FDA Halts Six Idelalisib Combination Studies

Six clinical trials exploring idelalisib (Zydelig) in combination with other therapies have been halted due to reports of an increased rate of adverse events, including death, for patients with hematologic malignancies, according to an alert issued by the FDA.

The halted studies were exploring idelalisib in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and indolent non-Hodgkin lymphomas (NHL). The FDA announcement follows a similar decision from the European Union, which placed idelalisib under a safety review following reports of infections that were associated with the medication.

“The US Food and Drug Administration is alerting healthcare professionals about reports of an increased rate of adverse events, including deaths, in clinical trials with the cancer medicine Zydelig (idelalisib) in combination with other cancer medicines,” the FDA said in a statement. “The FDA is reviewing the findings of the clinical trials and will communicate new information as necessary.”

Idelalisib is currently approved for CLL in combination with rituximab and for follicular lymphoma and SLL as a monotherapy following at least two prior therapies. The FDA noted in its alert that idelalisib is currently not approved for untreated patients with CLL.

The approval for idelalisib included a Boxed Warning regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation associated with the first-in-class PI3K-delta inhibitor. To address concerns with these side effects, idelalisib was approved along with a Risk Evaluation and Mitigation Strategy (REMS).

Idelalisib in Combination With Bendamustine/Rituximab

In addition to CLL, SLL, and indolent NHL, idelalisib is also being explored in various solid tumors. It remains unclear at this point whether these studies will be impacted by the hold.Adding idelalisib to bendamustine and rituximab (BR) reduced the risk of progression or death by 67% compared with BR alone for patients with relapsed/refractory CLL, according to data from a phase III trial presented at the 2015 ASH Annual Meeting.¹ Based on these findings, the trial was unblinded early to allow patients in the control arm to receive idelalisib, following a recommendation from an independent data monitoring committee.

After 12 months of follow-up, the median progression-free survival (PFS) with idelalisib was 23.1 months compared with 11.1 months for BR alone (HR, 0.33; 95% CI, 0.24-0.45; P <.0001). Additionally, there was a 45% reduction in the risk of death with the addition of idelalisib to BR, although the median OS had not yet been reached in either arm (HR, 0.55; 95% CI, 0.36-0.86; P = .008).

Grade ≥3 adverse events (AEs) were experienced by 93% of patients in the idelalisib arm versus 76% of those in the BR alone group. Serious AEs were seen in 66% of patients treated with idelalisib versus 44% of those in the control arm. AEs led to a dose reduction or treatment discontinuation in the idelalisib arm for 11% and 26% of patients, respectively. This was nearly double what was seen in the control arm, at 6% and 13%, respectively.

The most common all-grade AEs with idelalisib plus BR were neutropenia (63.3%), ALT abnormalities (59.9%), AST abnormalities (52.2%), and pyrexia (41.5%). The most common grade ≥3 AEs were neutropenia (59.9%), ALT abnormality (21.3%), febrile neutropenia (20.3%), and AST abnormality (15.5%).

For BR alone, the most frequent all-grade AEs were neutropenia (53.6%), nausea (34.4%), ALT abnormalities (30.6%), and AST abnormalities (27.8%). The most common grade ≥3 AEs were neutropenia (45.9%) and anemia (12%). Grade ≥3 ALT and AST abnormalities were seen in 2.9% and 3.3% of patients in the placebo arm, respectively.

Idelalisib With Rituximab

Grade ≥3 diarrhea occurred in 7.2% of patients treated with idelalisib versus 1.9% of those who received placebo. Additionally, serious pneumonitis occurred in 1.4% of patients treated with idelalisib compared with 0% for the placebo arm. At the second interim analysis of the phase III Study 116 trial,² the combination of idelalisib and rituximab demonstrated an improvement in PFS of 82% and a 72% elevation in OS. Based on findings from the first analysis, the trial was halted and crossover was allowed following a positive risk—benefit review. Data from this study were instrumental in the FDA approval for the medication.

At the second analysis of the study, the median PFS for idelalisib plus rituximab had not been reached compared with 5.5 months with placebo plus rituximab (HR, 0.18; 95% CI, 0.10-0.32; P < .0001). At 24 weeks, 90% of patients treated with idelalisib remained progression-free compared with 50% with placebo.

The ORR with idelalisib was 77% versus 15% with placebo (P < .0001). Of evaluable patients, 92% treated with idelalisib experienced a greater than 50% reduction in lymph node size compared with 6% with placebo (P < .0001). Additionally, treatment with idelalisib plus rituximab was superior across all organomegaly and hematologic response criteria.

Adverse events of any grade occurred in 95% of patients in both arms of the trial. The incidence of grade 3/4 adverse events was 64% with idelalisib versus 52% with placebo. The discontinuation rate associated with adverse events was 5% in the idelalisib arm and 6% in the placebo group.

References

1. Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA-5.
2. Coutre SE, Furman RR, Sharman JP, et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol. 2014;32:5s (suppl; abstr 7012).