Kerry A. Rogers, MD
Phase II findings of the combination of obinutuzumab (Gazyva), ibrutinib (Imbruvica), and venetoclax (Venclexta) showed a tolerable safety profile and promising response rates in treatment-naïve and relapsed/refractory patients with chronic lymphocytic leukemia (CLL).
at the 2018 ASH Annual Meeting, Rogers, assistant professor, Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, discussed the phase II findings of this trial and the future of dose-limited regimens in CLL.
OncLive: Could you please provide some background on this study?
: As everyone probably knows, combination regimens are a well-proven and effective strategy in CLL, but that was established in the era of chemoimmunotherapy. Since we have highly effective oral targeted agents now, the goal of this study was to combine an anti-CD20 monoclonal antibody with 2 oral targeted drugs: ibrutinib and venetoclax. In preclinical and clinical studies, these agents have shown to have complimentary mechanisms and nonoverlapping toxicities, except for neutropenia and hematologic toxicities. We combined this with obinutuzumab with the goal of developing a regimen that could achieve very deep remissions and have a fixed duration. Extended monotherapy can lead to extended toxicities over time and increases cost of treatments. We want to use our most effective agents in combination for a defined amount of time and see how long the remissions last, and if we can achieve deep responses.
How was the trial designed?
This is a study that had a phase Ib cohort, which included 12 patients with relapsed/refractory CLL. All 3 drugs are given at the FDA-approved dosing schedule except venetoclax, which was given between 100 mg and 400 mg. The phase Ib portion identified 400 mg as the optimal dose to be using in combination with obinutuzumab and ibrutinib. That portion of the study has already been reported. There are no dose-limiting toxicities, so we were able to get to 400 mg in all patients. There is a staggered start to the 3 drugs to reduce the tumor burden and the risk of tumor lysis syndrome. It does use the venetoclax ramp-up [schedule] as per the FDA label.
After our 12 patients in the phase Ib portion were treated, and we determined that this was the dose going forward, 2 phase II cohorts accrued. These cohorts were all treated at the recommended phase II dose for the phase Ib part. It was 25 patients with relapsed/refractory CLL, and 25 patients who were treatment-naïve. The goal of these phase II cohorts was to see how effective this is and get a response rate. The primary endpoint for both of these phase II cohorts is the rate of MRD-negative remission. They were developed to be analyzed independently.
What are the updated results?
I presented the results of the primary endpoint and the end-of-treatment results of these 2 phase II cohorts. These are the responses of the patients who completed treatment, and I also reported some of the adverse events (AEs). There was not anything unexpected in terms of AEs. For the final treatment responses, we had everyone who reached the response assessment and was assessed had an objective response according to International Workshop Group on CLL [iwCLL] criteria. The design was to be an intention-to-treat analysis, meaning patients who discontinued study treatment before the planned response assessment were considered not to respond. Therefore, everyone who made it there and was assessed had a response in both cohorts, but the overall response rate is lower, simply because not everyone reached that.
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