A CLL Trial in Progress for Those Who Relapsed After Venetoclax Plus Obinutuzumab

At the annual meetings of the American Society of Hematology or ASH, there is a special category for abstracts about trials in progress that explain the trials’ designs and objectives before there are any meaningful results to share. Here we review ReVenG, a phase 2 study of venetoclax plus obinutuzumab retreatment (“second time”) in patients with relapsed chronic lymphocytic leukemia (CLL) (ClinicalTrials.gov Identifier: NCT04895436) that fits that category. It was presented at ASH 2021 by Dr. Matthew Davids.

Background: The combination of venetoclax, a selective oral B-cell lymphoma-2 (BCL-2) inhibitor, and intravenous obinutuzumab, a potent anti-CD20 monoclonal antibody, is approved as a 12-cycle fixed duration treatment for adult patients with previously untreated chronic lymphocytic leukemia (CLL) in addition to other therapies.

The approval is based on a multicenter, randomized, open-label, phase 3 CLL14 study in which patients with CLL / SLL and coexisting medical conditions were treated with venetoclax plus obinutuzumab (V+O). They achieved high rates of undetectable measurable or minimal residual disease (uMRD), translating into a 4-year progression-free survival (PFS) of 74%. However, despite these favorable results, disease relapse occurs after cessation of the fixed duration therapy, particularly earlier for those with higher risk features such as TP53 mutation and unmutated IgHV.

Unanswered Question: The critical unanswered question this trial hopes to address is for the patient who initially had a clinical response after first-line venetoclax plus obinutuzumab treatment, how much clinical benefit would they receive from retreatment with venetoclax plus obinutuzumab after developing a relapse that requires restarting therapy, in other words, progressive disease?

At the annual meetings of the American Society of Hematology or ASH, there is a particular abstract category for trials in progress that discuss the trial’s design and objectives before there are any meaningful results to share.

Takeaways:

• Multicenter, open-label, non-randomized, phase 2 study
• Eligibility: Patients must have received fixed duration (9 to12 months) of previous venetoclax plus obinutuzumab as first-line therapy AND achieved more than or equal to partial response, generally defined as ≥decrease in 50% of CLL burden.
• Repeat venetoclax plus obinutuzumab (“ReVenG”) protocol will be administered in a patient who had a response lasting at least for 12 months, in other words, who had no disease progression while off all therapy for 12 months, but who have subsequently relapsed. These relapsed patients are further divided into two groups:
  1. Patients with progressive relapse disease more than two years after completing first-line treatment (group 1 consisting of 60 patients) and
  2. Patients with progressive relapse disease between 1 to 2 years after first-line therapy (group 2 with15 patients).
• The investigators expect a lower response rate in group 2 compared to group 1 since they had earlier treatment failure after the original fixed-dose regimen.
• Regimen schedule
  • Obinutuzumab for 6 cycles.
  • Venetoclax is ramped up using the standard dosing over five weeks starting 22 days after first Obinutuzumab infusion in cycle 1 and continued for a total of 12 or 24 cycles (every cycle is one-month duration) in group 1 and group 2, respectively.
  • Patients in group 2 with detectable MRD (≥10^-4; one CLL cell in 10,000 normal cells) after 15 months (after 15 cycles) of therapy may continue venetoclax monotherapy (since the higher risk of early failure!) beyond month 24 (“longer course”) at the investigator’s discretion

• Primary objective: The primary objective is to assess the repeat combination therapy’s overall response rate (ORR).

Conclusion: The ideal person who might want to consider this study is someone who had no or mild side effects with V+O and had at least two years of remission, preferably an undetectable MRD remission and/or complete remission, which suggest a higher likelihood of second good response with retreatment, but anyone who responded to the combination and did not progress for at least a year after stopping could discuss enrolling with their healthcare team.

The hope is that this study proves that the venetoclax plus obinutuzumab combination can be safely repeated and provide a high response rate and durable responses. That would offer patients another strong treatment option with the real advantage of not introducing new medications.

The ASH 2021 abstract describing the trial with the clever name ReVenG can be found here: ReVenG: A Phase 2 Study of Venetoclax Plus Obinutuzumab Retreatment in Patients with Relapsed Chronic Lymphocytic Leukemia.

If you are interested in this trial for yourself, it’s listed in Clinicaltrials.gov here: Study to Assess Change in Disease Activity and Adverse Events of Oral Venetoclax With Intravenous (IV) Obinutuzumab in Adult Participants With Recurring Chronic Lymphocytic Leukemia (CLL)