Clinical Trial - NCT03134638

A Phase 1 Study of SY-1365 in Adult Patients With Advanced Solid Tumors

Recruiting

Sponsor: Syros Pharmaceuticals

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03134638

Protocol Info

Short Description: Phase I SY-1365 in ASTs
Long Description: A Phase 1 Study of SY-1365, a Selective CDK7 Inhibitor, in Adult Patients with Advanced Solid Tumors
MGH Status: Open
Sponsor: Syros Pharmaceuticals
Disease Program: Phase I

Next Steps


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Purpose

This study will consist of two parts. Part 1 is a dose-escalation/safety evaluation to provisionally identify a dose and regimen of SY-1365 for further evaluation in Part 2. Approximately 35 patients with advanced solid tumors will be enrolled into Part 1 of the study. Following the identification of a recommended dose and regimen from Part 1, the study will enter Part 2 to further evaluate safety and the antitumor activity of SY-1365 in patients with select solid tumors, and to confirm target engagement and downstream pathway impact in patients with any solid tumor histology.
Condition Title Intervention Phase
Advanced Solid Tumors Ovarian Cancer Breast Cancer SY-1365 Carboplatin Fulvestrant Phase 1
Study Type Interventional
Official Title A Phase 1 Study of SY-1365, a Selective CDK7 Inhibitor, in Adult Patients With Advanced Solid Tumors

Primary Outcome Measures

First-cycle dose-limiting toxicities (DLTs) [Time Frame: Within 1 year] [Designated as safety issue: ]

Maximum tolerated dose (MTD) [Time Frame: Within 1 year] [Designated as safety issue: ]

Safety and tolerability of SY-1365 as a single agent and in combination with either carboplatin or fulvestrant [Time Frame: Within 1 year] [Designated as safety issue: ]


Secondary Outcome Measures

Evaluate the antitumor activity of SY-1365 in patients with ovarian cancer, breast cancer, and advanced solid tumors [Time Frame: Up to 1 year] [Designated as safety issue: ]

Peak plasma concentration (Cmax) [Time Frame: Up to 4 months] [Designated as safety issue: ]

Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last) [Time Frame: Up to 4 months] [Designated as safety issue: ]

Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-INF) [Time Frame: Up to 4 months] [Designated as safety issue: ]

Terminal elimination half-life (t1/2) [Time Frame: Up to 4 months] [Designated as safety issue: ]

Time of maximum observed plasma concentration (tmax) [Time Frame: Up to 4 months] [Designated as safety issue: ]

Evaluate the PD effects of SY-1365 by measuring the CDK7 occupancy after SY-1365 administration in PBMCs and tumor tissue [Time Frame: Up to 1 year] [Designated as safety issue: ]

Estimated Enrollment: 137
Study Start Date: May 2017
Estimated Study Completion Date: June 2022
Estimated Primary Completion Date: June 2020
Arms Assigned Interventions

Experimental:Dose Escalation

Dose escalation phase to explore maximum tolerated dose across two schedules. SY-1365 will be administered intravenously on two dosing schedules, weekly and twice-weekly for 3 weeks of each 4-week cycle
Drug:SY-1365
Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2. Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle. Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.

Experimental:Advanced Ovarian Cancer

Patients with ovarian cancer previously treated with ≥ 3 prior lines of therapy (SY-1365 single agent)

Experimental:Relapsed Ovarian Cancer

Patients with ovarian cancer previously treated with ≥ 1 prior line of therapy including a platinum-based regimen (SY-1365 + carboplatin)
Drug:Carboplatin
Carboplatin will be administered on Day 1 of each 3-week (21-day) cycle.

Experimental:Primary Platinum Refractory Ovarian Cancer

Patients with ovarian cancer considered primary platinum refractory (progression either during treatment or within 1 month after completion of a first-line platinum-based regimen) (SY-1365 single agent)

Experimental:Biopsy

Biopsy cohort of approximately 20-30 patients with advanced solid tumors from whom pre- and post-treatment biopsies will be obtained (SY-1365 single agent)

Experimental:HR+ breast cancer

Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer (BC) that has progressed following prior treatment with a cyclin-dependent kinase (CDK)4/6 inhibitor in combination with an aromatase inhibitor (SY-1365 + fulvestrant)
Drug:Fulvestrant
Fulvestrant will be administered as an intramuscular (IM) dose of 500 mg every 2 weeks for the first 3 doses on Day 1 and Day 15 of the first 28-day cycle (Cycle 1), and on Day 1 of the second 28-day cycle (Cycle 2), and monthly thereafter starting on Day 1 of Cycle 3.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Inclusion Criteria:

