MEI Pharma, Inc. reported initiation of enrollment in a 12-patient expansion cohort in the ongoing Phase 1 study evaluating voruciclib, an investigational selective oral cyclin-dependent kinase 9 inhibitor, in combination with venetoclax (Venclexta®), a B-cell lymphoma 2 inhibitor, in relapsed and refractory acute myeloid leukemia patients. The Safety Review Committee recommended initiating the expansion cohort after observing anti-leukemic activity in multiple heavily pretreated patients in the dose escalation cohorts, including responses, anticipated decreases in myeloid leukemia cell differentiation protein in available patient samples, no overlapping toxicity or dose limiting toxicities, and favorable safety results to date. The Phase 1 study is a multiple stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, an oral CDK9 inhibitor, as a monotherapy and in combination with venetoclax, a BCL2 inhibitor.

The first stage of the study evaluated the dose and schedule of voruciclib as a single-agent in patients with AML or B-cell malignances after failure of standard therapies. This stage is complete. The second stage of the study, evaluating voruciclib in combination with standard dose venetoclax in patients with R/R AML, has completed enrollment in the dose escalation cohorts evaluating seven voruciclib dose levels from 50 mg every other day to 300 mg daily for two weeks in a four-week cycle.

The study is currently enrolling a 12-patient expansion cohort evaluating voruciclib administered at 300 mg daily for two weeks in a four-week cycle in combination with venetoclax. Considering the tolerability results for the combination to date, another arm of the study will evaluate escalating doses of voruciclib administered over three weeks in a four-week cycle in combination with venetoclax to increase dose intensity and potentially optimize patient response. A total of 29 patients with R/R AML, median age 67 years (range 34-89), enrolled in the dose escalation stage of the study evaluating voruciclib in combination with venetoclax.

These patients were generally heavily pretreated; the median number of prior therapies was 3 (range 1-7), and 15 (52%) patients had =3 prior lines. Almost all patients (28/29) were treated with venetoclax in an earlier line of therapy. Additionally, 21 (72%) patients were noted as being in an adverse 2017 ELN Risk Category due to adverse cytogenetics and molecular mutations.

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. Voruciclib Plus Venetoclax Combination: Initial Safety and Tolerability Data Voruciclib at doses up to 300 mg administered on 14 consecutive days in a 28-day cycle in combination with standard dose venetoclax was well tolerated with no dose limiting toxicities observed.

The maximum tolerated dose of voruciclib administered on this schedule with venetoclax has not been established. There were no discontinuations due to drug-related adverse events. No evidence of overlapping toxicity has been observed to date.

The most common (=5% of patients) grade 3 adverse events were myelosuppression associated with AML. Only 1 patient was observed as having a non-hematologic grade 3 drug-related adverse event (diarrhea). Voruciclib Plus Venetoclax Combination: Initial Efficacy Data In the 20 patients administered voruciclib at a dose of 100 mg or more, three patients achieved a response, including two patients that achieved a complete response with incomplete hematologic recovery (CRi) and one patient that achieved a morphologic leukemia-free state (MLFS), in each case having received venetoclax in an earlier line of treatment.

Responses lasted 7 months in one patient, 5 months and ongoing in the second patient, and the third patient was referred to stem cell transplant. Further, an additional 14 patients had stable disease which lasted more than 90 days in 5 patients. In the patients administered voruciclib at a dose of 100 mg or more, initial results from correlative biomarker assay studies of available samples from patients treated with the combination demonstrate the anticipated decrease of Mcl-1. Further, the available assays from the dose escalation cohorts demonstrated dose proportional decreases in Mcl-1. Reductions in Mcl-1 are consistent with the known mechanism of action of CDK9, which regulates Mcl-1.