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Poster display session

4152 - A Phase 1 Study of SY-1365, a Selective CDK7 Inhibitor, in Adult Patients with Advanced Solid Tumors

Date

11 Sep 2017

Session

Poster display session

Presenters

Anthony Tolcher

Citation

Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367

Authors

A. Tolcher1, K.T. Do2, E. di Tomaso3, N. Waters3, K. Stephens3, D.A. Roth3, G. Shapiro2

Author affiliations

  • 1 Medical Oncology, South Texas Accelerated Research Therapeutics (START), 78229 - San Antonio/US
  • 2 Early Drug Development Center, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 3 Clinical Development, Syros Pharmaceuticals, 02139 - Cambridge/US
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Resources

Abstract 4152

Background

SY-1365 is a selective and potent covalent CDK7 inhibitor. CDK7 activity has been implicated in malignancies with transcriptional dependencies such as SCLC, TNBC, ovarian cancer, MYCN-amplified neuroblastoma, and various hematologic malignancies including AML and T-ALL. Preclinical studies in solid tumor and hematologic malignancies show treatment with SY-1365 leads to antitumor activity, showing apoptosis in vitro and complete regressions in xenograft models. This first clinical study is focused on patients with advanced solid tumors. The primary objectives are to assess the safety and tolerability of SY-1365 administered intravenously as a single agent, and to determine dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose. Secondary objectives include evaluation of pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of SY-1365 in tumor and surrogate tissues, as well as assessment of preliminary anti-tumor activity.

Trial design

This is a multi-center, open-label Phase 1 trial that is expected to enroll approximately 70 patients with advanced solid tumors. The dose escalation phase of the trial is open to solid tumor patients for whom standard curative or palliative measures do not exist or are no longer effective. Initially, SY-1365 will be administered intravenously twice weekly for 3 weeks of each 4-week cycle. Regimen optimization will be based upon PK, PD, and safety data prior to an expansion phase to evaluate preliminary antitumor activity of SY-1365 in 25 patients with SCLC, TNBC or ovarian cancer. A second expansion cohort will enroll 10 patients with tumors of any histology to evaluate PD endpoints in paired tumor biopsies. SY-1365 target engagement in peripheral blood mononuclear cells and available tumor biopsies will be assessed by measuring CDK7 occupancy over the course of treatment. Downstream biological pathway impact of SY-1365 will be measured by quantifying changes in gene expression as a result of transcriptional inhibition. Induction of tumor cell apoptosis will also be investigated. This trial opened in May 2017. ClinicalTrials.gov identifier: NCT03134638.

Clinical trial identification

Study Protocol Number: SY-1365-101. ClinicalTrials.gov NCT03134638

Legal entity responsible for the study

Syros Pharmaceuticals, Inc

Funding

Syros Pharmaceuticals, Inc

Disclosure

A. Tolcher: Co-owner of South Texas Acelerated Research Therapeutics which receives fees for consulting and board memberships from companies (17); and research funding from companies (34) for his role as principle investigator. E. di Tomaso: Employee and stock owner of Syros Pharamceuticals. N. Waters, D.A. Roth, K. Stephens: An employee and stock holder of Syros Pharmaceuticals. G. Shapiro: Advisory boards for Pfizer, Lilly, G1 Therapeutics, Roche and Vertex Pharmaceuticals. Research funding from Pfizer and Lilly for CDK inhibitor-based projects. All other authors have declared no conflicts of interest.

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