19 November 2018 - - Data from the dose escalation portion of its Phase 1 trial of SY-1365, its first-in-class selective cyclin-dependent kinase 7 inhibitor, demonstrated proof-of-mechanism at tolerable doses in patients with advanced solid tumors, US-based Syros Pharmaceuticals (NASDAQ: SYRS) said.

These data, the first clinical data reported on a selective CDK7 inhibitor, were highlighted in an oral plenary session at the 30th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium in Dublin.

The dose escalation portion of the Phase 1 trial characterized the safety, pharmacokinetics and pharmacodynamics of SY-1365 in patients with advanced solid tumors to establish a dose and regimen for the expansion portion of the trial.

PD assays used to establish proof-of-mechanism included a CDK7 occupancy assay to evaluate SY-1365 binding and a custom gene expression assay to evaluate downstream transcriptional changes in patients. Preliminary anti-tumor activity was also assessed.

Enrollment in the dose escalation portion of the trial was completed in September. In total, 32 patients were treated with SY-1365 as a single agent at doses ranging from 2 mg/m2 to 112 mg/m2 using either a weekly or twice weekly dosing regimen.

Patients were treated for three weeks out of each four-week cycle. Patients had a range of solid tumors, the most prevalent being ovarian cancer (eight patients), breast cancer (eight patients) and endometrial cancer (five patients).

Patients' median age was 63 (ranging from 25 to 87), with a median of five prior therapies (ranging from one to 13).

As of an October 15th data snapshot, the median treatment duration was 46.5 days (ranging from two to 147 days) and four patients remained on treatment.

As of the October 15th data snapshot, clinical activity per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was observed in seven of the 19 patients who were evaluable for clinical responses, including:

One patient with ovarian cancer in her fourth relapse who had a confirmed partial response after two cycles of treatment at the 80 mg/m2 twice-weekly dose.

The patient remained in PR at her CT assessment after six cycles and recently entered her seventh month on study treatment.

Six additional patients who had stable disease, lasting between 50 and 127 days. Most of these patients received doses equal to or greater than 32 mg/m2.

Based on these data, Syros selected a twice-weekly dose of 80 mg/m2 of SY-1365 when administered as a single agent, and a once-weekly target dose of 80 mg/m2 of SY-1365 when administered in combination with other agents, for further evaluation in the ongoing Phase 1 expansion cohorts in multiple ovarian and breast cancer patient populations.

Upon completing enrollment in the dose-escalation portion of the trial, Syros opened expansion cohorts to further assess the safety and anti-tumor activity of SY-1365 in multiple ovarian and breast cancer patient populations.

The initial expansion strategy is based on preclinical data showing anti-tumor activity in these tumor types, a strong mechanistic rationale and high unmet need.

The expansion cohorts are evaluating SY-1365: as a single agent in primary platinum-refractory ovarian cancer patients; as a single agent in ovarian cancer patients who have relapsed after three or more therapies; in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies; and in combination with fulvestrant in patients with hormone-receptor positive metastatic breast cancer who have progressed after treatment with a CDK4/6 inhibitor.

An additional cohort is enrolling patients with any solid tumor accessible for biopsy to further evaluate the mechanism of action of SY-1365.

Syros is pioneering the understanding of the non-coding regulatory region of the genome to advance a new wave of medicines that control the expression of genes. Syros has built a proprietary platform that is designed to systematically and efficiently analyse this unexploited region of DNA to identify and drug novel targets linked to genomically defined patient populations.

Because gene expression is fundamental to the function of all cells, Syros' gene control platform has broad potential to create medicines that achieve profound and durable benefit across a range of diseases.

Syros is currently focused on cancer and monogenic diseases and is advancing a growing pipeline of gene control medicines.

Syros' lead drug candidates are SY-1425, a selective RARα agonist in a Phase 2 clinical trial for genomically defined subsets of patients with acute myeloid leukemia and myelodysplastic syndrome, and SY-1365, a selective CDK7 inhibitor in a Phase 1 clinical trial for patients with ovarian and breast cancers.

Syros is also developing a deep preclinical and discovery pipeline, including SY-5609, an oral CDK7 inhibitor, as well as programs in immuno-oncology and sickle cell disease. Led by a team with deep experience in drug discovery, development and commercialization, Syros is located in Cambridge, Mass.