Clinical trial NCT04247126: A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors
Official title: A Phase 1 Study of SY 5609, an Oral, Selective CDK7 Inhibitor, in Adult Patients With Select Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumor
Breast Cancer
Small-cell Lung Cancer
Pancreatic Cancer
Lead sponsor: Syros Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2020-01-29
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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) .


Eligibility 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)

Primary outcomes:
measure: Groups 1 and 2: Dose-Limiting Toxicity of SY-5609
timeFrame: Up to 28 days after first administration
measure: Groups 1 and 2: Number of Participants With Treatment Emergent Adverse Events
timeFrame: From Baseline up to 30 days after last dose of study drug (up to 1 year)
measure: Groups 3 and 4 (Safety Lead-ins): Number of Participants With Dose-Limiting Toxicity
timeFrame: Up to 28 days after first administration
measure: Groups 3 and 4 (Safety Lead-ins): Number of Participants With TEAEs
timeFrame: From Baseline up to 30 days after last dose of study drug (up to 1 year)
measure: Groups 3 and 4 (Expansions): Progression Free Survival
timeFrame: Up to 1 year
Secondary outcomes:
measure: Groups 1 and 2: Area Under The Concentration Versus Time Curve of SY-6509
timeFrame: 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)
measure: Groups 1 and 2: Apparent Clearance of SY-5609
timeFrame: 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)
measure: Groups 1 and 2: Apparent Volume of Distribution of SY-5609
timeFrame: 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)
measure: Groups 1 and 2: Elimination Half-Life of SY-5609
timeFrame: 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)
measure: Groups 1 and 2: Maximum Plasma Concentration (Cmax) of SY-5609
timeFrame: 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)
measure: Groups 1 and 2: Time of Maximum Plasma Concentration (Tmax) of SY-5609
timeFrame: 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)
measure: Groups 1 and 2: Minimum or Trough Plasma Concentration (Cmin) of SY-5609
timeFrame: 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)
measure: Groups 1 and 2: Time of Minimum or Trough Plasma Concentration (Tmin) of SY-5609
timeFrame: 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)
measure: Groups 3 and 4 (Safety Lead-ins): Progression Free Survival
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Safety Lead-ins): Objective Response Rate (ORR)
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Safety Lead-ins): Complete Response/Remission (CR) Rate
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Safety Lead-ins): Disease Control Rate
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Safety Lead-ins): Time to Response
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Safety Lead-ins): Duration of Response
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Expansions): Objective Response Rate
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Expansions): Complete Response Rate
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Expansions): Disease Control Rate
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Expansions): Time to Response
timeFrame: Up to 1 year
measure: Groups 3 and 4 (Expansions): Duration of Response
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Orlando
country: United States
facility: Orlando Health Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: The University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest, LLC
state: Michigan
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute - Tennessee Oncology
state: Tennessee
city: San Antonio
country: United States
facility: South Texas Accelerated Research Theraputics (START), LLC
state: Texas
Study officials:
References:
citation: 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.
citation: 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.