A Study of SY-1365 in Adult Patients With Advanced Solid Tumors

NCT ID: NCT03134638

Last Updated: 2021-03-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 107 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-12
• Study Completion Date: 2020-06-24

Brief Summary

This study consists of two parts. Part 1 is a dose-escalation/safety evaluation to provisionally identify a dose and regimen of SY-1365 for further evaluation in Part 2.

Following the identification of a recommended dose and regimen from Part 1, the study entered Part 2 to further evaluate safety and the antitumor activity of SY-1365 in patients with select solid tumors, and to confirm target engagement and downstream pathway impact in patients with any solid tumor histology.

Detailed Description

This study consists of two parts. Part 1 is a dose-escalation/safety evaluation to identify a dose and regimen for further evaluation in Part 2. SY-1365 will be administered intravenously weekly & twice weekly for 3 weeks of each 4 week cycle. Dose escalation will proceed until the determination of the maximum tolerated dose (MTD) or a recommended dose and regimen for evaluation in Part 2 of the study. Part 1 was concluded in September 2018 with a total of 32 evaluable patients.

Following the identification of a recommended dose and regimen from Part 1, the study entered Part 2 to further evaluate safety and the antitumor activity of SY-1365 in patients with select solid tumors, and to confirm target engagement and downstream pathway impact in patients with any solid tumor histology.

Preliminary anti-tumor activity will be evaluated in up to approximately 102 evaluable patients in Part 2, with SY-1365 administered alone, in combination with carboplatin, or in combination with fulvestrant. Part 2 will consist of five cohorts:

• Cohort 1: approximately 24 patients with advanced ovarian cancer with 3+ previous lines of treatment. Monotherapy
• Cohort 2: approximately 24 patients with relapsed ovarian cancer with previous platinum therapy. SY-1365 + Carboplatin
• Cohort 3: approximately 12 patients with clear cell ovarian cancer. Monotherapy
• Cohort 4: approximately 20-30 patients with biopsy-accessible, advanced solid tumors of any histology. Monotherapy.
• Cohort 5: approximately 12 patients with HR+ metastatic breast cancer post CDK4/6 + hormonal therapy treatment. SY-1365 + fulvestrant.

Overall, the study may enroll up to approximately 137 evaluable patients across dose escalation (Part 1) and expansion cohorts (Part 2, Cohorts 1, 2, 3, 4, and 5).

Conditions

Advanced Solid Tumors; Ovarian Cancer; Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation

Dose escalation phase to explore maximum tolerated dose across two dosing schedules. SY-1365 will be administered intravenously weekly and twice-weekly for 3 weeks of each 4-week cycle

Group Type: EXPERIMENTAL

SY-1365 (Part 1)

Intervention Type: DRUG

Two dosing schedules will be evaluated in dose escalation and a dose(s)/schedule(s) will be determined for Part 2:

• Twice weekly: SY-1365 will be administered by intravenous infusion over 1 or 2 hours twice a week for 3 weeks of each 4 week (28 day) cycle.
• Weekly: SY-1365 will be administered by intravenous infusion over 1 or 2 hours once a week for 3 weeks of each 4 week (28 day) cycle.

Advanced Ovarian Cancer

Patients with ovarian cancer previously treated with ≥ 3 prior lines of therapy (SY-1365 single agent)

Group Type: EXPERIMENTAL

SY-1365 (Part 2 Single Agent)

Intervention Type: DRUG

SY-1365 will be administered by intravenous infusion over 1 or 2 hours twice a week for 3 weeks of each 4 week (28 day) cycle

Relapsed Ovarian Cancer

Patients with ovarian cancer previously treated with ≥ 1 prior line of therapy including a platinum-based regimen (SY-1365 + carboplatin)

Group Type: EXPERIMENTAL

Carboplatin

Intervention Type: DRUG

Carboplatin will be administered on Day 1 of each 3 week (21-day) cycle (Part 2 only)

SY-1365 (Cohort 2)

Intervention Type: DRUG

In combination with carboplatin, SY-1365 will be administered by intravenous infusion over 1 or 2 hours for 2 weeks of each 3 week (21-day) cycle (Part 2 only)

Clear Cell Ovarian Cancer

Patients with clear cell ovarian cancer previously treated with ≥ 1 prior line of therapy (SY-1365 single agent)

