose finding for patients in schedule B after a data review by an internal monitoring safety team and a scientific overview committee. Venetoclax ramp-up: 3 weeks for the 100-mg cohort, 4 weeks for the 200-mg cohort, and 5 weeks for the 400-mg cohort; each cohort dose was continued for a total of 12 months with potential for extension if BM MRD+ or PR (1L) or until disease progression (R/R); venetoclax plus obinutuzumab (6 cycles), then venetoclax monotherapy. Cohort 4 (600 mg) was planned but not explored. Venetoclax ramp-up and maximum cohort dose are indicated by the blue arrows. Obinutuzumab dosing schedule: C1D1, 100 mg; C1D2, 900 mg; C1D8 and 15, 1000 mg; C2-6D1, 1000 mg. C, cycle; D, day; G, GA101/obinutuzumab; PR, partial response; RD1, ramp-up day 1; W, week.

Figure 2.

MRD rates in PB and BM. (A) MRD rates in PB according to time after last dose of obinutuzumab in the R/R population. (B) MRD rates in BM by best response achieved in the R/R population. (C) MRD rates in PB according to time after the last dose of obinutuzumab in the 1L population. (D) MRD rates in PB after completion of all treatment (last dose of venetoclax) in the 1L population. (E) MRD rates in BM by best response achieved in the 1L population. “Discontinued” specifies the number of patients who discontinued the study before the landmark time point due to PD, death, or AE (if applicable). “Missing” specifies the number of patients who reached the landmark time point but did not have samples available for MRD assessment. *Of 43 R/R patients included in the efficacy analysis, 1 was excluded from the MRD analysis because of an undetectable MRD result at screening assumed to be due to the use of anti-CD20 <2 months before starting the trial. †Two patients discontinued the study before achieving this time point due to other reasons than PD, death, or AE, and were excluded from the MRD analysis at this landmark time point. ‡Undetermined: <10−4, but <200 000 leukocytes analyzed. §Median 4.4 months (range, 2.8-8.5 months) from last dose of venetoclax. CRi, complete response with incomplete marrow recovery; G, GA101/obinutuzumab; Tx, treatment.

Figure 3.

MRD kinetics in individual patients (MRD efficacy-evaluable population). uMRD was defined as <1 CLL cell per 104 mononuclear cells in samples with a minimum of 200 000 leukocytes (<10−4). Low-level MRD was defined as between 1 CLL cell per 104 and 1 cell per 102 mononuclear cells (≥10−4 to <10−2). One patient was excluded from the MRD analysis because of an undetectable MRD result at screening assumed to be due to the use of anti-CD20 <2 months before starting the trial. High-level MRD was defined as ≥1 CLL cell per 102 mononuclear cells (≥10−2). del, deletion; mut, mutated; ven, venetoclax.