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sNDA Submitted to FDA for Approval of Venetoclax/Obinutuzumab in Treatment Naive CLL

Gina Columbus
Published Online:7:10 PM, Thu March 7, 2019
Sandra Horning, MD

Sandra Horning, MD

The combination regimen of venetoclax (Venclexta) and obinutuzumab (Gazyva) is seeking FDA approval; a supplemental new drug application (sNDA) has been submitted to the FDA for the combination as a treatment for patients with previously untreated chronic lymphocytic leukemia (CLL) who also have coexisting medical conditions, according to an announcement from Genentech (Roche), which jointly develops venetoclax with AbbVie.1

The agency is reviewing the sNDA under the Real-Time Oncology Review pilot program, which is designed to have a more efficient review process to make therapies more quickly available to patients, the company noted. 

The sNDA was submitted based on the results of the randomized, phase III CLL14 study, in which a fixed-duration combination of venetoclax and obinutuzumab demonstrated a statistically significant reduction in the risk of disease progression or death compared with obinutuzumab plus chlorambucil in treatment-naïve patients with CLL and coexisting medical conditions.

Additionally, no new safety signals were reported with the combination, and the safety profile of the 2-drug regimen was consistent with that of each agent alone. Full data from the CLL14 trial will be presented at an upcoming medical meeting, according to the announcement. 

“More than 20,000 people will be diagnosed with untreated chronic lymphocytic leukemia in the United States this year, and many are ineligible for intensive chemotherapy-based options,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech (Roche). “We are encouraged that this chemotherapy-free, fixed-duration combination is being reviewed under the FDA’s Real-Time Oncology Review pilot program, and we are working closely with the agency to bring this new option to people with previously untreated chronic lymphocytic leukemia as quickly as possible.”

In the phase III CLL14 trial (NCT02242942), the combination of fixed-duration venetoclax and obinutuzumab was compared with obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab (arm A) or 6 months of obinutuzumab followed by 6 months of chlorambucil (arm B).

The primary endpoint of the trial was investigator-assessed progression-free survival (PFS); secondary endpoints included independent review committee (IRC)-assessed PFS, minimal residual disease (MRD) status, overall response rate (ORR), complete response (CR), CR with incomplete blood count recovery (CRi), overall survival (OS), duration of response, event-free survival, time to next CLL treatment, and safety.

Preliminary data from the CLL14 trial were presented at the 2015 ASH Annual Meeting.2 Early results showed that after 3 cycles of treatment with venetoclax and obinutuzumab, the ORR was 92%. However, following 6 cycles of treatment with the combination, the ORR increased 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 results that were presented at the 2015 ASH Annual Meeting 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 co-existing 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.

Regarding safety, all patients experienced at least one grade 1 or 2 adverse event (AE), 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 3/4 AEs, with neutropenia being the most common (38.5%). Although no clinical TLS was reported, 2 patients developed laboratory TLS. Neither AE, however, resulted in treatment delays or dose modification.
 
References:
  1. Genentech Submits Supplemental New Drug Application to FDA for Venclexta Plus Gazyva for Previously Untreated Chronic Lymphocytic Leukemia with Co-Existing Medical Conditions. Genentech (Roche). Published March 7, 2019. https://bit.ly/2C9as21. Accessed March 7, 2019.
  2. 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: 2015 ASH Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 496.


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