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

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ClinicalTrials.gov Identifier: NCT04247126
Recruitment Status : Recruiting
First Posted : January 29, 2020
Last Update Posted : March 18, 2022
Sponsor:
Information provided by (Responsible Party):
Syros Pharmaceuticals

Study Description
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Brief Summary:
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) .

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Breast Cancer Small-cell Lung Cancer Pancreatic Cancer Drug: SY-5609 Drug: Fulvestrant Drug: Gemcitabine Drug: Nab-paclitaxel Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of SY 5609, an Oral, Selective CDK7 Inhibitor, in Adult Patients With Select Advanced Solid Tumors
Actual Study Start Date : January 23, 2020
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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


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

Secondary Outcome Measures :
  1. Groups 1 and 2: Area Under The Concentration Versus Time Curve of SY-6509 [ Time Frame: 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) ]
  2. Groups 1 and 2: Apparent Clearance of SY-5609 [ Time Frame: 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) ]
  3. Groups 1 and 2: Apparent Volume of Distribution of SY-5609 [ Time Frame: 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) ]
  4. Groups 1 and 2: Elimination Half-Life of SY-5609 [ Time Frame: 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) ]
  5. Groups 1 and 2: Maximum Plasma Concentration (Cmax) of SY-5609 [ Time Frame: 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) ]
  6. Groups 1 and 2: Time of Maximum Plasma Concentration (Tmax) of SY-5609 [ Time Frame: 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) ]
  7. Groups 1 and 2: Minimum or Trough Plasma Concentration (Cmin) of SY-5609 [ Time Frame: 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) ]
  8. Groups 1 and 2: Time of Minimum or Trough Plasma Concentration (Tmin) of SY-5609 [ Time Frame: 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) ]
  9. Groups 3 and 4 (Safety Lead-ins): Progression Free Survival [ Time Frame: Up to 1 year ]
  10. Groups 3 and 4 (Safety Lead-ins): Objective Response Rate (ORR) [ Time Frame: Up to 1 year ]
    ORR is defined as the proportion of participants who achieve complete response (CR) and partial remission (PR) (as determined by the investigator).

  11. Groups 3 and 4 (Safety Lead-ins): Complete Response/Remission (CR) Rate [ Time Frame: Up to 1 year ]
    CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).

  12. Groups 3 and 4 (Safety Lead-ins): Disease Control Rate [ Time Frame: Up to 1 year ]
  13. Groups 3 and 4 (Safety Lead-ins): Time to Response [ Time Frame: Up to 1 year ]
    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.

  14. Groups 3 and 4 (Safety Lead-ins): Duration of Response [ Time Frame: Up to 1 year ]
    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.

  15. Groups 3 and 4 (Expansions): Objective Response Rate [ Time Frame: Up to 1 year ]
    ORR is defined as the proportion of participants who achieve CR and partial remission (PR) (as determined by the investigator).

  16. Groups 3 and 4 (Expansions): Complete Response Rate [ Time Frame: Up to 1 year ]
    CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).

  17. Groups 3 and 4 (Expansions): Disease Control Rate [ Time Frame: Up to 1 year ]
  18. Groups 3 and 4 (Expansions): Time to Response [ Time Frame: Up to 1 year ]
    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.

  19. Groups 3 and 4 (Expansions): Duration of Response [ Time Frame: Up to 1 year ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04247126


Contacts
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Contact: Senior Clinical Trial Manager 857-321-8698 gcraig@syros.com
Contact: Vice President Clinical Operations

Locations
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United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Anna Rosen       anna.rosen@cshs.org   
Principal Investigator: Monica Mita, MD         
United States, Florida
Orlando Health Cancer Institute Recruiting
Orlando, Florida, United States, 32806
Contact: Kiera Grofsik       kiera.grofsik@orlandohealth.com   
Principal Investigator: Sajeve Thomas, MD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Emma Judson       ejudson@emory.edu   
Principal Investigator: Mehmet Akce, MD         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21205
Contact: Clarissa Frimpong       cfrimpo2@jhmi.edu   
Principal Investigator: Jessica Tao, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Brittney Peterkin       BPETERKIN@mgh.harvard.edu   
Principal Investigator: Dejan Juric, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Illya Dixon       Illya_Dixon@dfci.harvard.edu   
Principal Investigator: Geoffrey Shapiro, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Cliff Abat       abatcn@med.umich.edu   
Principal Investigator: Vaibhav Sahai, MD         
START Midwest, LLC Recruiting
Grand Rapids, Michigan, United States, 49546
Contact: Shannon Skibinski-Preston    616-954-5552    shannon.skibinski@startmidwest.com   
Principal Investigator: Manish Sharma, MD         
United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27705
Contact: Jeremy Jenkins       jeremy.jenkins@duke.edu   
Principal Investigator: Niharika Mettu, MD         
United States, Oklahoma
Stephenson Cancer Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Dana Low       Dana-Low@ouhsc.edu   
Principal Investigator: Debra Richardson, MD         
United States, Pennsylvania
Sidney Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Allison Scott       Allison.Scott@jefferson.edu   
Principal Investigator: Babar Bashir, MD         
United States, Tennessee
Sarah Cannon Research Institute - Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Contact: Jacquelyn Spence    615-340-2830    jacquelyn.spence@sarahcannon.com   
Principal Investigator: Erika Hamilton, MD         
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Principal Investigator: Douglas Orr, MD         
South Texas Accelerated Research Theraputics (START), LLC Recruiting
San Antonio, Texas, United States, 78229
Contact: Isabel Jimenez, RN, MSN    210-593-5265    isabel.jimenez@startsa.com   
Principal Investigator: Kyriakos Papadopoulos, MD         
Sponsors and Collaborators
Syros Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Syros Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04247126    
Other Study ID Numbers: SY-5609-101
First Posted: January 29, 2020    Key Record Dates
Last Update Posted: March 18, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Small Cell Lung Carcinoma
Neoplasms
Neoplasms by Site
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Gemcitabine
Paclitaxel
Fulvestrant
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
 Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists