ReVenG: A Phase 2 Study of Venetoclax Plus Obinutuzumab Retreatment in Patients with Relapsed Chronic Lymphocytic Leukemia

Abstract

Background: The combination of venetoclax (Ven), a selective oral B-cell lymphoma-2 inhibitor, and obinutuzumab (Obi), a type II anti-CD20 monoclonal antibody, is approved as a 12-cycle fixed duration treatment for adult patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, pts with CLL and coexisting conditions treated with Ven-Obi achieved high rates of undetectable minimal residual disease (uMRD), translating into a 4-year progression free survival (PFS) of 74%. Despite these favorable results, disease relapse may occur after cessation of the fixed duration therapy, particularly for those with higher risk genetics, such as TP53 aberrancy and unmutated IgHV. A key unanswered question in the field is, for pts who initially had a clinical response after first-line (1L) Ven-Obi treatment, how much clinical benefit would they receive from retreatment with Ven-Obi after developing progressive disease (PD)? Retreatment with Ven-Obi would provide a line of treatment in addition to other regimens such as BTK inhibitors. In patients with relapsed/refractory (R/R) CLL, one of the current standard therapies is the combination of Ven and rituximab (R). Updated results from the phase 3 MURANO trial of 24-cycle fixed duration Ven-R demonstrated that patients with disease progression after treatment completion and clinical response had a best overall response rate (ORR) of 72.2% upon Ven-R retreatment. The results of the MURANO study and the favorable safety profile of Ven-Obi suggest that retreatment with Ven-Obi after initial therapy with Ven-Obi may be effective in pts with relapsed CLL. The present study is the first prospective clinical trial to evaluate the efficacy and safety of retreatment with Ven-Obi at the time of PD in pts who had initially responded to 1L Ven-Obi for at least 12 months (mo) after completing therapy. Study Design and Methods: Pts are eligible for this multicenter, open-label, non-randomized, phase 2 study (NCT04895436) if they have a diagnosis of CLL according to iwCLL criteria, were treated with Ven-Obi fixed duration therapy, and achieved a best response of either complete remission (CR), CR with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR). Pts must also have had at least 12 mo of remission between the last dose of Ven and PD. Pts will be divided into two cohorts: PD more than 2 years after completing 1L treatment (Co-1), and pts with PD between 1-2 years post 1L therapy (Co-2). Pts receive Obi (100 mg intravenously [IV] on Day [D] 1 and additional 900mg on either D1 or D2, then 1000mg on D8 and D15 of Cycle [C] 1 and subsequently on D1C2-6). Ven is administered orally once daily (QD) beginning on C1D22, including a 5-week ramp-up period (weekly dose increases from 20, 50, 100, 200, to 400mg QD), followed by 400mg QD thereafter on 28-day cycles, for a total of 12 or 24 cycles in Co-1 and Co-2, respectively. Pts in Co-2 with detectable MRD (≥10 -4) after 15 months of therapy may continue Ven monotherapy beyond mo 24 at the investigator's discretion. The primary objective is to assess the efficacy of Ven-Obi in Co-1 as measured by ORR, defined as a proportion of pts achieving a best response of PR/nPR or CR/CRi at the end of combination therapy (EOCT) assessment (EOCT + 3 mo). Key secondary objectives are CR/CRi at EOCT, CR/CRi rate at end of therapy (EOT), ORR at EOT, time to response (TTR), duration of response (DOR), PFS, overall survival (OS), time to next treatment (TTNT), and uMRD (10 -4)rate at EOCT and EOT. Safety endpoints include the type, frequency, and severity of treatment-emergent adverse events (AEs), and serious AEs. Prespecified exploratory biomarker endpoints include MRD kinetics up to 12 mo post-treatment, and correlations of baseline characteristics of IgHV, TP53 mutation, and del (17p) status with outcomes. Point and interval estimates will be used to characterize the efficacy of Ven-Obi retreatment; exact binomial (Clopper-Pearson) 95% confidence intervals will be provided alongside the corresponding point estimates for the response rates of interest (ORR, CR rate, and uMRD rate), while Kaplan-Meier methodology will be used to summarize the time-to-event endpoints (DOR, PFS, OS, and TTNT). Finally, descriptive statistical summaries will be reported for several patient-reported outcome (PRO) measures, including the EORTC QLQ-CLL-17, EQ-5D-5L, and FACIT-F. Figure 1 Figure 1. Disclosures Davids: Takeda: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; Research to Practice: Consultancy; Ascentage Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Porro Lurà: F. Hoffmann - La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sinai: AbbVie Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sail: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Komlosi: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Brown: Beigene: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Eli Lilly and Company: Consultancy; Nextcea: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Morphosys AG: Consultancy; MEI Pharma: Consultancy; Acerta/Astra-Zeneca: Consultancy; Abbvie: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Sun: Research Funding; SecuraBio: Research Funding; Loxo/Lilly: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy. Al-Sawaf: AbbVie: Honoraria, Research Funding; Adaptive: Honoraria; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with Obinutuzumab, a type II anti-CD20 monoclonal antibody, for first-line therapy for chronic lymphocytic leukemia.

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“…The ORR was 72%, with a median PFS of 23.3 months with a 56% probability of achieving uMRD at the end of treatment (EOT). There is an ongoing phase II study, the ReVenG trial, which is exploring the efficacy and safety of retreatment also with venetoclax + obinutuzumab [42]. Similarly, preliminary data from the CAPTIVATE trial support the use of retreatment with ibrutinib for patients who received a first-line fixed-duration ibrutinib + venetoclax combination: the ORR in 21 evaluable patients was 86%, mainly PR (81%).…”

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“…In addition, retreatment with I+V is allowed in the CAPTIVATE study and preliminary results are encouraging [25]. ReVenG will assess the efficacy and safety of VG in patients who initially responded to first-line VG for at least 12 months [37].…”

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“…Given the dismal prognosis of patients who are resistant to both venetoclax and BTKis [ 74 ], venetoclax re-treatment may become an attractive option, prolonging the clinical benefit of this therapeutic modality. A prospective phase II study of venetoclax–obinutuzumab re-treatment for patients with CLL relapsing > 1 year after previous time-limited venetoclax–obinutuzumab is in progress (ReVenG: NCT 04895436)[ 75 ].…”