Voruciclib plus venetoclax appears to yield no dose-limiting toxicities in a small population of patients with acute myeloid leukemia, according to early findings from a phase 1 study.
Treatment with voruciclib both with and without venetoclax (Venclexta) appears to be tolerable and efficacious for patients with relapsed/refractory acute myeloid leukemia (AML) and B-cell malignancies, according to a press release by MEI Pharma on early findings from a phase 1 study (NCT03547115).
In the first stage of the study, voruciclib monotherapy yielded a disease control rate (DCR) of 50% among the 10 patients with AML who received the highest evaluated dose of 200 mg. The median duration on therapy was 72 days (range, 27-127). Moreover, the treatment yielded no grade 3 or higher treatment-related adverse effects (TRAEs) and no dose-limiting toxicities before dose escalation halted at 200 mg. The most common grade 1/2 AEs were diarrhea (15%), nausea (10%), and fatigue (7.5%).
The agent also yielded a DCR of 50% in combination with venetoclax among 6 patients with relapsed/refractory AML. This finding comes from the dose-escalation phase of the study’s second stage and includes a patient who had received 5 prior therapies, including stem cell transplant, and experienced a partial response after their first cycle of therapy. Moreover, an additional patient achieved stable disease and a reduction in transfusion dependence.
No dose-limiting toxicities or overlapping bone toxicities have occurred in the study’s second stage as of this update.
“We are gratified to see preliminary evidence of clinical activity with voruciclib in combination with venetoclax at the lowest dose level evaluated,” Richard Ghalie, MD, chief medical officer of MEI Pharma, said in the press release. “These results are supportive of the hypothesis that voruciclib may reverse a mechanism of resistance to venetoclax.”
Voruciclib is an oral CDK9 inhibitor, hypothesized to inhibit MCL-1 via CDK9 and thereby counteract a common mechanism of resistance to venetoclax.
These findings come from an ongoing, two-stage, open-label, 3+3 dose-escalation study. The first stage assessed voruciclib as a monotherapy in patients with relapsed/refractory AML or B-cell malignances; the second stage is examining voruciclib plus standard-dose venetoclax in patients with relapsed/refractory AML.
The first stage included 40 patients. The first 16 patients in the cohort received daily voruciclib at continuous doses of 50 and 100 mg, and the remaining 24 received treatment over 14 consecutive days during a 28-day cycle at doses of 100 mg, 150 mg, and 200 mg. These patients had a median of 3 prior therapies (range, 1-7).
The first cohort of the second stage included 6 patients who received 50 mg of voruciclib every other day for 14 days, and then went 14 days without therapy in a 28-day cycle. They also received standard-dose venetoclax. These patients also had a median of 3 prior therapies, and all 6 had experienced progression following prior venetoclax therapy.
The safety review committee has approved enrollment in the next dose level of the second stage. This will consist of voruciclib at a dose of 50 mg daily for 14 consecutive days followed by 14 days without therapy in a 28-day cycle.
The primary end point of the study is the safety and biologic effective dose. Secondary end points include the preliminary efficacy, pharmacokinetics, pharmacodynamics, and relevant biomarkers.
“These initial results provide encouraging support for the potential of voruciclib administered in combination with venetoclax to address a common resistance mechanism to venetoclax therapy and deliver improved clinical benefit to patients without significant myelosuppression,” Dan Gold, PhD, president and chief executive officer of MEI Pharma, said in the press release.
“We look forward to disclosing more data from this study around year-end, including data from patients receiving higher doses of voruciclib plus venetoclax, to further evaluate the potential of the combination to safely provide synergistic benefit to patients.”
MEI Pharma announces update of ongoing phase 1 study evaluating oral CDK9 inhibitor voruciclib alone and in combination with venetoclax in patients with acute myeloid leukemia or B-cell malignancies. News release. MEI Pharma, Inc. May 23, 2023. Accessed May 24, 2023. https://bit.ly/3MTCsLR