A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors

A Phase 1 Study of SY 5609, an Oral, Selective CDK7 Inhibitor, in Adult Patients With Select Advanced Solid Tumors

The study consists of 2 parts. Part 1 is dose escalation and will first administer SY-5609 alone to participants with select advanced solid tumors and then in combination with fulvestrant to participants with HR positive, HER2-negative breast cancer. Part 2 is a dose expansion and will first administer SY-5609 in combination with gemcitabine and then SY-5609 in combination with gemcitabine and nab-paclitaxel in participants with pancreatic ductal adenocarcinoma (PDAC) .

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Pancreatic Cancer; Advanced Solid Tumor; Small-cell Lung Cancer
• Intervention / Treatment: Drug: SY-5609; Drug: Fulvestrant; Drug: Gemcitabine; Drug: Nab-paclitaxel

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health Cancer Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • The University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Grand Rapids, Michigan, United States, 49546
      • START Midwest, LLC
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Sidney Kimmel Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute - Tennessee Oncology
  • Texas
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Theraputics (START), LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Advanced Solid Tumors for which standard curative or palliative measures do not exist or are no longer effective (Group 1 only).
3. Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Participants must have failed prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with hormonal therapy in a previous line of therapy (Group 2 only).
4. Participants with histologically or cytologically confirmed PDAC with measurable metastatic lesion(s) (Groups 3 and 4 only).
5. Participants must have at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
6. All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 before enrollment.
7. For women of childbearing potential (WCBP): negative serum β human chorionic gonadotropin pregnancy test within 1 week before the first dose of SY 5609
8. Adequate organ and marrow function
9. Participants must be willing and able to comply with all aspects of the protocol
10. Participants must provide written informed consent before any study-specific screening procedures.
11. Albumin ≥ 3.0 grams/deciliters (g/dL) (Groups 3 and 4 only).

Exclusion Criteria:

1. Chemotherapy or limited field radiotherapy within 2 weeks, wide field radiotherapy within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks before entering the study
2. Major surgery within 2 weeks before starting the study treatment, or not recovered to baseline status from the effects of surgery received > 2 weeks prior
3. Received any other investigational agents within 4 weeks before enrollment, or < 5 half-lives since completion of previous investigational therapy, whichever is shorter
4. Received previous noncytotoxic, US Food and Drug Administration-approved anticancer agent within previous 2 weeks, or < 5 half-lives since completion of previous therapy, whichever is shorter
5. Known brain metastases or carcinomatous meningitis
6. Immunocompromised participants with increased risk of opportunistic infections
7. Participants with known active or chronic hepatitis B or active hepatitis C infection. Participants with a history of hepatitis C virus (HCV) infection who have completed curative therapy for HCV at least 12 weeks before Screening and have a documented undetectable viral load at Screening are eligible for enrollment.

8. Baseline QT interval corrected (QTc) with Fridericia's method > 480 milliseconds

   • NOTE: criterion does not apply to participants with a right or left bundle branch block (QTc interval)

