On December 11, 2017 Verastem, Inc. (NASDAQ: VSTM), focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, reported the presentation of new preclinical and Phase 1 clinical data from an investigator-sponsored study evaluating the safety and activity of oral duvelisib in combination with romidepsin (Istodax) or bortezomib (Velcade) in relapsed or refractory T-cell lymphomas (TCL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 Annual Meeting held December 9-12, 2017 in Atlanta (Press release, Verastem, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322203 [SID1234522563]). Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma which is currently being developed for the treatment of relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) and Follicular Lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including both peripheral and cutaneous T cell lymphoma (TCL).
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"The data presented today at ASH (Free ASH Whitepaper) demonstrate that oral duvelisib, combined with either romidepsin or bortezomib, has an acceptable safety profile in patients with relapsed or refractory TCL with response rates, while still preliminary, that appear promising when compared to those seen with currently approved therapies," said Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center (MSKCC), co-principal investigator of the Phase 1 study, and lead author of the oral presentation. "We were especially pleased to see that these response rates were even higher in patients with peripheral TCL (PTCL), a rare and aggressive type of non-Hodgkin lymphoma. These clinical results were further bolstered by important preclinical findings showing duvelisib’s cell killing activity in vitro and its ability to promote beneficial changes within the in vivo tumor microenvironment."
"The preclinical and Phase 1 results reported today by the team at MSKCC are important because they provide further validation for our continued expansion of the duvelisib development program into T-cell malignancies including PTCL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem. "Overall, our data presentations at ASH (Free ASH Whitepaper) this year continue to build upon the strong foundation of preclinical research and clinical investigation for Verastem’s product candidates, demonstrating their anti-cancer activity, either alone or in combination with other agents, across a wide variety of hematologic malignancies."
Phase 1 Safety and Activity Results
This multicenter, Phase I trial is comprised of parallel arms evaluating oral duvelisib in combination with romidepsin (arm A) or bortezomib (arm B) in patients with relapsed/refractory TCL, including PTCL and cutaneous T-cell lymphoma (CTCL). Oral duvelisib was dosed at 25mg, 50mg, or 75mg twice-daily (BID) on days 1-28. Romidepsin 10mg/m2 was dosed on Days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on Days 1, 4, 8, and 11 (arm B), both cohorts on 28-day cycles.
In arm A, there were 15 patients evaluable for efficacy (PTCL, n=11; CTCL, n=4). Of these, nine responded (4 complete responses (CR) and 5 partial responses (PR) for an overall response rate (ORR) of 60%. Seven of the 11 patients with PTCL responded (4 CR and 3 PR) for an ORR of 64%. Among the 9 patients evaluable for safety (25mg, n=3; 50mg, n=3; 75mg, n=3), there were no dose limiting toxicities (DLT), therefore oral duvelisib 75mg BID in combination with romidepsin 10mg/m2 IV was defined as the maximum tolerated dose (MTD). The most common Grade 1/2 adverse events were fatigue (n=9), nausea (n=8), altered taste (n=8) and diarrhea (n=6), rash (n=5), dysphagia (n=4) and anorexia (n=4). The most common Grade 3/4 adverse events were neutropenia (n=6), thrombocytopenia (n=1), lung infection (n=1), pleural effusion (n=1) and hyponatremia (n=1). There were two deaths (sepsis and diffuse alveolar hemorrhage following allogeneic stem cell transplant) that were both assessed as unrelated to study drug.
In arm B, there were 17 patients evaluable for efficacy (PTCL, n=10; CTCL, n=7). Of these, six responded (3 CRs and 3 PRs) for an ORR of 35%. Five of the 10 patients with PTCL responded (3 CRs and 2 PRs) for an ORR of 50%. Among the 14 patients evaluable for safety (25mg, n=6; 50mg, n=3; 75mg, n=5), there was one DLT (pneumonia) in the 25mg group. The MTD was determined to be oral duvelisib 25mg BID in combination with bortezomib 1mg/m2 IV. The most common Grade 1/2 adverse events were diarrhea/colitis (n=11), nausea/vomiting (n=4), chills (n=4) and fatigue (n=4). The most common Grade 3/4 adverse events were ALT and AST elevation (n=6), rash (n=2) and neutropenia (n=2). There was a case of Stevens-Johnson syndrome resulting in death which was assessed by the investigator as possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was initiated at the start of the study.
A copy of this oral presentation will be available here following the conclusion of the session.
About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular populations and extracellular matrices within the tumor or cancer niche that support cancer cell survival. This includes immunosuppressive cell populations such as regulatory T-cells, myeloid-derived suppressor cells, M2 TAMS, as well as tumor-associated fibroblasts and extracellular matrix proteins which can hamper the entry and therapeutic benefit of cytotoxic immune cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s compounds duvelisib and defactinib target the tumor microenvironment as a mechanism of action to potentially improve a patient’s response to therapy.
About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib is currently being evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints and Verastem intends to submit a New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL). Duvelisib is also being developed by Verastem for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov
About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase encoded by the PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability. Defactinib (VS-6063) and VS-4718 are orally available compounds that are potent inhibitors of FAK. Defactinib and VS-4718 utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. Defactinib is currently being studied in multiple clinical trials for patients with cancer.