Voruciclib +/- Venetoclax Yeilds Promising Efficacy in AML or B-Cell Malignancies

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Voruciclib alone or combined with venetoclax (Venclexta) was generally well tolerated and with no significant myelosuppression when used for the treatment of patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) or B-cell malignancies, according to updated findings from a phase 1 study (NCT03547115).¹

As of the data cut off, voruciclib alone or given with venetoclax continue to demonstrate an encouraging preliminary effect signal with clinical activity in this heavily pretreated patient population. These data are consistent with what has been hypothesized of voruciclib regarding its ability to inhibit MCL-1 through CDK 9 inhibition to address a common venetoclax resistance mechanism.

The dose-escalation portion of the study is continuing in the voruciclib plus venetoclax arm among patients with R/R AML.

“We are gratified to see preliminary evidence of clinical activity with voruciclib in combination with venetoclax at the lowest dose level evaluated,” stated Richard Ghalie, MD, chief medical officer of MEI Pharma, in a press release “These results are supportive of the hypothesis that voruciclib may reverse a mechanism of resistance to venetoclax.”

Voruciclib is a CDK9 inhibitor that is orally administered and shows potential to treat hematologic malignancies and solid tumors. Currently, the agent is in clinical development for the treatment of patients with AML and B-cell malignancies, but applications in solid tumors are also being examined.

In the 2-stage, open-label, phase 1 study, investigators are utilizing a 3+3 dose-escalation and dose-expansion study to assess voruciclib as both a monotherapy and in combination with venetoclax, a BCL-2 inhibitor, for the treatment of patients with AML or B-cell malignancies.² In the first stage of the study, the dose and schedule of single-agent voruciclib in patients with R/R AML or B-cell malignancies after failure or standard therapies was evaluated. Following part 1, stage 2 will assess voruciclib in combination with standard dose venetoclax in patients with R/R AML.

Enrollment in the trial is open to patients aged 18 years and older with a histologically-confirmed diagnosis of follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, or AML whose disease has relapsed or is refractory to 2 of more prior regimens. Patients must require treatment due to progressive disease, have measurable disease, adequate hematologic parameters, and adequate renal and hepatic function.

The primary end points of the study are to determine the safety and tolerability of voruciclib monotherapy or voruciclib in combination with venetoclax. Secondary end points will assess the preliminary efficacy, including overall response rate, duration of response, and progression-free survival, pharmacokinetics, pharmacodynamics, and biomarkers of voruciclib alone or voruciclib combined with venetoclax.

The first part of the study was the dose-escalation and -expansion stage where 40 patients with R/R AML and B-cell malignancies were enrolled and given voruciclib monotherapy.¹ The first 16 patients were dosed daily and continuously at 50 mg and 100 mg. The other 24 patients were dosed on an intermittent schedule of 14 consecutive days on therapy in a 28-day cycle at 100, 150 and 200 mg. Among those enrolled, patients were heavily pretreated with a median of 3 prior therapies (range, 1-7).

Findings showed that the most common adverse events (AEs) related to voruciclib included diarrhea (15%), nausea (10%), and fatigue (7.5%). All AEs were grade 1 or 2. The intermittent dosing schedule which was selected for further development yielded no dose-limiting toxicities. Additionally, there were no grade 3 or higher toxicities related to voruciclib, and dose-escalation stopped at 200 mg prior to reaching the maximum tolerated dose due to the plasma concentrations reaching levels which were considered sufficient for target inhibition.

Among the 10 patients with AML who were treated at the highest dose evaluated of 200 mg daily on the intermittent schedule, their disease control rate was 50%, and the median duration of therapy was 72 days (range, 27-127).

Investigators are currently studying the combination of voruciclib and venetoclax in patients with R/R AML as the second part of the trial. In the first cohort in the dose-escalation phase, 6 patients were enrolled and given voruciclib 50 mg every other day for 14 days followed by 14 days of no therapy in a 28-day cycle, in addition to standard dose venetoclax. This part of the trial enrolled patients who all were heavily pretreated with a median of 3 prior therapies and all patients previously progressed after receiving treatment with venetoclax.

According to what has already been reported from this part of the trial, no DLTs or overlapping bone marrow toxicities were observed and the disease control rate was 50%. This includes 1 patient who received 5 prior therapies, including stem cell transplant, and who achieved a partial response after the 1st cycle of therapy, as well as another patient with stable disease and a reduction in transfusion requirement.

Enrollment in the next dose level of 50 mg administered daily for 14 consecutive days followed by 14 days of no therapy in a 28-day cycle has been cleared to begin by the Safety Review Committee.

“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,” said Dan Gold, PhD, president and chief executive officer of MEI Pharma, 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.”

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, Inc. May 23, 2023. Accessed May 24, 2023. https://tinyurl.com/yck8x346

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