Clinical Trials /

A Phase 1/2 Trial of SRA737 in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer

NCT02797977

Description:

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose (RP2D) and schedule of SRA737 in combination with low dose gemcitabine; and to evaluate the efficacy of SRA737 in combination with low dose gemcitabine in prospectively-selected subjects with genetically-defined tumors that have predicted sensitivity to Chk1 inhibition based on factors including: genetic profiling of tumor tissue or ctDNA, HPV status, and germline BRCA1 and BRCA2 gene status. Specific cancer indications that frequently feature these factors will be studied. Preclinical and clinical data support the hypothesis that active doses of SRA737 may be strongly potentiated by sub-therapeutic doses of gemcitabine, which should lead to clinical efficacy. To test this hypothesis, SRA737 in combination with low dose gemcitabine is being explored in this study.

Related Conditions:
  • Anal Carcinoma
  • Cervical Carcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Malignant Solid Tumor
  • Penile Carcinoma
  • Soft Tissue Sarcoma
  • Vaginal Carcinoma
  • Vulvar Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1/2 Trial of SRA737 in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer
  • Official Title: A Phase 1/2 Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer

Clinical Trial IDs

  • ORG STUDY ID: SRA737-02
  • NCT ID: NCT02797977

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
SRA737, gemcitabine, cisplatinStandard-Dose Triplet Combination
SRA737, gemcitabineLow-Dose Gemcitabine Combination

Purpose

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose (RP2D) and schedule of SRA737 in combination with low dose gemcitabine; and to evaluate the efficacy of SRA737 in combination with low dose gemcitabine in prospectively-selected subjects with genetically-defined tumors that have predicted sensitivity to Chk1 inhibition based on factors including: genetic profiling of tumor tissue or ctDNA, HPV status, and germline BRCA1 and BRCA2 gene status. Specific cancer indications that frequently feature these factors will be studied. Preclinical and clinical data support the hypothesis that active doses of SRA737 may be strongly potentiated by sub-therapeutic doses of gemcitabine, which should lead to clinical efficacy. To test this hypothesis, SRA737 in combination with low dose gemcitabine is being explored in this study.

Detailed Description

      SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a
      key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress
      response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as
      oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g., BRCA1 or
      FA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other
      genomic alterations. This replication stress results in persistent DNA damage and genomic
      instability leading to an increased dependency on Chk1 for survival. Targeted inhibition of
      Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic
      RS.

      The critical role of Chk1 in mediating cellular responses to RS affords the opportunity to
      combine SRA737 with sub-therapeutic concentrations of the RS-inducing agent gemcitabine. Low
      concentrations of gemcitabine cause a prolonged cell cycle S-phase and induce hallmarks of RS
      without inducing overt cytotoxicity. Gemcitabine profoundly depletes DNA replication building
      blocks and targets proliferating cells by inducing RS through induction of stalled
      replication forks. In response, Chk1 has an important role in stabilizing and preserving
      replication fork complexes in the context of RS, preventing catastrophic replication fork
      collapse and double strand breaks. Extensive preclinical data, as well as clinical data,
      support the synergistic interaction between Chk1 inhibition and gemcitabine.

      The purpose of this clinical study is to: establish the safety profile, determine the MTD,
      and propose a RP2D and schedule for SRA737 in combination with low dose gemcitabine. In
      addition, the study aims to evaluate the preliminary efficacy of SRA737 in combination with
      low dose gemcitabine in prospectively-selected subjects with tumors that have predicted
      sensitivity to Chk1 inhibition.

      This clinical study consists of three phases:

        1. A Standard-Dose Triplet Combo Dose Escalation Phase 1. This phase, which has concluded,
           evaluated a triplet combination of SRA737 with standard-dose gemcitabine and cisplatin
           in subjects with solid tumors.

        2. A Low-Dose Gemcitabine Combo Dose Escalation Phase 1. Cohorts of 3 to 6 subjects are
           being given escalating doses of SRA737 on an intermittent schedule in addition to low
           dose gemcitabine until the combination MTD is reached. The dose or frequency of
           gemcitabine may also be reduced during this process and alternative dosing schedules for
           SRA737 may be considered. When the MTD or a minimum efficacious dose range has been
           achieved for SRA737, or when evidence of anti-tumor activity is observed, the
           gemcitabine dose may be escalated with corresponding decreases in the SRA737 dose as
           necessary for safety.

        3. A Low-Dose Gemcitabine Combo Cohort Expansion Phase 2. After the MTD and/or RP2D has
           been identified, the trial will explore the preliminary efficacy of SRA737 plus low dose
           gemcitabine in prospectively-selected subjects with tumors that harbor genomic
           alterations linked to increased replication stress and that are hypothesized to be more
           sensitive to Chk1 inhibition via synthetic lethality. Enrollment for expansion cohorts
           may alternatively begin prior to the completion of dose escalation and determination of
           MTD or RP2D, if there is evidence of anti-tumor activity or if the minimal plasma
           concentration of SRA737 is maintained above a threshold at which sustained Chk1
           inhibition is anticipated at 24 hours after dosing.

      This phase is targeting enrollment of genetically-selected patients into four expansion
      cohorts from specific indications that are predicted to have a high prevalence of such
      alterations, including locally advanced or metastatic:

        -  high-grade serous ovarian cancer (HGSOC),

        -  small cell lung cancer (SCLC);

        -  soft tissue sarcoma (STS); and

        -  cervical/anogenital cancer.

      To qualify for enrolment into these cohorts, the subject's tumor must have evidence of
      predicted sensitivity to Chk1 inhibition based on factors including:

        -  For subjects with HGSOC, documented somatic or germline BRCA1 and BRCA2 wild-type status
           will confer eligibility without requirement for prospective genetic profiling. If
           documented BRCA status is not available, genetic profiling may be performed
           prospectively to determine eligibility.

