On September 9, 2021 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported that the first patient has been dosed in the SELECT-AML-1 clinical trial of tamibarotene, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with venetoclax and azacitidine (Press release, Syros Pharmaceuticals, SEP 9, 2021, View Source [SID1234587550]). The randomized Phase 2 trial is enrolling RARA-positive newly diagnosed unfit patients with acute myeloid leukemia (AML).
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"Despite recent advances, one third of newly diagnosed unfit AML patients still don’t respond to front-line treatment and many more relapse," said Eytan M. Stein, M.D., Assistant Professor of Medicine and Director of the Program for Drug Development in Leukemia at Memorial Sloan Kettering Cancer Center. "These patients need new therapies that can deliver durable remissions with minimal or manageable toxicities. I am encouraged by tamibarotene’s distinct safety profile, as well as the compelling clinical and translational data that has emerged, suggesting it may benefit patients in the greatest need of new treatment options. I look forward to further exploring its potential in this clinical trial as part of a triplet regimen with venetoclax and azacitidine."
Tamibarotene has demonstrated promising results in combination with azacitidine in RARA-positive newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. At the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020, Syros presented data from a Phase 2 clinical trial, demonstrating a 67% overall response rate and a 61% composite complete response (CR/CRi) rate. The data also showed that tamibarotene in combination with azacitidine was generally well-tolerated, with no evidence of increased myelosuppression compared to single-agent azacitidine.
Also at ASH (Free ASH Whitepaper), Syros presented translational data demonstrating that most RARA-positive newly diagnosed unfit AML patients in the Phase 2 trial of tamibarotene had a monocytic disease phenotype associated with resistance to venetoclax, which, in combination with azacitidine, is the standard of care for newly diagnosed unfit patients. These data suggest that the RARA biomarker selects for patients who are more likely to benefit from tamibarotene and who may be less likely to benefit from venetoclax.
"AML is a complex, heterogenous disease, and many patients may present upfront with both monocytic and non-monocytic leukemia cells," said David A. Roth, M.D., Chief Medical Officer at Syros. "By employing a triplet strategy that combines tamibarotene with venetoclax and azacitidine, we believe we can simultaneously target both cell types, reducing the emergence of resistant disease and increasing the likelihood of deeper and more durable responses. We are excited to be actively enrolling patients in this study, as we advance our portfolio of targeted hematology therapies with the aim of setting new standards of care for people with acute leukemias and myelodysplastic syndrome."
The SELECT-AML-1 trial is designed with a single-arm safety lead-in, followed by the randomized portion of the trial, which will evaluate the safety and efficacy of tamibarotene in combination with venetoclax and azacitidine compared to venetoclax and azacitidine in approximately 80 patients randomized 1:1. The trial will also evaluate the triplet regimen as a salvage strategy in patients in the control arm who do not respond to venetoclax and azacitidine. The primary endpoint of the trial will be composite CR rate.
Syros is also evaluating tamibarotene in combination with azacitidine in the SELECT-MDS-1 Phase 3 clinical trial in RARA-positive patients with newly diagnosed higher-risk myelodysplastic syndrome.