9. Female participants who are pregnant or breastfeeding
10. History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors
11. Uncontrolled intercurrent illness.
12. Poorly controlled ascites requiring paracentesis within 1 month prior to entering the study. (Groups 3 and 4 only)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Single Agent Dose Escalation; Dose escalation phase to explore maximum tolerated dose of SY-5609 given as a single agent.	Drug: SY-5609; An oral CDK7 Inhibitor
Experimental: Group 2: SY-5609 + Fulvestrant; Participants 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 hormonal therapy will receive SY-5609 in combination with fulvestrant.	Drug: SY-5609; An oral CDK7 Inhibitor; Drug: Fulvestrant; Estrogen receptor antagonist
Experimental: Group 3: SY-5609 + Gemcitabine; Participants with PDAC will receive SY-5609 in combination with gemcitabine in Safety Lead-in to identify a recommended combination dose for the expansion. The expansion part will assess the safety, tolerability, and preliminary clinical activity of SY-5609 in combination with gemcitabine at the recommended combination dose.	Drug: SY-5609; An oral CDK7 Inhibitor; Drug: Gemcitabine; Nucleoside metabolic inhibitor
Experimental: Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel; Participants with PDAC will receive SY-5609 in combination with gemcitabine plus nab-paclitaxel in Safety Lead-in to identify a recommended combination dose for the expansion. The expansion part will assess the safety, tolerability, and preliminary clinical activity of SY-5609 in combination with gemcitabine plus nab-paclitaxel at the recommended combination dose.	Drug: SY-5609; An oral CDK7 Inhibitor; Drug: Gemcitabine; Nucleoside metabolic inhibitor; Drug: Nab-paclitaxel; Taxane-type chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Groups 1 and 2: Dose-Limiting Toxicity of SY-5609	Up to 28 days after first administration
Groups 1 and 2: Number of Participants With Treatment Emergent Adverse Events	From Baseline up to 30 days after last dose of study drug (up to 1 year)
Groups 3 and 4 (Safety Lead-ins): Number of Participants With Dose-Limiting Toxicity	Up to 28 days after first administration
Groups 3 and 4 (Safety Lead-ins): Number of Participants With TEAEs	From Baseline up to 30 days after last dose of study drug (up to 1 year)
Groups 3 and 4 (Expansions): Progression Free Survival	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Groups 1 and 2: Area Under The Concentration Versus Time Curve of SY-6509		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Apparent Clearance of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Apparent Volume of Distribution of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Elimination Half-Life of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Maximum Plasma Concentration (Cmax) of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Time of Maximum Plasma Concentration (Tmax) of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Minimum or Trough Plasma Concentration (Cmin) of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 1 and 2: Time of Minimum or Trough Plasma Concentration (Tmin) of SY-5609		Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days)
Groups 3 and 4 (Safety Lead-ins): Progression Free Survival		Up to 1 year
Groups 3 and 4 (Safety Lead-ins): Objective Response Rate (ORR)	ORR is defined as the proportion of participants who achieve complete response (CR) and partial remission (PR) (as determined by the investigator).	Up to 1 year
Groups 3 and 4 (Safety Lead-ins): Complete Response/Remission (CR) Rate	CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).	Up to 1 year
Groups 3 and 4 (Safety Lead-ins): Disease Control Rate		Up to 1 year
Groups 3 and 4 (Safety Lead-ins): Time to Response	Time to response is defined as the duration from the date of randomization to the date of the first documented evidence of response as determined by the investigator.	Up to 1 year
Groups 3 and 4 (Safety Lead-ins): Duration of Response	Duration of response is defined as duration from the date of first documented evidence of response to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first.	Up to 1 year
Groups 3 and 4 (Expansions): Objective Response Rate	ORR is defined as the proportion of participants who achieve CR and partial remission (PR) (as determined by the investigator).	Up to 1 year
Groups 3 and 4 (Expansions): Complete Response Rate	CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).	Up to 1 year
Groups 3 and 4 (Expansions): Disease Control Rate		Up to 1 year
Groups 3 and 4 (Expansions): Time to Response	Time to response is defined as the duration from the date of randomization to the date of the first documented evidence of response as determined by the investigator.	Up to 1 year
Groups 3 and 4 (Expansions): Duration of Response	Duration of response is defined as duration from the date of first documented evidence of response to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first.	Up to 1 year

Collaborators and Investigators

• Sponsor: Syros Pharmaceuticals

Publications and helpful links

General Publications

• Marineau JJ, Hamman KB, Hu S, Alnemy S, Mihalich J, Kabro A, Whitmore KM, Winter DK, Roy S, Ciblat S, Ke N, Savinainen A, Wilsily A, Malojcic G, Zahler R, Schmidt D, Bradley MJ, Waters NJ, Chuaqui C. Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7. J Med Chem. 2022 Jan 27;65(2):1458-1480. doi: 10.1021/acs.jmedchem.1c01171. Epub 2021 Nov 2.
• Sava GP, Fan H, Coombes RC, Buluwela L, Ali S. CDK7 inhibitors as anticancer drugs. Cancer Metastasis Rev. 2020 Sep;39(3):805-823. doi: 10.1007/s10555-020-09885-8.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2020
• Primary Completion (Actual): January 31, 2023
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: January 22, 2020
• First Submitted That Met QC Criteria: January 27, 2020
• First Posted (Actual): January 29, 2020

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 26, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Paclitaxel; Fulvestrant; Gemcitabine
• Other Study ID Numbers: SY-5609-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No