MEI Pharma, Inc. announced clinical data from the monotherapy dose escalation stage of the ongoing Phase 1 study evaluating voruciclib, a selective oral cyclin-dependent kinase 9 (CDK9) inhibitor, alone and in combination with venetoclax (Venclexta®?), a B-cell lymphoma 2 (BCL2) inhibitor, in patients with acute myeloid leukemia (AML) or B-cell malignancies, is highlighted in a poster session at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition. Clinical Data from the Monotherapy Dose Escalation Stage of the Ongoing Phase 1 Study Evaluating Voruciclib in Combination with Venetoclax: Presentation Title: A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML); Session Title: Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III (616); Presenter: Matthew S. Davids, MD, MMSc., Associate Professor, Harvard Medical School, Director, Clinical Research, Division of Lymphoma, Dana-Farber Cancer Institute; Date: December 11, 2023, 6:00-8:00 PM (Pacific Time); Publication Number: 4286; Phase 1 Study Details: The Phase 1 study is a two stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, a CDK9 inhibitor, as a monotherapy and in combination with venetoclax (marketed as Venclexta®), a BCL2 inhibitor. The first stage of the study, evaluating the dose and schedule of voruciclib as a single-agent in patients with relapsed and refractory (?R/R?) acute myeloid leukemia (AML) or B-cell malignances after failure of standard therapies, is complete.

The second stage of the study is ongoing and is evaluating voruciclib in combination with venetoclax in patients with R/R AML. A total of 40 patients, median age 75 years (range 63-80), were enrolled in the first stage of the study evaluating voruciclib as a monotherapy. The majority of patients (n=21) had AML and the remaining patients (n=19) had B-cell malignancies.

Enrolled patients were generally heavily pretreated; the median number of prior therapies was 3 (range 1-9) and 5 patients had prior hematopoietic stem cell transplant. Patients enrolled in Cohort 1 (n= 16) of the monotherapy stage of the study were administered voruciclib once daily continuously at doses of 50 mg and 100 mg. Patients enrolled in Cohort 2 (n=24) were administered voruciclib on an intermittent schedule (IS) on days 1-14 in a 28-day cycle implemented after 2 dose limiting toxicities (DLT) were observed at 100 mg daily continuously.

Dose escalation in Cohort 2 was stopped at 200 mg before reaching the maximum tolerated dose (MTD) at this schedule to focus on evaluation of venetoclax in combination with voruciclib. The primary objectives of the study are to determine the safety and biologic effective dose of voruciclib monotherapy or voruciclib in combination with venetoclax. Secondary objectives of the study include assessing the preliminary efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of voruciclib monotherapy or voruciclib in combination with venetoclax.

Monotherapy Safety and Tolerability: Voruciclib at doses up to 200 mg administered on 14 consecutive days in a 28-day cycle (Cohort 2) was well tolerated with no DLT reported. The most common adverse events (=20% of patients) were diarrhea, nausea, anemia and fatigue. The large majority of adverse events were Grade 1-2; of note, the only Grade 3-4 adverse events in Cohort 2 were diarrhea (n=1) and anemia (n=5).

Pharmacokinetics were dose proportional and mean half-life of approximately 24 hours supports once daily dosing. Monotherapy Efficacy: In the 21 patients enrolled with AML, 1 patient at 100 mg achieved a morphologic leukemia-free state and 9 patients had disease stabilization, which lasted at least 3 months in 2 patients. In the 19 patients enrolled with B-cell malignancies, 4 patients had stable disease with a decrease in tumor size.

Initial results from correlative studies assessing myeloid leukemia cell differentiation protein (Mcl-1) and RNA Pol II phosphorylation on Ser2 (RNA Pol II p-S2) demonstrated reduction in expression consistent with the anticipated on-target pharmacodynamic effect of voruciclib on Mcl-1 and RNA Pol II p-S2.