FDA Lifts Hold on Phase 3 Trial Testing Venclexta in Myeloma Patients with Common Genetic Abnormality

The U.S. Food and Drug Administration (FDA) has lifted its hold on the CANOVA Phase 3 clinical trial, which is evaluating the experimental therapeutic Vencexta (venetoclax) plus dexamethasone in people with relapsed or refractory multiple myeloma who test positive for a common genetic abnormality.

Venclexta (sold as Venclyxto in Europe), developed jointly by AbbVie and Roche, works by inhibiting the protein BCL-2, which can help cancer cells survive when they might otherwise die.

Currently, Venclexta is not approved for multiple myeloma treatment by any regulatory authority in any country, though it is approved for some patients with other blood cancers, including chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia.

In March, the FDA instituted a hold on all trials of Venclexta for multiple myeloma based on safety concerns from the BELLINI Phase 3 clinical trial (NCT02755597), in which relapsed or refractory multiple myeloma patients were treated with either Venclexta or placebo in combination with Velcade (bortezomib) and dexamethasone.

That trial reached its primary goal: patients receiving Venclexta lived without their disease getting worse for a median of 22.4 months, compared to 11.5 months in the placebo group. Additionally, significantly more patients in the Venclexta group had any response (82% vs. 68%) or a partial response that was deemed “very good” or better (59% vs. 36%).

Serious adverse events (side effects) and infections occurred at similar rates in both groups (48% vs. 50% and 28% vs. 27%). However, a pre-planned safety analysis revealed that the rate of death was significantly higher in the Venclexta group — 21% vs. 12%.

Indeed, patients in that trial who were receiving Venclexta had twice the risk of death as those taking placebo, which led the FDA to stop all clinical trials of Venclexta for multiple myeloma patients.

However, there was a subset of patients in BELLINI whose risk of death was reduced with Venclexta compared to placebo — those with the translocation (11;14), which is a genetic abnormality that is one of the most commonly tested biomarkers in multiple myeloma. This suggested the treatment was safe and effective for these patients.

The CANOVA trial (NCT03539744) trial is comparing treatment with Venclexta plus dexamethasone to a combination of Pomalyst (pomalidomide) and dexamethasone specifically in this subset of multiple myeloma patients.

So, after revisions were made to the trial protocol — including “new risk mitigation measures, protocol-specified guidelines and updated futility criteria,” according to an AbbVie press release — the agency lifted the hold on the CANOVA trial. Other trials of Venclexta in multiple myeloma remain on hold.

“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, MD, PhD, global head of hematology development at AbbVie. “We are working closely with regulatory authorities worldwide to continue our efforts to understand the potential of [Venclexta] for patients with multiple myeloma while continuing to advance research in patients with the t(11;14) genetic abnormality.”