Voruciclib Plus Venetoclax Shows Early Activity, Tolerability in Relapsed/Refractory AML

The CDK9 inhibitor voruciclib (ME-522) in combination with the BCL-2 inhibitor venetoclax (Venclexta) demonstrated antileukemic activity with an acceptable safety profile in patients with relapsed or refractory acute myeloid leukemia (AML), according to data from an ongoing phase 1 study (NCT03547115).¹

No dose-limiting toxicities were observed, and the maximum tolerated dose of voruciclib has not yet been identified. Moreover, no patients discontinued treatment because of drug-related toxicities and no overlapping toxicity has been reported. Among the most common grade 3 adverse effects (AEs) occurring in at least 5% of patients was disease-related myelosuppression. One patient experienced grade 3 diarrhea, which was related to the study treatment.

Of the 20 patients who received voruciclib at a dose of 100 mg or higher, 3 responded to the combination. Two of those patients experienced a complete response with incomplete hematologic recovery and 1 patient achieved a morphologic leukemia-free state. Among the 3 responders, one had a response that persisted for 7 months, one for 5 months and was ongoing at the time of the report, and the last was referred for a stem cell transplant. An additional 14 patients achieved stable disease; 5 of these patients had stability for longer than 90 days. Notably, these patients had received venetoclax in an earlier line of therapy.

“We are participating in the ongoing multicenter phase 1 study, where preliminary results are demonstrating good treatment tolerance and safety to date,” Yesid Alvarado-Valero, MD, associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center. “When voruciclib is used in combination with venetoclax, the combination appears to have no added toxicity, in addition there is evidence of synergistic, early clinical activity, with disease responses, in a group of heavily pretreated acute myeloid leukemia patients.”

The open-label, dose-escalation and -expansion study comprises multiple stages and utilizes a 3+3 design. To participate, patients needed to have histologically confirmed AML or other B-cell malignancies, such as follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma.² They needed to have disease that was relapsed or refractory to at least 2 previous regimens and requiring treatment because of disease progression. Patients were at least 18 years of age and had acceptable renal function, hepatic function, and hematologic parameters.

Patients with AML could not have acute promyelocytic leukemia, nor could they have a peripheral blast count higher than 25 x 10⁹/L. Other exclusion criteria included having a history of pneumonitis, known central nervous system involvement, significant cardiovascular disease, or significant electrocardiogram abnormalities.

In the first stage of the study, which is now complete, investigators examined voruciclib as a monotherapy in patients with AML or B-cell malignancies following progression on standard options.¹ The second stage of the study is examining voruciclib at 7 dose levels ranging from 50 mg every other day to 300 mg daily for 2 weeks in a 4-week cycle plus venetoclax given at a standard dose in patients with relapsed/refractory AML.

The primary objective of the research is to understand the safety and biologic effective dose of voruciclib as a single agent and paired with venetoclax. Secondary objectives focus on evaluating preliminary efficacy, assessing the pharmacokinetic and pharmacodynamic profiles of voruciclib, and examining biomarkers of the monotherapy and combination.

Earlier data showed that single-agent voruciclib given at 200 mg daily on a 2-weeks-on/2-weeks-off schedule led to a disease control rate of 50% in patients with relapsed/refractory AML (n = 10) with a median treatment duration of 72 days (range, 27-127).³ Voruciclib plus venetoclax led to a DCR of 50% in 6 patients with relapsed/refractory AML.

At the time of the current report, a total of 29 patients with relapsed/refractory AML had been enrolled in the dose-escalation stage of the study.¹ The median patient age was 67 years (range, 34-89). More than half of patients (72%) had adverse cytogenetics and molecular mutations that put them in an adverse 2017 European LeukemiaNet Risk Category. The population was also heavily pretreated, with a median number of prior therapies received of 3, and a range of 1 to 7 lines of treatment. Notably, 52% of patients had previously received 3 or more lines of therapy. Twenty-eight patients had received venetoclax in an earlier line of treatment.

Additional data from correlative biomarker assay studies of available samples from those who received voruciclib at a dose of 100 mg or higher revealed a reduction in MCL-1, which has been linked with poor prognosis and resistance to BCL-2 inhibition. Moreover, assays from the dose-escalation cohorts revealed dose-proportional decreases in the marker.

The study is now enrolling an expansion cohort in which voruciclib will be evaluated at a daily dose of 300 mg for 2 weeks in a 4-week cycle in combination with venetoclax in 12 patients. Another arm of the study will assess escalating doses of voruciclib given over 3 weeks in a 4-week cycle plus venetoclax to boost dose intensity and potentially enhance responses to treatment.

“We see the voruciclib data to date demonstrating anti-leukemic activity as promising, particularly alongside the consistent reductions of MCL-1 that provide evidence we are eliciting the anticipated biological response in patients, and we are excited to share additional updates as appropriate in the second half of 2024,” Richard Ghalie, MD, chief medical officer of MEI Pharma, added in the press release. “As we enroll the expansion cohort evaluating the potential of voruciclib in combination with venetoclax among a larger group of patients, I would like to thank and recognize the continued engagement of our investigators, and the participation of the patients enrolling in this study.”

References

1. MEI Pharma reports update from clinical study evaluating oral CDK9 inhibitor voruciclib in combination with venetoclax in patients with relapsed and refractory acute myeloid leukemia. News release. MEI Pharma, Inc. March 26, 2024. Accessed March 29, 2024. https://investor.meipharma.com/news-releases/news-release-details/mei-pharma-reports-update-clinical-study-evaluating-oral-cdk9
2. A study of voruciclib alone or in combination with venetoclax in subjects with B-cell malignancies or AML. ClinicalTrials.gov. Updated August 7, 2023. Accessed March 29, 2024. https://clinicaltrials.gov/study/NCT03547115
3. 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 March 29, 2024. https://www.meipharma.com/press-releases/mei-pharma-announces-update-ongoing-phase-1-study-evaluating-oral-cdk9-inhibitor