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

NCT04247126 | Completed Phase 1 FDA Drug

• 1 other identifier: SY-5609-101
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 16

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) .

Conditions

Advanced Solid Tumor; Breast Cancer; Small-cell Lung Cancer; Pancreatic Cancer

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (19)

• 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)

Study Arms (4)

Group 1: Single Agent Dose Escalation

EXPERIMENTAL

Dose escalation phase to explore maximum tolerated dose of SY-5609 given as a single agent.

Drug: SY-5609

Group 2: SY-5609 + Fulvestrant

EXPERIMENTAL

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; Drug: Fulvestrant

Group 3: SY-5609 + Gemcitabine

EXPERIMENTAL

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; Drug: Gemcitabine

Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel

EXPERIMENTAL

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; Drug: Gemcitabine; Drug: Nab-paclitaxel

Interventions

SY-5609 DRUG

An oral CDK7 Inhibitor

Group 1: Single Agent Dose Escalation; Group 2: SY-5609 + Fulvestrant; Group 3: SY-5609 + Gemcitabine; Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel

Fulvestrant DRUG

Estrogen receptor antagonist

Group 2: SY-5609 + Fulvestrant

Gemcitabine DRUG

Nucleoside metabolic inhibitor

Group 3: SY-5609 + Gemcitabine; Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel

Nab-paclitaxel DRUG

Taxane-type chemotherapy

Group 4: SY-5609 + Gemcitabine + Nab-paclitaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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
• 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
• Received any other investigational agents within 4 weeks before enrollment, or \< 5 half-lives since completion of previous investigational therapy, whichever is shorter
• 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
• Known brain metastases or carcinomatous meningitis
• Immunocompromised participants with increased risk of opportunistic infections
• 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.
• 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)
• Female participants who are pregnant or breastfeeding
• History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors
• Uncontrolled intercurrent illness.
• Poorly controlled ascites requiring paracentesis within 1 month prior to entering the study. (Groups 3 and 4 only)

Sponsors & Collaborators

• Syros Pharmaceuticals: lead

Study Sites (16)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

University of California Los Angeles

Los Angeles, California, 90095, United States

Location

Orlando Health Cancer Institute

Orlando, Florida, 32806, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

The University of Iowa

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

START Midwest, LLC

Grand Rapids, Michigan, 49546, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

Location

Sarah Cannon Research Institute - Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

South Texas Accelerated Research Theraputics (START), LLC

San Antonio, Texas, 78229, United States

Location

Related Publications (2)

• 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.

  PMID: 34726887 DERIVED

• 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.

  PMID: 32385714 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Small Cell Lung Carcinoma; Pancreatic Neoplasms

Interventions

SY-5609; Fulvestrant; Gemcitabine; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2020
• First Posted: January 29, 2020
• Study Start: January 23, 2020
• Primary Completion: January 31, 2023
• Study Completion: March 30, 2023
• Last Updated: October 27, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (16)