Zandelisib Moves Along in Development for B- Cell Malignancies

The first patient with marginal zone lymphoma (MZL) has been dosed in the global phase 2 TIDAL study of zandelisib (ME-401), a phosphatidylinositol 3-kinase (PI3K) delta inhibitor, for the treatment of MZL and follicular lymphoma (FL) in patients who have received at least 2 or more prior therapies.¹

Zandelisib is meant to be an oral, once daily treatment for B-cell malignancies. The agent was granted a fast track designation by the FDA in March of 2020 for the treatment of adult patients with relapsed or refractory FL who have received at least 2 prior lines of treatment.

"The initiation of the marginal zone lymphoma study arm in TIDAL is an important step in our commitment, in partnership with Kyowa Kirin, to identify and explore the full potential of zandelisib across multiple B-cell malignancies, including combinations with other therapies, and to meet the need for new innovative medicines across a range of hematological cancers," said Richard Ghalie, MD, chief medical officer, of MEI Pharma, in a press release.

The multicenter, open-label, single arm study (NCT03768505) has an estimated enrollment of 180 patients with an estimated study completion date of December 2025. The primary end point of the study is objective response rate. Secondary end points include duration of response, complete response, progression-free survival, overall survival, and the overall incidences of treatment-emergent adverse events (TEAEs).²

During the study, patients with either relapsed/refractory FL or MZL will receive 60 mg of zandelisib once a day on an intermittent schedule.

In order to participate in TIDAL, patients must have confirmed follicular lymphoma or MZL, be at least 18 years of age, have at least 1 measurable nodal lesion, have adequate hematological, renal, and hepatic parameters at screening, and a left ventricle ejection fraction of ≥ 45%.

Patients with a history of known lymphomatous involvement of the central nervous system, uncontrolled clinically significant illness, ongoing or history of drug-induced pneumonitis, a history of clinically significant cardiovascular abnormalities, a history of clinically significant GI condition, or a known history of or active HIV infection, are not eligible to participate.

"I am delighted that this important milestone was achieved for zandelisib in the marginal zone lymphoma study arm of the global TIDAL study," said Yoshifumi Torii PhD, executive officer, vice president and head of R&D Division, Kyowa Kirin, in a press release. "Under the partnership with MEI, we continue to work with medical professionals and patients to demonstrate zandelisib's potential to help those in need with B-cell malignancies."

Zandelisib has already shown promise in other hematologic malignancies. Recently, data were reported from a phase 1b study (NCT02914938) of zandelisib in combination with the Bruton’s tyrosine kinase inhibitor zanubrutinib (Brukinsa) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. The combination induced significant responses, including several complete responses (CRs) in the study population.³

At a median follow-up of 6.6 months for all patients, regardless of malignancy, the CR rate was 100%. Notably, the study included 2 patients with MZL and 8 patients with FL. Twenty-five percent of them achieved either a CR or a CR with incomplete hematologic recovery.

Treatment with zandelisib/zanubrutinib also appeared safe in the study. The most common grade 3 or higher treatment-emergent AEs (TEAEs) in group A included neutropenia (43%), ALT increase (29%), AST increase (29%), and thrombocytopenia (29%). Common all grade TEAEs included neutropenia (57%), thrombocytopenia (57%), and diarrhea (43%). In group B, the most common grade 3 or higher TEAEs included neutropenia (23%), ALT increase (15%), and AST increase (15%), with any grade TEAEs including neutropenia (46%), AST increase (23%), thrombocytopenia (23%), and diarrhea (23%).

The TIDAL study is actively recruiting patients with MZL and FL at 19 cancer centers in the United States as well as at international locations.

_REFERENCE:

_{1 MEI Pharma and Kyowa Kirin announce first patient with marginal zone lymphoma dosed in expanded global phase 2 TIDAL Study evaluating zandelisib. News Release. MEI Pharma. June 7, 2021. Accessed August 11, 2021. https://bit.ly/3jNLI4n.}

_{2 Zandelisib (ME-401) in subjects with follicular lymphoma or marginal zone lymphoma after failure of two or more prior therapies (TIDAL). Clinicaltrials.gov. Accessed August 12, 2021.}

_{3. Soumerai JD, Jagadeesh D, Salman HS, et al. Tolerability and efficacy of the combination of PI3KΔ inhibitor zandelisib (ME-401) and BTK inhibitor zanubrutinib in patients with relapsed or refractory (R/R) B-cell malignancies: initial results. Presented at 2021 European Hematology Association Annual Congress; June 9-17, 2021; virtual. Abstract S214.}