The FDA has lifted a partial clinical hold that was placed on the phase III CANOVA (M13-494; NCT03539744) trial, which is examining venetoclax in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma that harbors t(11;14), according to AbbVie, the company that co-develops the BCL-2 inhibitor with Roche.
The FDA has lifted a partial clinical hold that was placed on the phase III CANOVA (M13-494; NCT03539744) trial, which is examining venetoclax (Venclexta) in combination with pomalidomide (Pomalyst) and dexamethasone in patients with relapsed/refractory multiple myeloma that harbors t(11;14), according to AbbVie, the company that co-develops the BCL-2 inhibitor with Roche.1
The lift on the partial hold is based on an agreement on revisions to the CANOVA study protocol, which includes new risk mitigation measures, protocol-specified guidelines, and fully updated criteria.
"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," Mohamed Zaki, MD, PhD, global head of hematology development at AbbVie, stated in a press release. "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."
The lift does not apply to other clinical trials evaluating venetoclax in multiple myeloma while next steps continue to be addressed with the FDA, AbbVie stated. However, the partial clinical hold does not impact the FDA-approved indications for venetoclax in chronic lymphocytic leukemia or acute myeloid leukemia.
The FDA previously placed a partial clinical hold on all studies that are evaluating the BCL-2 inhibitor in patients with multiple myeloma. In the phase III BELLINI trial of venetoclax with bortezomib (Velcade) and dexamethasone versus placebo in patients with relapsed/refractory multiple myeloma, a higher proportion of deaths (21%) was observed in the venetoclax arm compared with the control arm of the trial (11%; HR, 2.027; 95% CI, 1.042-3.945).2 Forty-five patients died due to progressive disease.
Between the 2 arms, the rates of serious adverse events (AEs; 48% vs 50%) and serious infections (28% vs 27%) were comparable between arms.
In the multicenter, open-label, phase III CANOVA trial, investigators sought to evaluate venetoclax in combination with dexamethasone compared with pomalidomide/dexamethasone in 244 patients with relapsed/refractory multiple myeloma who harbor t(11;14). Patients who progressive on pomalidomide/dexamethasone are permitted to cross over to the venetoclax arm as per International Myeloma Working Group criteria.
To be eligible for enrollment, patients had to have measurable disease at screening, received ≥2 prior lines of therapy, ≥2 consecutive cycles of lenalidomide (Revlimid) and be refractory to it, ≥2 cycles of a proteasome inhibitor, be positive for t(11;14), and have an ECOG performance status ≤2.
Venetoclax is administered orally once daily in combination with oral dexamethasone given once weekly in 28-day cycles. In the pomalidomide arm, the immunomodulatory agent is administered orally once daily on days 1 to 21 for each 21-day cycle plus weekly dexamethasone for each 28-day cycle.
The primary endpoint is progression-free survival; secondary endpoints are very good partial response or better response rate, overall response rate, overall survival (OS), duration of response, time to disease progression, time to response, and quality of life.
In the updated results of the phase III BELLINI trial, which were presented at the 2019 European Hematology Association Congress, the majority of deaths on both arms occurred after 30 days of the last dose, with 27 (14%) on the venetoclax arm compared with 10 (10%) in the placebo group. Of these, 3% versus 2% were due to infection, 8% versus 7% were due to progressive disease, and 3% versus 1% were due to other causes, respectively.
Moreover, a review of OS and safety data indicated of the deaths that of the deaths that occurred on venetoclax versus placebo, 14 (7%) versus 2 (2%) were due to infection, 17 (9%) versus 8 (8%) due to progressive disease, and 9 (5%) versus 1 (1%) were due to other causes, respectively.