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A Phase 1 Study of SY-1365 in Adult Patients With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03134638
Recruitment Status : Recruiting
First Posted : May 1, 2017
Last Update Posted : January 8, 2019
Sponsor:
Information provided by (Responsible Party):
Syros Pharmaceuticals

Brief Summary:

This study will consist 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. Approximately 35 patients with advanced solid tumors will be enrolled into Part 1 of the study.

Following the identification of a recommended dose and regimen from Part 1, the study will enter 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.


Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Ovarian Cancer Breast Cancer Drug: SY-1365 Drug: Carboplatin Drug: Fulvestrant Phase 1

Detailed Description:

This study will consist 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. Approximately 35 patients may be enrolled into Part 1, with the ultimate number based on the safety (DLTs).

Following the identification of a recommended dose and regimen from Part 1, the study will enter 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 approximately 102 patients in 5 cohorts of 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 primary platinum refractory 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 + aromatase inhibitor treatment. SY-1365 + fulvestrant.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 137 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of SY-1365, a Selective CDK7 Inhibitor, in Adult Patients With Advanced Solid Tumors
Actual Study Start Date : May 12, 2017
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
Experimental: Dose Escalation
Dose escalation phase to explore maximum tolerated dose across two schedules. SY-1365 will be administered intravenously on two dosing schedules, weekly and twice-weekly for 3 weeks of each 4-week cycle
Drug: SY-1365

Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2.

Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle.

Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.


Experimental: Advanced Ovarian Cancer
Patients with ovarian cancer previously treated with ≥ 3 prior lines of therapy (SY-1365 single agent)
Drug: SY-1365

Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2.

Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle.

Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.


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

Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2.

Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle.

Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.


Drug: Carboplatin
Carboplatin will be administered on Day 1 of each 3-week (21-day) cycle.
Other Name: paraplatin

Experimental: Primary Platinum Refractory Ovarian Cancer
Patients with ovarian cancer considered primary platinum refractory (progression either during treatment or within 1 month after completion of a first-line platinum-based regimen) (SY-1365 single agent)
Drug: SY-1365

Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2.

Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle.

Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.


Experimental: Biopsy
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)
Drug: SY-1365

Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2.

Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle.

Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.


Experimental: 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 an aromatase inhibitor (SY-1365 + fulvestrant)
Drug: SY-1365

Two dosing schedules will be evaluated in dose escalation and a dose/schedule will be determined for part 2.

Twice weekly: SY-1365 will be administered by intravenous infusion over 1 hour twice a week for three weeks in each 28 day cycle.

Weekly: SY-1365 will be administered by intravenous infusion over 1 hour once a week for 3 weeks within each 28-day cycle. In combination with carboplatin SY-1365 will be dosed once a week for 2 weeks within each 21-day cycle.


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.
Other Name: faslodex




Primary Outcome Measures :
  1. First-cycle dose-limiting toxicities (DLTs) [ Time Frame: Within 1 year ]
  2. Maximum tolerated dose (MTD) [ Time Frame: Within 1 year ]
  3. Safety and tolerability of SY-1365 as a single agent and in combination with either carboplatin or fulvestrant [ Time Frame: Within 1 year ]
    Assessed by investigator reported type and frequency of Adverse Events and Serious Adverse Events


Secondary Outcome Measures :
  1. Evaluate the antitumor activity of SY-1365 in patients with ovarian cancer, breast cancer, and advanced solid tumors [ Time Frame: Up to 1 year ]
    Clinical activity of SY-1365 as measured by RECIST 1.1 response criteria including the Objective Response Rate (ORR) and duration of response (DoR)

  2. Peak plasma concentration (Cmax) [ Time Frame: Up to 4 months ]
  3. Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last) [ Time Frame: Up to 4 months ]
  4. Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-INF) [ Time Frame: Up to 4 months ]
  5. Terminal elimination half-life (t1/2) [ Time Frame: Up to 4 months ]
  6. Time of maximum observed plasma concentration (tmax) [ Time Frame: Up to 4 months ]
  7. Evaluate the PD effects of SY-1365 by measuring the CDK7 occupancy after SY-1365 administration in PBMCs and tumor tissue [ Time Frame: Up to 1 year ]


Information from the National Library of Medicine

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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:

  • 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 1-3, 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 OC 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, Must have received ≥ 1 prior treatment regimen for ovarian cancer, at least 1 of which is a platinum-based regimen
    • Part 2,Cohort 3, Must have received only 1 prior platinum-based regimen. Patient must have primary platinum refractory OC (defined as progression either while on initial treatment with the platinum-based therapy or within 1 month following the last dose of treatment)
    • 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- and post-treatment
    • Part 2, Cohort 5, Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer who have failed prior treatment with a CDK 4/6 inhibitor in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy.
  • 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 109/L
  • platelets: ≥ 100 x 109/L
  • hemoglobin: ≥ 9 g/dL
  • total bilirubin ≤ 1.5 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 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. See list in Appendix 3
  • Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms
  • Significant cardiac risk, including: History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors

Part 2 Only:

  • Cohorts 1, 2, and 3: Patients with low-grade ovarian cancer (eg, low grade serous, mucinous carcinoma) are not eligible
  • Cohort 2: Prior adverse reaction(s) to carboplatin
  • Cohort 5: Prior treatment with fulvestrant; Prior treatment with chemotherapy for advanced/metastatic disease; Any line(s) of therapy following treatment failure with a CDK 4/6 inhibitor in combination with an AI; Prior treatment with chemotherapy in the advanced/metastatic setting or with fulvestrant; Advanced/metastatic disease that is symptomatic and/or with visceral spread

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): NCT03134638


Contacts
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Contact: Amre I Khreim, BSc 617-674-9074 akhreim@syros.com

Locations
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United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35233
United States, Arizona
Scottsdale Healthcare Hospitals Recruiting
Scottsdale, Arizona, United States, 85258
United States, California
Palo Alto Medical Foundation Group Recruiting
San Francisco, California, United States, 94118
United States, Illinois
University of Chicago Medical Center Not yet recruiting
Chicago, Illinois, United States, 60637
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
United States, Oklahoma
Stephenson Cancer Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
United States, Rhode Island
Women and Infants Hospital of Rhode Island Recruiting
Providence, Rhode Island, United States, 02905
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
South Texas Accelerated Research Therapeutics Recruiting
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Syros Pharmaceuticals
Investigators
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Study Director: David A Roth, MD Syros Pharmaceuticals

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Responsible Party: Syros Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03134638     History of Changes
Other Study ID Numbers: SY-1365-101
First Posted: May 1, 2017    Key Record Dates
Last Update Posted: January 8, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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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Carboplatin
Fulvestrant
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs