Sandra Horning, MD
The combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) reduced the risk of disease progression or death versus obinutuzumab plus chlorambucil in treatment-naïve patients with chronic lymphocytic leukemia (CLL) with comorbidities.
Genentech, which co-develops venetoclax with AbbVie, announced in a press release that the phase III CLL14 study had met its primary endpoint of a statistically significant improvement in progression-free survival with the venetoclax combination versus the standard-of-care regimen. The company is withholding specific results for presentation at a future medical meeting, but noted that no new safety signals emerged in the trial.
“People with chronic lymphocytic leukemia continue to need more treatment options because some patients are unable to tolerate chemotherapy regimens due to their underlying health,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement.
“CLL14 is the first study to show superior progression-free survival for Venclexta plus Gazyva compared to a standard-of-care regimen. We will work with health authorities to bring this potential chemotherapy-free treatment option to people who need it as quickly as possible,” added Horning.
Preliminary data from the CLL14 trial were presented at the 2015 ASH Annual Meeting. The early results showed that after 3 cycles of treatment with venetoclax and obinutuzumab, the overall response rate (ORR) was 92%. After 6 cycles of treatment with the combination, the ORR rose to 100%. Based on a recommendation from an independent data monitoring committee review, the randomized portion of the trial was opened in August 2015.
The data presented at ASH in 2015 were from the safety run-in phase of the trial, which was performed to assess the tolerability of obinutuzumab and venetoclax. In this stage of the trial, 13 previously untreated patients with confirmed CLL and coexisting medical conditions were enrolled and received 6 cycles of obinutuzumab and venetoclax followed by venetoclax alone for 6 cycles. The median age of patients was 75 years, with 62% of patients being classified as Binet stage C.
In the first cycle, obinutuzumab was administered intravenously at 100 mg on day 1 followed by 900 mg on day 2, and 1000 mg on days 8 and 15. In subsequent cycles, obinutuzumab was administered at 1000 mg on day 1. Venetoclax was administered weekly beginning on day 22 of cycle 1, starting at 20 mg and ramping up to a 400 mg dose.
The study defined stopping criteria for the 13 patients as one treatment-related death or a grade 4 adverse event related to a clinical tumor lysis syndrome (TLS). Risk assessment for TLS was performed before treatment in order to direct prophylactic measures. Six patients were assessed as medium risk for TLS and 7 patients as high risk.
At the time of data cutoff, 12 of 13 patients have been on treatment for at least 4 weeks and completed the venetoclax dose ramp up. The median time on treatment with venetoclax was 64.5 days. None of the protocol defined stopping criteria for the safety run-in phase of the study were met.
All patients experienced at least one grade 1 or 2 adverse event, with infusion-related reactions being the most common. One patient involved in the study developed a grade 4 infusion-related reaction during the first dose of obinutuzumab and was withdrawn from the trial.
Several patients experienced serious grade 3 or 4 adverse events, with neutropenia being the most common (38.5%). Although no clinical TLS was reported, 2 patients developed laboratory TLS. Neither event, however, resulted in treatment delays or dose modification.
Fischer K, Fink A-M, Bishop H, et al. Results of the Safety Run-in Phase of CLL14 (BO25323): A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare the Efficacy and Safety of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) with Obinutuzumab and Chlorambucil in Patients with Previously Untreated CLL and Coexisting Medical Conditions. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 496.