The FDA has lifted a partial clinical hold placed on the phase III CANOVA trial, which is investigating the combination of venetoclax and dexamethasone in comparison with pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma and a transformation (11;14) abnormality.
The FDA has lifted a partial clinical hold placed on the phase III CANOVA trial, which is investigating the combination of venetoclax (Venclexta) and dexamethasone in comparison with pomalidomide (Pomalyst) and dexamethasone in patients with relapsed or refractory multiple myeloma and a transformation (11;14) abnormality (NCT03539744).1
The partial clinical hold was removed as a result of revisions to the study protocol for the CANOVA trial, which will include new risk mitigation strategies, protocol-specified guidelines, and updated futility criteria. Patient enrollment in the trial may now resume.
"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, which is developing venetoclax jointly with Roche, said in a statement. "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."
In the CANOVA trial, patients eligible for enrollment must have received at least 2 prior lines of therapy, including at least 2 consecutive cycles of lenalidomide (Revlimid) and of a proteasome inhibitor. The patient must also be refractory to lenalidomide and have an ECOG performance status of 0-2. Patients with ongoing graft-versus-host disease post stem cell transplant or other active malignancies are excluded from enrolling in the trial.
The primary endpoint is progression-free survival (PFS) and secondary endpoints include very good partial response rate, overall response rate (ORR), overall survival (OS), duration of response, time to disease progression, time to response, and minimal residual disease negativity rate. Additional endpoints will focus on pharmacokinetic studies and quality-of-life scores.
Although the partial hold was lifted on the CANOVA trial specifically, a partial hold still remains on all other clinical trials evaluating venetoclax in patients with multiple myeloma.2
Thepartial clinical trial hold was announced in March 2019following a review of data from the phase III BELLINI trial which is investigating venetoclax in combination with bortezomib (Velcade) and dexamethasone (Vd) versus Vd alone in patients with relapsed/refractory multiple myeloma. Results from the trial demonstrated a higher rate of patient deaths from the addition of venetoclax in the trial.
Updated results of the BELLINI trialpresented at the 2019 European Hematology Association Congress showed that there was still a concerning number of patient deaths in the venetoclax-treatment arm of the trial. There were 40 deaths among patients treated with venetoclax plus Vd compared with 11 deaths among patients who received Vd alone. Fourteen deaths in the venetoclax arm were due to infection, 17 due to progressive disease, and 9 were due to other causes. The majority of these deaths occurred more than 30 days after the last dose.3
The primary endpoint was met in the BELLINI trial, showing an improvement in PFS with added venetoclax (22.4 months vs 11.5 months; HR, 0.63;P= .01). The ORR was 82% with venetoclax plus Vd compared with 68% for Vd plus placebo (P<.01). OS favored the Vd plus placebo arm, however, due to the increased risk of death with the addition of venetoclax (HR, 2.027; 95% CI, 1.042-3.945). The median OS was not reached in either arm, though.
The agency is continuing to evaluate next steps for continued research of the BCL-2 inhibitor in multiple myeloma.