  • 18 years of age or older
  • Disease status
  • Part 1: any histologically-confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective
  • Part 2, Cohorts 1-3, all patients must have a histologically-confirmed diagnosis of high grade serous ovarian cancer (including fallopian tube cancer and/or primary peritoneal cancer)
  • Part 2, Cohort 1, Patients must have received ≥ 3 prior treatment regimens for ovarian cancer including a platinum-based regimen. Patients whose OC harbors a mutation in breast cancer gene (BRCA), either germline or somatic, must have been previously treated with a poly(ADP ribose) polymerase (PARP) inhibitor, or be considered unwilling or ineligible for treatment with a PARP inhibitor
  • Part 2, Cohort 2, Must have received ≥ 1 prior treatment regimen for ovarian cancer, at least 1 of which is a platinum-based regimen
  • Part 2,Cohort 3, Must have received only 1 prior platinum-based regimen. Patient must have primary platinum refractory OC (defined as progression either while on initial treatment with the platinum-based therapy or within 1 month following the last dose of treatment)
  • Part 2, Cohort 4, Any histologically-confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective. Must have accessible tumor tissue and be willing to undergo tumor tissue sampling (biopsies/aspirates) pre- and post-treatment
  • Part 2, Cohort 5, Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer who have failed prior treatment with a CDK 4/6 inhibitor in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy.
  • At least 1 measurable lesion by RECIST 1.1
  • All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 or returned to baseline levels prior to enrollment
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Life expectancy > 3 months
  • absolute neutrophil count: ≥ 1.5 x 109/L
  • platelets: ≥ 100 x 109/L
  • hemoglobin: ≥ 9 g/dL
  • total bilirubin ≤ 1.5 institutional upper limit of normal [ULN])
  • AST (SGOT)/ ALT (SGPT): ≤ 3.0 x institutional ULN
  • Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance ≥ 60 mL/min by Crockoft-Gault for participants with creatinine levels above institutional normal
  • Negative pregnancy test for women of child bearing potential

Exclusion Criteria:

  • Chemotherapy or limited field radiotherapy within 2 weeks, wide field radiotherapy within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks prior to entering the study
  • Major surgery within 2 weeks of starting the study treatment, or not recovered to baseline status from the effects of surgery received > 2 weeks prior
  • Received any other investigational agents within 4 weeks prior to enrollment, or < 5 half-lives since completion of previous investigational therapy, whichever is shorter
  • Received previous non-cytotoxic, FDA-approved anticancer agent within previous 2 weeks, or < 5 half-lives since completion of previous therapy, whichever is shorter
  • Prior exposure to transcriptional kinase family CDK inhibitors, such as the CDK7 and CDK9 inhibitors alvocidib (Flavopiridol), dinaciclib, and seliciclib. Exception: previous exposure to cell cycle CDK inhibitors such as CDK4 and CDK6 (eg, palbociclib) is allowed
  • Known brain metastases or carcinomatous meningitis. Exception: previously treated brain metastatic disease that remains stable on MRI ≥ 4 weeks prior to enrollment, without steroids or anti-epileptic medications
  • History of allergic reactions attributed to compounds of similar chemical composition to SY-1365
  • Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients
  • Patients with known active Hepatitis B or Hepatitis C infection
  • Prior treatment (< 2 weeks before start of SY-1365) with moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors. See list in Appendix 3
  • Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms
  • Significant cardiac risk, including: History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors

Part 2 Only:

  • Cohorts 1, 2, and 3: Patients with low-grade ovarian cancer (eg, low grade serous, mucinous carcinoma) are not eligible
  • Cohort 2: Prior adverse reaction(s) to carboplatin
  • Cohort 5: Prior treatment with fulvestrant; Prior treatment with chemotherapy for advanced/metastatic disease; Any line(s) of therapy following treatment failure with a CDK 4/6 inhibitor in combination with an AI; Prior treatment with chemotherapy in the advanced/metastatic setting or with fulvestrant; Advanced/metastatic disease that is symptomatic and/or with visceral spread

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03134638

Locations

  • United States, Alabama
    • University of Alabama at Birmingham Birmingham, Alabama, United States, 35233
  • United States, Arizona
    • Scottsdale Healthcare Hospitals Scottsdale, Arizona, United States, 85258
  • United States, California
    • Palo Alto Medical Foundation Group San Francisco, California, United States, 94118
  • United States, Illinois
    • University of Chicago Medical Center Chicago, Illinois, United States, 60637
  • United States, Massachusetts
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215
  • United States, New York
    • Columbia University Medical Center New York, New York, United States, 10032
  • United States, Oklahoma
    • Stephenson Cancer Center Oklahoma City, Oklahoma, United States, 73104
  • United States, Rhode Island
    • Women and Infants Hospital of Rhode Island Providence, Rhode Island, United States, 02905
  • United States, Tennessee
    • Tennessee Oncology Nashville, Tennessee, United States, 37203
  • United States, Texas
    • University of Texas Southwestern Medical Center Dallas, Texas, United States, 75390
    • South Texas Accelerated Research Therapeutics San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Syros Pharmaceuticals

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03134638
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Additional relevant MeSH terms:

Carboplatin

Fulvestrant

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019