Group Type: EXPERIMENTAL

SY-1365 (Part 2 Single Agent)

Intervention Type: DRUG

SY-1365 will be administered by intravenous infusion over 1 or 2 hours twice a week for 3 weeks of each 4 week (28 day) cycle

Advanced Solid Tumors

Biopsy cohort of approximately 20-30 patients with advanced solid tumors from whom pre- and post-treatment biopsies will be obtained (SY-1365 single agent)

Group Type: EXPERIMENTAL

SY-1365 (Part 2 Single Agent)

Intervention Type: DRUG

SY-1365 will be administered by intravenous infusion over 1 or 2 hours twice a week for 3 weeks of each 4 week (28 day) cycle

HR+ breast cancer

Patients 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 (SY-1365 + fulvestrant)

Group Type: EXPERIMENTAL

Fulvestrant

Intervention Type: DRUG

Fulvestrant will be administered as an intramuscular (IM) dose of 500 mg every 2 weeks for the first 3 doses on Day 1 and Day 15 of the first 28-day cycle (Cycle 1), and on Day 1 of the second 28 day cycle (Cycle 2), and monthly thereafter starting on Day 1 of Cycle 3 (Part 2 only)

SY-1365 (Cohort 5)

Intervention Type: DRUG

In combination with fulvestrant, SY-1365 will be administered by intravenous infusion over 1 or 2 hours once a week for 3 weeks of each 4 week (28-day) cycle (Part 2 only)

Interventions

SY-1365 (Part 1)

Two dosing schedules will be evaluated in dose escalation and a dose(s)/schedule(s) will be determined for Part 2:

• Twice weekly: SY-1365 will be administered by intravenous infusion over 1 or 2 hours twice a week for 3 weeks of each 4 week (28 day) cycle.
• Weekly: SY-1365 will be administered by intravenous infusion over 1 or 2 hours once a week for 3 weeks of each 4 week (28 day) cycle.

Intervention Type: DRUG

Carboplatin

Carboplatin will be administered on Day 1 of each 3 week (21-day) cycle (Part 2 only)

Intervention Type: DRUG

Fulvestrant

Fulvestrant will be administered as an intramuscular (IM) dose of 500 mg every 2 weeks for the first 3 doses on Day 1 and Day 15 of the first 28-day cycle (Cycle 1), and on Day 1 of the second 28 day cycle (Cycle 2), and monthly thereafter starting on Day 1 of Cycle 3 (Part 2 only)

Intervention Type: DRUG

SY-1365 (Cohort 2)

In combination with carboplatin, SY-1365 will be administered by intravenous infusion over 1 or 2 hours for 2 weeks of each 3 week (21-day) cycle (Part 2 only)

Intervention Type: DRUG

SY-1365 (Cohort 5)

In combination with fulvestrant, SY-1365 will be administered by intravenous infusion over 1 or 2 hours once a week for 3 weeks of each 4 week (28-day) cycle (Part 2 only)

Intervention Type: DRUG

SY-1365 (Part 2 Single Agent)

SY-1365 will be administered by intravenous infusion over 1 or 2 hours twice a week for 3 weeks of each 4 week (28 day) cycle

