Voruciclib With or Without Venetoclax Shows Safety, Activity in R/R AML, B-cell Malignancies

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Voruciclib (ME-522) monotherapy and in combination with venetoclax (Venclexta) demonstrated clinical activity and was well tolerated with no significant myelosuppression in heavily pretreated patients with relapsed/refractory acute myeloid leukemia (AML) or B-cell malignancies, according to initial data from a phase 1 trial (NCT03547115).

Clinical activity was observed with voruciclib alone and at the initial dose level in combination with venetoclax. The early results were consistent with the hypothesized ability of voruciclib to inhibit MCL-1 through CDK9 inhibition, which is thought to address a common venetoclax resistance mechanism.

In 10 patients with relapsed/refractory AML who received voruciclib monotherapy at 200 mg per day on a 2-weeks-on/2-weeks-off schedule, the disease control rate was 50% with a median duration of treatment of 72 days (range, 27-127).

Among 6 patients with relapsed/refractory AML treated with voruciclib plus venetoclax, the disease control rate was 50%. One patient who received 5 prior lines of therapy, including stem cell transplant, experienced a partial response after the 1st cycle of therapy. Another patient had stable disease and a reduction in transfusion requirement.

The dose-escalation portion of the trial is ongoing in the voruciclib and venetoclax combination arm in patients with relapsed/refractory AML.

“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, stated in a news 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.”

The 2-stage, open-label, 3+3, phase 1 dose-escalation and -expansion study is evaluating voruciclib monotherapy in patients with relapsed and refractory AML or B-cell malignances in part 1, and voruciclib in combination with the standard dose of venetoclax in patients with relapsed/refractory AML in part 2.

Patients are required to be at least 18 years of age with histologically confirmed follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma, or AML that is relapsed or refractory to 2 or more prior regimens and in need of treatment due to progressive disease.²

Key exclusion criteria include a history of pneumonitis, known central nervous system involvement, significant cardiovascular disease, prior solid organ transplantation, or receipt of an allogeneic stem cell transplant within 6 months or autologous stem cell transplant within 3 months of the start of study treatment. Prior treatment with a CDK9 inhibitor is not allowed.

Patients with CLL cannot have a known histological transformation to an aggressive lymphoma, and those with AML cannot have acute promyelocytic leukemia or a peripheral blast count of more than 25 × 109/L.

The primary end point of the study is the safety and tolerability of voruciclib alone and in combination with venetoclax. Secondary end points include overall response rate, duration of response, progression-free survival, and pharmacokinetics.

Forty patients were enrolled in part 1.1 The first 16 patients received continuous daily doses of voruciclib at 50 mg and 100 mg. The next 24 patients received 100 mg, 150 mg, and 200 mg of voruciclib on an intermittent schedule for 14 consecutive days of each 28-day cycle. Patients in part 1 had median of 3 prior lines of therapy (range, 1-7).

The most common treatment-related adverse effects reported in at least 5% of patients who received with voruciclib monotherapy included diarrhea (15%), nausea (10%) and fatigue (7.5%), which were all grade 1 or 2. No dose-limiting toxicities (DLTs) or grade 3 or higher drug-related toxicities were reported with the intermittent dosing schedule. Dose escalation ended at 200 mg before reaching the maximum tolerated dose because plasma concentrations reached levels considered sufficient for target inhibition.

In part 2, 6 patients received 50 mg of voruciclib every other day for 14 days followed by 14 days of no therapy, plus standard dose venetoclax. These patients received a median of 3 prior lines of therapy, and all patients previously progressed after treatment with venetoclax.

No DLTs or overlapping bone marrow toxicities were reported in part 2, and the trial’s safety review committee has cleared enrollment in the next dose level of 50 mg of voruciclib per day for 14 consecutive days followed by 14 days of no therapy in a 28-day cycle.

“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 a news release. “These results are supportive of the hypothesis that voruciclib may reverse a mechanism of resistance to venetoclax.”

References

1. 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. May 23, 2023. Accessed May 24, 2023. https://www.meipharma.com/press-releases/mei-pharma-announces-update-ongoing-phase-1-study-evaluating-oral-cdk9-inhibitor
2. A phase 1 study of voruciclib and venetoclax in subjects with B-cell malignancies or AML. ClinicalTrials.gov. Updated August 12, 2022. Accessed May 24, 2023. https://clinicaltrials.gov/ct2/show/NCT03547115