Clinical Trials /

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

NCT03134638

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Ovarian Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Study of SY-1365 in Adult Patients With Advanced Solid Tumors
  • Official Title: A Phase 1 Study of SY-1365, a Selective CDK7 Inhibitor, in Adult Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: SY-1365-101
  • NCT ID: NCT03134638

Conditions

  • Advanced Solid Tumors
  • Ovarian Cancer
  • Breast Cancer

Interventions

DrugSynonymsArms
SY-1365Dose Escalation
CarboplatinparaplatinRelapsed Ovarian Cancer
FulvestrantfaslodexHR+ breast cancer

Purpose

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.

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).
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalDose 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
  • SY-1365
Advanced Ovarian CancerExperimentalPatients with ovarian cancer previously treated with ≥ 3 prior lines of therapy (SY-1365 single agent)
  • SY-1365
Relapsed Ovarian CancerExperimentalPatients with ovarian cancer previously treated with ≥ 1 prior line of therapy including a platinum-based regimen (SY-1365 + carboplatin)
  • SY-1365
  • Carboplatin
Primary Platinum Refractory Ovarian CancerExperimentalPatients 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)
  • SY-1365
BiopsyExperimentalBiopsy cohort of approximately 20-30 patients with advanced solid tumors from whom pre- and post-treatment biopsies will be obtained (SY-1365 single agent)
  • SY-1365
HR+ breast cancerExperimentalPatients 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)
  • SY-1365
  • Fulvestrant

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 1-3, 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:First-cycle dose-limiting toxicities (DLTs)
Time Frame:Within 1 year
Safety Issue:
Description:Assessed by investigator reported type and frequency of Adverse Events and Serious Adverse Events

Secondary Outcome Measures

Measure:Evaluate the antitumor activity of SY-1365 in patients with ovarian cancer, breast cancer, and advanced solid tumors
Time Frame:Up to 1 year
Safety Issue:
Description:Clinical activity of SY-1365 as measured by RECIST 1.1 response criteria including the Objective Response Rate (ORR) and duration of response (DoR)
Measure:Peak plasma concentration (Cmax)
Time Frame:Up to 4 months
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-last)
Time Frame:Up to 4 months
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-INF)
Time Frame:Up to 4 months
Safety Issue:
Description:
Measure:Terminal elimination half-life (t1/2)
Time Frame:Up to 4 months
Safety Issue:
Description:
Measure:Time of maximum observed plasma concentration (tmax)
Time Frame:Up to 4 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Syros Pharmaceuticals

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