Verastem doses first patient in Phase I/II clinical trial of duvelisib in combination with venetoclax

Verastem, Inc., operating as Verastem Oncology, a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, today announced dosing of the first patient in a multicenter Phase I/II clinical trial at the Dana-Farber/Harvard Cancer Center of duvelisib in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

"Duvelisib and venetoclax target different pathways fundamental to CLL biology and have distinct mechanisms of action. We have found that CLL cells from duvelisib-treated patients are primed for apoptosis in response to treatment with agents such as venetoclax. We now have the opportunity to explore whether this combination may be an effective therapy for the treatment of patients with CLL," said Matthew Davids, MD, MMSc, Assistant Professor of Medicine, Harvard Medical School, and Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute and the study's principal investigator. "We are excited to conduct this trial, as these new, targeted agents in development have the potential to improve patients' response through combination therapies."

This trial will investigate venetoclax, an oral, potent, selective inhibitor of BCL-2 - a key mediator of the intrinsic pathway of apoptosis, the process of programmed cell death - given in combination with duvelisib. Preclinical data support this combination, as duvelisib has been shown to upregulate BCL-2 transcript and protein expression levels and enhance the ability of venetoclax to induce apoptosis in ex vivo human CLL cells. The trial will use BH3 profiling - a functional assay that determines the apoptotic threshold of a cell - which Davids and colleagues previously used to show that inhibition of phosphoinositide 3-kinase (PI3K) enhances the apoptotic threshold of CLL cells and sensitivity to BCL-2 inhibition.

The phase I primary objectives are to determine the maximum tolerated dose, as well as the recommended phase II dose of venetoclax for this combination regimen with duvelisib in patients with relapsed or refractory CLL/SLL. The phase II primary objective is to determine the rate of complete response (CR) of the combination, as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria.

"As we continue to explore the potential of duvelisib, we are very encouraged by the strong scientific rationale and the preclinical data supporting the combination of duvelisib and venetoclax. We expect this trial will help enhance our understanding of the effects of this combination in the treatment of patients with CLL/SLL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem Oncology. "Our goal at Verastem Oncology is to bring innovative therapeutic options to patients living with cancers that are in need of additional treatment options. Given the significant unmet need that exists among patients living with CLL and SLL, we look forward to the insight generated from this trial that could inform potential future clinical development for duvelisib."