Two AbbVie scientists discuss finalizing details of an in vitro assay before conducting the study. Photo Courtesy: AbbVie |photo by Kevin J. Miyazaki/Redux
Two AbbVie scientists discuss finalizing details of an in vitro assay before conducting the study. Photo Courtesy: AbbVie |photo by Kevin J. Miyazaki/Redux

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold placed on CANOVA (M13-494) trial (NCT03539744), a Phase III multicenter, randomized, open label clinical study evaluating venetoclax (Venclexta®/Venclyxto®; previously known as ABT-199; AbbVie and Genentech/Roche) for the investigational treatment of relapsed/refractory multiple myeloma.

Venetoclax is a first-in-class agent designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. Venetoclax targets the BCL-2 protein and works to help restore the process of apoptosis.

Clinical trials
The CANOVA trial evaluates venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone in patients with relapsed/refractory multiple myeloma positive for the translocation (11;14) abnormality. The t(11;14) genetic biomarker is among the most common and routinely tested genetic abnormalities in patients with multiple myeloma.[1]

Revised study protocol
The FDA removed the partial clinical hold based upon agreement on revisions to the CANOVA study protocol, including new risk mitigation measures, protocol-specified guidelines and updated futility criteria. Based on the decision, enrollment in the CANOVA trial may resume as determined by each participant site based on the approved protocol.

Other trials on hold
All other clinical trials evaluating venetoclax in patients with multiple myeloma remain on partial clinical hold while next steps continue to be evaluated with the agency. The partial clinical hold does not impact any of the approved indications for venetoclax, such as chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). AbbVie remains confident in the benefit/risk profile of venetoclax in those approved indications.

“We are pleased to move forward with the CANOVA study which, with the t(11;14) biomarker test, can help identify patients who may respond better to treatment and add clarity for physicians when choosing a therapy, if approved,” said Mohamed Zaki, M.D., Ph.D., global head of hematology development, AbbVie.

“We are working closely with regulatory authorities worldwide to continue our efforts to understand the potential of venetoclax for patients with multiple myeloma while continuing to advance research in patients with the t(11;14) genetic abnormality,” Zaki added.

European Hematology meeting
Results from the Phase III BELLINI trial (NCT02755597), a multicenter, randomized, double blind study evaluating patients with relapsed/refractory multiple myeloma, were presented at the 24th European Hematology Association (EHA) Annual Congress during the late-breaking oral presentation session on Sunday, June 16, 2019.

Additional data will be presented at a future congress and published in a medical journal.[2]

The BELLINI trial looked at either venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior lines of therapy and are sensitive or naïve to proteasome inhibitors. The study included 291 patients with 194 in the venetoclax arm and 97 in the placebo arm.

The study met its primary endpoint of improved progression-free survival (PFS) (22.4 months vs. 11.5 months, [hazard ratio=0.63, p=0.01]), with a median follow-up of 18.7 months, and demonstrated statistically significant improvement in overall response rate (ORR) (82% vs. 68%, p<0.01) and very good partial or better response (59% vs. 36%, p<0.01) in the venetoclax arm compared to the control arm. Median overall survival was not reached (HR 2.027, 95% CI (1.042, 3.945)).[2]

Safety analyses showed the majority of deaths in the venetoclax arm were related to infection and progressive disease. There were 52 deaths in the study population, 41 (21%) in the venetoclax arm and 11 (12%) in the placebo arm, with progressive disease the most common cause (45%). The rates of serious AEs (48% vs 50%) and serious infections (28% vs 27%) were comparable between arms.[2]

Partial hold
In March 2019, AbbVie confirmed that the FDA had placed a partial clinical hold on all trials evaluating venetoclax for the investigational treatment of multiple myeloma, following a review of data from the Phase III BELLINI trial of venetoclax with bortezomib and dexamethasone (Ven + Vd) versus placebo (placebo + Vd) in patients with relapsed/refractory multiple myeloma, in which a higher proportion of deaths (41/194 (21%)) was observed in the venetoclax arm compared to the control arm of the trial (11/97 (11%) — overall survival hazard ratio (HR) 2.027, 95% confidence interval (CI): [1.042, 3.945]).

Progressive disease was the most common cause (45%) of death. The rates of serious adverse events (AEs) (48% vs 50%) and serious infections (28% vs 27%) were comparable between arms.[2]

Optimal therapy
Despite the availability of multiple myeloma therapies, there is no optimal treatment sequence.[3]

Nearly all multiple myeloma patients eventually relapse, which is associated with poor outcomes, and each remission is typically shorter than the previous one.[4]

Patients with multiple myeloma have an average life expectancy of approximately five to six years after diagnosis.[5] It is the second most common blood cancer with nearly 140,000 cases expected to be diagnosed worldwide this year.[6][7]

Joint development program
Venetoclax is being developed by AbbVie and Roche and jointly commercialized by both AbbVie and Genentech in the U.S. and by AbbVie outside of the U.S.

Clinical trials
A Study of Venetoclax and Dexamethasone Compared With Pomalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (CANOVA) – NCT03539744

A Study Evaluating Venetoclax (ABT-199) in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy – NCT02755597

References
[1] Anderson, K. C. (2014). Multiple myeloma: NCCN clinical practice guidelines in oncology (NCCN Guidelines®).
[2] Kumar, et al. EHA 2019 Abstract #LBA2601.
[3] Costello, C., & Mikhael, J. R. (2018). Therapy sequencing strategies in multiple myeloma: Who, what and why? Future Oncology, 14(2), 95-99.
[4] Myeloma UK. Infopack for relapsed and/or refractory myeloma patients. Online. Last accessed June 24, 2019.
[5] SEER Cancer Stat Facts: Myeloma. National Cancer Institute. Bethesda, MD, Online. Last accessed, June 24, 2019.
[6] Kazandjian D. Multiple myeloma epidemiology and survival, a unique malignancy. Semin Oncol. 2016; 43(6): 676-681.
[7] Cowan AJ, Allen C, Barac A, et al. Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018; 4(9): 1221-1227.

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