Study Demonstrates Tolerability of Obinutuzumab Combo in Patients with Previously Untreated CLL

A combination of venetoclax and obinutuzumab, followed by additional cycles of venetoclax, has shown tolerability in elderly patients with previously untreated chronic lymphocytic leukemia (CLL) with comorbidities, data from the CLL14 trial (BO25323) shows. The trial has begun enrolling patients in its randomized phase based on these preliminary results.

“The treatment regimen developed for the experimental arm of the CLL14 trial, comprising obinutuzumab and venetoclax ... appears tolerable,” said Kirsten Fischer, MD, Department of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany, at the 2015 American Society of Hematology (ASH) Annual Meeting. “None of the protocol defined stopping criteria for the safety run-in phase of the study were met.”

Venetoclax, a Bcl-2 inhibitor, shows promising results in patients with relapsed/refractory CLL as both a monotherapy and in combination with rituximab, said Fischer.

Additionally, data from a separate trial, the CLL11 trial, shows that combining obinutuzumab, a type II, glycoengineered anti-CD20-antibody, with chlorambucil, resulted in improved overall survival (OS). This is in comparison to chlorambucil as a single agent in patients with previously untreated CLL and coexisting medical condition.

CLL14 Trial: Safety Run-In Phase

Prior to the randomized phase of the CLL14 trial, the successor to CLL11, a safety run-in phase was performed to assess the tolerability of obinutuzumab and venetoclax. From December 2014 and April 2015, researchers enrolled 13 previously untreated patients with confirmed CLL and coexisting medical conditions. The median age of enrolled patients was 75 years, with 62% of patients being classified as Binet stage C.

Patients enrolled received 6 cycles of obinutuzumab and venetoclax, followed by 6 additional cycles of venetoclax. Obinutuzumab was administered intravenously with 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of cycle 1, and 1000 mg on day 1 for cycles 2 through 6. 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 all 13 patients, noted Fischer. These criteria included one treatment-related death or one 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 cut-off, 12 of 13 patients have been on treatment for at least 4 weeks and completed the venetoclax dose ramp up,” said Fischer, who added the median time on treatment with venetoclax is 64.5 days.

Manageable Toxicities

All patients experienced at least a single grade 1 or 2 adverse event, with infusion-related reactions being the most common, Fischer reported.

One patient involved in the study developed a grade 4 infusion related reaction (IRR) during the first dose of obinutuzumab and was withdrawn from the trial, according to the protocol requirements.

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, said Fischer.

Preliminary Data on Efficacy

“Preliminary data indicate a profound reduction in absolute lymphocyte count after first dose, and a profound reduction in lymphadenopathy, with the exception of an 88-year-old patient with high disease burden,” said Fischer.

After 3 cycles, the overall response rate (ORR) was 92%, and after 6 cycles, the ORR rose to 100%.

“Initiating treatment with obinutuzumab followed by venetoclax appears tolerable in this population,” Fischer concluded. “The preliminary data are promising.”

Based on the IDMC (Independent Data Monitoring Committee) review of the safety data, the randomized phase of the CLL14 trial was opened in August 2015 and has already enrolled 120 patients, which is one third of the target.