Intervention Type: DRUG

Other Intervention Names

paraplatin; faslodex

Eligibility Criteria

Inclusion Criteria

• 18 years of age or older
• Disease status

• Part 1: any histologically-confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective
• Part 2, Cohorts 1 and 2, all patients must have a histologically-confirmed diagnosis of high grade serous ovarian cancer (including fallopian tube cancer and/or primary peritoneal cancer)
• Part 2, Cohort 1, patients must have received ≥ 3 prior treatment regimens for ovarian cancer including a platinum-based regimen. Patients whose ovarian cancer harbors a mutation in breast cancer gene (BRCA), either germline or somatic, must have been previously treated with a poly(ADP ribose) polymerase (PARP) inhibitor, or be considered unwilling or ineligible for treatment with a PARP inhibitor
• Part 2, Cohort 2, patients must have received ≥ 1 prior treatment regimen for ovarian cancer, at least 1 of which is a platinum-based regimen
• Part 2,Cohort 3, all patients must have a histologically-confirmed diagnosis of clear cell ovarian cancer and must have received ≥ 1 prior treatment regimen for clear cell ovarian cancer, at least 1 of which is a platinum-based regimen.
• Part 2, Cohort 4, any histologically-confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective. Must have accessible tumor tissue and be willing to undergo tumor tissue sampling (biopsies/aspirates) pre-, during, and post-treatment
• At least 1 measurable lesion by RECIST 1.1
• All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 or returned to baseline levels prior to enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Life expectancy > 3 months
• Absolute neutrophil count: ≥ 1.5 x 10^9/L
• Platelets: ≥ 100 x 10^9/L
• Hemoglobin: ≥ 9 g/dL
• Total bilirubin ≤ 1.5 x institutional upper limit of normal [ULN]
• AST (SGOT)/ ALT (SGPT): ≤ 3.0 x institutional ULN
• Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance ≥ 60 mL/min by Crockoft-Gault for participants with creatinine levels above institutional normal
• Negative serum pregnancy test for women of child bearing potential

Exclusion Criteria

• Chemotherapy or limited field radiotherapy within 2 weeks, wide field radiotherapy within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks prior to entering the study
• Major surgery within 2 weeks of 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 prior to enrollment, or < 5 half-lives since completion of previous investigational therapy, whichever is shorter
• Received previous non-cytotoxic, FDA-approved anticancer agent within previous 2 weeks, or < 5 half-lives since completion of previous therapy, whichever is shorter
• Prior exposure to transcriptional kinase family CDK inhibitors, such as the CDK7 and CDK9 inhibitors alvocidib (Flavopiridol), dinaciclib, and seliciclib. Exception: previous exposure to cell cycle CDK inhibitors such as CDK4 and CDK6 (eg, palbociclib) is allowed
• Known brain metastases or carcinomatous meningitis. Exception: previously treated brain metastatic disease that remains stable on MRI ≥ 4 weeks prior to enrollment without steroids or anti-epileptic medications
• History of allergic reactions attributed to compounds of similar chemical composition to SY-1365
• Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients
• Patients with known active Hepatitis B or Hepatitis C infection
• Prior treatment (< 2 weeks before start of SY-1365) with moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors
• Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms. NOTE: criterion does not apply to patients with a right or left bundle branch block (QTc interval)
• Significant cardiac risk, including: History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors
• Uncontrolled intercurrent illness

Part 2 Only:

• Cohorts 1 and 2: Patients with low-grade ovarian cancer (eg, low grade serous, mucinous carcinoma) are not eligible
• Cohort 2: Prior adverse reaction(s) to carboplatin or any medical condition that precludes re-treatment with carboplatin
• Cohort 5: More than 1 prior line of treatment with systemic chemotherapy for advanced/metastatic disease; Advanced/metastatic disease that is symptomatic and/or with visceral spread that are at risk of life-threatening complications in the short term; Contraindication to receiving fulvestrant OR any medical condition that requires a lower dose of fulvestrant at the initiation of therapy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Syros Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kate Madigan, MD

Role: STUDY_DIRECTOR

Syros Pharmaceuticals

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Honor Health Research Institute

Scottsdale, Arizona, United States

Palo Alto Medical Foundation Group

San Francisco, California, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Columbia University Medical Center

New York, New York, United States

Stephenson Cancer Center

Oklahoma City, Oklahoma, United States

Willamette Valley Cancer Institute and Research Center

Eugene, Oregon, United States

Women and Infants Hospital of Rhode Island

Providence, Rhode Island, United States

Tennessee Oncology

Nashville, Tennessee, United States

Texas Oncology

Austin, Texas, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Texas Oncology

Fort Worth, Texas, United States

South Texas Accelerated Research Therapeutics

San Antonio, Texas, United States

Hamilton Health Sciences

Hamilton, Ontario, Canada

McGill University Health Center

Montreal, Quebec, Canada

Centre Léon Bérard

Lyon, , France

Institut de Cancérologie de l'Ouest

Saint-Herblain, , France

Institut Gustave Roussy

Villejuif, , France

Countries

United States; Canada; France

References

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.

Reference Type: DERIVED

PMID: 32385714 (View on PubMed)

Other Identifiers

SY-1365-101

Identifier Type: -

Identifier Source: org_study_id