A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors
- Conditions
- Breast CancerPancreatic CancerAdvanced Solid TumorSmall-cell Lung Cancer
- Interventions
- Registration Number
- NCT04247126
- Lead Sponsor
- Syros Pharmaceuticals
- 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) .
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 105
- Age ≥ 18 years
- Advanced Solid Tumors for which standard curative or palliative measures do not exist or are no longer effective (Group 1 only).
- 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).
- Participants with histologically or cytologically confirmed PDAC with measurable metastatic lesion(s) (Groups 3 and 4 only).
- Participants must have at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 before enrollment.
- For women of childbearing potential (WCBP): negative serum β human chorionic gonadotropin pregnancy test within 1 week before the first dose of SY 5609
- Adequate organ and marrow function
- Participants must be willing and able to comply with all aspects of the protocol
- Participants must provide written informed consent before any study-specific screening procedures.
- Albumin ≥ 3.0 grams/deciliters (g/dL) (Groups 3 and 4 only).
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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
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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
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Received any other investigational agents within 4 weeks before enrollment, or < 5 half-lives since completion of previous investigational therapy, whichever is shorter
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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
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Known brain metastases or carcinomatous meningitis
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Immunocompromised participants with increased risk of opportunistic infections
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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.
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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)
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Female participants who are pregnant or breastfeeding
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History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors
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Uncontrolled intercurrent illness.
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Poorly controlled ascites requiring paracentesis within 1 month prior to entering the study. (Groups 3 and 4 only)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Group 2: SY-5609 + Fulvestrant SY-5609 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. Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel SY-5609 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. Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel 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. Group 2: SY-5609 + Fulvestrant 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. Group 3: SY-5609 + Gemcitabine 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. Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel Gemcitabine 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. Group 1: Single Agent Dose Escalation SY-5609 Dose escalation phase to explore maximum tolerated dose of SY-5609 given as a single agent. Group 3: SY-5609 + Gemcitabine SY-5609 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.
- Primary Outcome Measures
Name Time Method 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 Groups 1 and 2: Dose-Limiting Toxicity of SY-5609 Up to 28 days after first administration
- Secondary Outcome Measures
Name Time Method Groups 3 and 4 (Expansions): Complete Response Rate Up to 1 year CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).
Groups 3 and 4 (Expansions): Disease Control Rate Up to 1 year 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 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: 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 3 and 4 (Safety Lead-ins): Objective Response Rate (ORR) 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).
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: 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: 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 3 and 4 (Safety Lead-ins): Duration of Response 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.
Groups 3 and 4 (Expansions): Time to Response 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.
Groups 3 and 4 (Expansions): Duration of Response 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.
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 (Expansions): Objective Response Rate Up to 1 year ORR is defined as the proportion of participants who achieve CR and partial remission (PR) (as determined by the investigator).
Groups 3 and 4 (Safety Lead-ins): Complete Response/Remission (CR) Rate Up to 1 year CR rate is defined as proportion of participants who achieve CR (as determined by the investigator).
Groups 3 and 4 (Safety Lead-ins): Disease Control Rate Up to 1 year Groups 3 and 4 (Safety Lead-ins): Time to Response 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.
Trial Locations
- Locations (16)
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Sidney Kimmel Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
South Texas Accelerated Research Theraputics (START), LLC
🇺🇸San Antonio, Texas, United States
Duke University
🇺🇸Durham, North Carolina, United States
Sarah Cannon Research Institute - Tennessee Oncology
🇺🇸Nashville, Tennessee, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
University of California Los Angeles
🇺🇸Los Angeles, California, United States
Orlando Health Cancer Institute
🇺🇸Orlando, Florida, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
The University of Iowa
🇺🇸Iowa City, Iowa, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
START Midwest, LLC
🇺🇸Grand Rapids, Michigan, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States