FDA Informs Developers of Zandelisib of Need for Randomized Phase 3 Trial for Approval

The FDA supported submission of application for approval of zandelisib in follicular lymphoma and other indolent non-Hodgkin lymphomas based on the phase 3 COASTAL trial.

Following a meeting with the FDA regarding approval of zandelisib (MEI-401) for B-cell malignancies, the drug developer will no longer submit results from the single-arm phase 2 TIDAL trial (NCT03768505) and instead continue exploration with the randomized phase 3 COASTAL trial (NCT04745832), according to a press release from MEI Pharma Inc.1

The FDA noted that for PI3K inhibitors to become approved, they need to be examined in a randomized trial rather than a single-arm study. The drugs developer will be focusing on safety and efficacy as well as continued dose-exploration in the phase 3 trial.

“Clearly, the outcome of our recent FDA meeting is a disappointing development. Nonetheless we will continue to focus on the ongoing phase 3 COASTAL study as we consider options that provide the most expeditious approval pathway utilizing randomized data, and which we believe will demonstrate the potential of zandelisib to help patients. Today’s announcement in no way diminishes our conviction to the development of zandelisib and the promise of its emerging clinical profile. Based on current projections, MEI believes we have sufficient cash for operations to complete the COASTAL study enrollment in 2024,” Daniel P. Gold, PhD, president and chief executive officer of MEI Pharma, said in the press release.

Zandelisib is a PI3K inhibitor which drug developers were considering for regulatory submission via the accelerated approval pathway under the 21 CFR Part 314.500 subpart H. This section is for drugs that are intended to help treat a serious or life-threatening condition while helping to provide meaningful benefits over existing treatments. Previously, the FDA has granted accelerated approvals to PI3K inhibitors under this section for the treatment of patients with relapsed or refractory marginal zone or follicular lymphoma.

The phase 2 TIDAL trial enrolled 121 patients into the cohort of patients with relapsed/refractory follicular lymphoma, of whom 91 were in the primary efficacy evaluation.2 Patients had a median age of 64 years and had received a median of 3 lines of prior treatment (range, 2-8). A dosing schedule of zandelisib once daily for two 28-day cycles was administered followed by once-daily dosing for the first 7 days of each subsequent 28-day cycle.

The primary end point of overall response rate was 70.3% (95% CI, 59.8%-79.5%) and was assessed by an independent review committee after a follow-up of 6 months. Complete responses were observed in 35.2% of patients (95% CI, 25.4%-45.9%).

At the median follow-up for response of 8.4 months, the duration of response (DOR) had not been reached, with data cut-off being 6 months after the last patient received the first dose of zandelisib.

Grade 3 or higher adverse effects (AEs) of special interest were elevated alanine aminotransferase and aspartate aminotransferase (1.7%), colitis (1.7%), diarrhea (5%), mucositis (2.5%), pneumonitis (0.8%), and rash (3.3%). The discontinuation rate due to drug-related AEs was 9.9%.

The ongoing phase 3 COASTAL study is comparing zandelisib plus rituximab (Rituxan) with rituximab plus bendamustine (Treanda) or rituximab plus chemotherapy for patients with grade 1 to 3a follicular lymphoma or splenic, nodal, or extra-nodal marginal zone lymphoma. The estimated enrollment is 534 patients.

Patients are to receive 60 mg of zandelisib for 2 cycles followed by an intermittent schedule in cycle 3. Rituximab will be administered at 375 mg/m2 intravenously for 6 cycles; bendamustine at 90 mg/m2 intravenously on days 1 and 2 for 6 cycles; cyclophosphamide at 750 mg/m2, hydrodoxorubicin at 50 mg/m2, vincristine at 1.4 mg/m2, and prednisone at 100 mg daily.

The primary end point is progression-free survival, with secondary end points of overall response rate, complete response rate, and overall survival.

“In partnership with Kyowa Kirin, we remain committed to the ultimate potential of zandelisib to address important medical needs as a single agent or in combination with other therapies providing physicians, and their patients, important new treatment options. We plan on completing evaluation of the Phase 2 TIDAL study, and look forward to sharing final data later this year to further advance an understanding of zandelisib’s clinical utility,” concluded Gold.

References

1. MEI Pharma and Kyowa Kirin provide regulatory update on zandelisib following meeting with FDA. News Release. MEI Pharma Inc. March 24, 2022. Accessed March 25, 2022. https://yhoo.it/3DbLyNE

2. MEI Pharma and Kyow Kirin announce data from the ongoing global phase 2 TIDAL study evaluating zandelisib as a single agent in patients with relapsed or refractory follicular lymphoma. News Release. MEI Pharma Inc. November 30, 2021. Accessed March 25, 2022. https://bit.ly/3tGuzQx