Therapy Areas: AIDS & HIV
The Lancet Oncology Publishes Data from Phase 1b Clinical Study of Zandelisib in Patients with Relapsed or Refractory B-cell Malignancy
18 July 2022 - - Data from the Phase 1b clinical study of zandelisib, an orally administered investigational phosphatidylinositol 3-kinase delta inhibitor, in patients with relapsed or refractory B-cell malignancy, has been published in The Lancet Oncology, US-based pharmaceutical company MEI Pharma, Inc. (NASDAQ: MEIP) and Japan-based pharmaceutical company Kyowa Kirin Co., Ltd. (TSX: 4151) said.

The published data demonstrate that an intermittent dosing regimen of zandelisib resulted in lower cumulative risk of Grade 3 or worse adverse events of special interest compared to a continuous daily dosing regimen without loss of efficacy.

The publication, entitled "Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial," is available on the journal website.

The Phase 1b study (NCT02914938) is an open-label, dose escalation and expansion study evaluating zandelisib in patients with B-cell malignancies.

The manuscript reported on a total of 97 patients, including 31 patients in the dose escalation stage that established 60 mg once daily as the recommended Phase 2 dose.

The study evaluated zandelisib in 56 patients as a monotherapy and 41 patients in combination with rituximab.

Zandelisib was administered either on a continuous schedule of 60 mg once daily or an intermittent dosing schedule of 60 mg once daily for the initial two 28-day cycles followed by the intermittent dosing schedule of 60 mg once daily on days 1-7 in cycles ≥3.

In the initial monotherapy dose-finding part of the study, no dose-limiting toxicities were observed across the evaluated doses of 60 mg, 120 mg and 180 mg given daily continuously, and anti-tumor activity was similar across doses.

With a median duration of treatment of 10.4 months and 15.2 months, in the continuous and intermittent dosing group respectively, Grade 3 or worse adverse events of special interest occurred less frequently in the intermittent dosing group than in the continuous dosing group.

For example, Grade 3 diarrhea or colitis in 8% vs 24%, and Grade 3 lung infection or pneumonia in 2% vs 16%, of patients in the intermittent dosing group vs the continuous dosing group, respectively.

Grade 3 or worse AST or ALT elevation and rash were uncommon with each dosing schedules.

There was a continued increased risk of Grade 3 diarrhea or colitis in the continuous dosing group, compared with a decreased risk over time in the intermittent dosing group after switching to the intermittent dosing.

At a median follow-up of 24.9 months in the continuous dosing group and 15.7 months (95% CI 6·5-33·9) in the intermittent dosing group the cumulative incidence of Grade 3 or worse adverse events of special interest was 45% in the continuous dosing group and 20% in the intermittent dosing group.

Intermittent dosing showed comparable efficacy to continuous dosing. Patients with indolent B-cell malignancies (follicular lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, and marginal zone lymphoma) demonstrated an objective overall response rate of 87%.

The published Phase 1b safety and efficacy results for zandelisib 60 mg once daily on an intermittent dosing schedule warranted initiating the ongoing global Phase 2 TIDAL and Phase 3 COASTAL studies evaluating zandelisib alone or in combination with rituximab, respectively.

Zandelisib, a selective PI3Kδ inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, potential therapeutic option for patients with B-cell malignancies.

Clinical trials are investigating the efficacy and safety of zandelisib as a single agent and in combination with other modalities while administered on an Intermittent Dosing Regimen and in a time-limited manner when dosed in combination.

The ID leverages molecular and biologic properties specific to zandelisib.

Ongoing zandelisib studies include the cohort in TIDAL evaluating patients with r/r marginal zone lymphoma and continuing evaluation of the cohort of patients in the study with r/r FL.

Also ongoing is the Phase 3 COASTAL study (NCT04745832), comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab in patients with r/r FL or MZL who received more than one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide.

COASTAL, which is also evaluating time-limited intermittent administration of zandelisib, is intended to support marketing applications in the US and globally.

Other ongoing studies include a Phase 2 pivotal study in Japan (NCT04533581) in patients with indolent B-cell non-Hodgkin's lymphoma (iB-NHL) without small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and Waldenström's macroglobulinemia conducted by Kyowa Kirin.

In March 2020, the FDA granted zandelisib Fast Track designation for the treatment of adult patients with r/r follicular lymphoma who have received at least two prior systemic therapies.

In November 2021, the FDA granted zandelisib Orphan Drug designation for the treatment of patients with follicular lymphoma.

In April 2020, MEI and Kyowa Kirin entered a global license, development, and commercialization agreement to further develop and commercialize zandelisib. MEI and Kyowa Kirin will co-develop and co-promote zandelisib in the US, with MEI booking all revenue from the US sales.

Kyowa Kirin has exclusive commercialization rights outside of the US.

MEI Pharma, Inc. (NASDAQ: MEIP) is a late-stage pharmaceutical company focused on developing potential new therapies for cancer.

Kyowa Kirin is in antibody research and engineering, to address the needs of patients across multiple therapeutic areas such as nephrology, oncology, immunology/allergy and neurology.
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