Researchers can move forward with the phase III CANOVA trial, now that the U.S. Food and Drug Administration (FDA) has lifted a partial clinical hold. The trial is studying the BCL2 inhibitor venetoclax in combination dexamethasone, versus pomalidomide and dexamethasone, in patients with relapsed/refractory multiple myeloma that harbors the t(11:14) translocation.
Worldwide regulatory authorities reached an agreement with AbbVie, the company that co-develops venetoclax with Roche, to revise the study protocol to include new risk mitigation measures, protocol specified guidelines, and fully updated criteria.
The FDA placed the partial clinical hold on all studies evaluating venetoclax in patients with multiple myeloma based on results from the phase III BELLINI trial, which compared venetoclax versus placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. In this trial, a higher proportion of deaths was observed in the venetoclax arm compared with the control arm of the trial (21% vs. 11%; hazard ratio = 2.027; 95% CI 1.042-3.945). Forty-five patients died due to progressive disease.
However, a review of overall survival and safety data from the BELLINI trial indicated that, of the deaths that occurred on the venetoclax arm compared to the placebo arm, 14 (7%) versus 2 (2%) were due to infection, 17 (9%) versus 8 (8%) were due to progressive disease, and 9 (5%) versus 1 (1%) were due to other causes, respectively.
In the updated results of the phase III BELLINI trial, which were presented at the 24th Congress of the European Hematology Association, most deaths in both arms occurred after 30 days of the last dose, with 27 (14%) in 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.
In the CANOVA trial, venetoclax is administered orally once daily in combination with oral dexamethasone given once weekly in 28-day cycles. In the control arm, pomalidomide is administered orally once daily on days 1 to 21 for each 21-day cycle plus weekly dexamethasone for each 28-day cycle.