        -  Subjects with SCLC are eligible without requirement for prospective genetic profiling on
           the basis of very high prevalence of cancer related alterations in the tumor suppressor
           genes (eg, TP53 and RB1) in this population.

        -  For subjects with STS, and any others for whom genetic profiling is performed
           prospectively, eligibility will be determined by the sponsor's review of genetic
           abnormalities detected in genes in the following categories:

             -  Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RB1,
                TP53, etc.

             -  The DNA damage response pathway including ATM, BRCA1, BRCA2, mismatch repair
                genetic alterations and/or high microsatellite instability.

             -  Genetic indicators of replicative stress such as gain of function/amplification of
                Chk1 or ATR or other related gene.

             -  Oncogenic drivers such as MYC, CCNE1, etc.

        -  For subjects with anogenital cancer, known HPV positive status will confer eligibility
           without requirement for prospective genetic profiling. If HPV status is not known or not
           positive, genetic profiling (or HPV testing where appropriate) may be performed
           prospectively to determine eligibility. Subjects with cervical cancer or squamous cell
           carcinoma of the anus are eligible without requirement for prospective genetic profiling
           based on the very high prevalence of HPV positivity in these populations.

      Tumor genetics will be determine using Next-Generation Sequencing.
    

Trial Arms

NameTypeDescriptionInterventions
Standard-Dose Triplet CombinationExperimentalSRA737 will be administered orally on Days 2, 3, 9, and 10 of each 21-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Gemcitabine will be administered intravenously on Days 1 and 8 of each 21-day cycle. Cisplatin will be administered on Day 1 of each 21-day cycle. Subjects can continue taking the study treatment if they are safely receiving clinical benefit and able to follow the requirements of the study.
  • SRA737, gemcitabine, cisplatin
Low-Dose Gemcitabine CombinationExperimentalSRA737 will be administered orally on Days 2, 3, 9, 10, 16, and 17 of each 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle. Gemcitabine will be administered intravenously on Days 1, 8, and 15 of each 28-day cycle. Subjects can continue taking the study treatment if they are safely receiving clinical benefit and able to follow the requirements of the study.
  • SRA737, gemcitabine

Eligibility Criteria

        Key Inclusion Criteria:

          1. For Dose Escalation: subjects with locally advanced or metastatic, histologically or
             cytologically proven solid tumor, relapsed after or progressing despite conventional
             treatment

          2. Life expectancy of at least 12 weeks

          3. World Health Organization (WHO) performance status of 0-1

          4. Must meet select hematological and biochemical laboratory indices

          5. Archival tumor tissue or accessible tumor and willingness to consent to a biopsy

        Expansion Only:

          1. Histologically or cytologically proven advanced malignancy of the following types, for
             which no other conventional therapy is considered appropriate:

               -  High-grade serous ovarian cancer (HGSOC)

               -  Small cell lung cancer

               -  Soft tissue sarcoma

               -  Cervical/anogenital cancer

          2. Measurable disease per RECIST v1.1

          3. Subjects must have predicted sensitivity to Chk1 inhibition based on factors
             including: genetic profiling of tumor tissue or ctDNA, HPV status, and germline BRCA1
             and BRCA2 gene status. All subjects will have genetic profiling from tumor tissue or
             ctDNA; profiling will be performed prospectively if required to evaluate Chk1
             sensitivity or otherwise performed retrospectively.

               1. For subjects with HGSOC, documented somatic or germline BRCA1 and BRCA2 wild-type
                  status will confer eligibility without requirement for prospective genetic
                  profiling. If documented BRCA status is not available, genetic profiling may be
                  performed prospectively to determine eligibility.

               2. Subjects with SCLC are eligible without requirement for prospective genetic
                  profiling on the basis of very high prevalence of cancer related alterations in
                  the tumor suppressor genes (eg, TP53 and RB1) in this population.

               3. For subjects with STS, and any others for whom genetic profiling is performed
                  prospectively, eligibility will be determined by the sponsor's review of genetic
                  abnormalities detected in genes in the following categories:

                  Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as
                  RB1, TP53, etc. For relevant cancers, positive human papilloma virus (HPV) status
                  is also considered for eligibility.

                    -  The DNA damage response pathway including ATM, BRCA1, BRCA2, mismatch repair
                       genetic alterations and/or high microsatellite instability.

                    -  Genetic indicators of replicative stress such as gain of
                       function/amplification of Chk1 or ATR or other related gene.

                    -  Oncogenic drivers such as MYC, CCNE1, etc.

               4. For subjects with anogenital cancer, known HPV positive status will confer
                  eligibility without requirement for prospective genetic profiling. If HPV status
                  is not known or not positive, genetic profiling (or HPV testing where
                  appropriate) may be performed prospectively to determine eligibility. Subjects
                  with cervical cancer or squamous cell carcinoma of the anus are eligible without
                  requirement for prospective genetic profiling based on the very high prevalence
                  of HPV positivity in these populations.

        Key Exclusion Criteria:

          1. Received the following prior or current anticancer therapy in the timeframes noted
             prior to receiving SRA737 and have recovered from toxicity:

               1. Radiotherapy, chemotherapy, PARP inhibitors, other targeted therapies, or other
                  IMPs within 2 weeks

               2. Nitrosoureas or Mitomycin C within 6 weeks

               3. Any prior treatment with a Chk1 inhibitor at any point or prior treatment with an
                  ATR inhibitor within 6 months

          2. No more than 3 previous treatment regimens for advanced disease (not applicable to
             HGSOC expansion cohort)

          3. Other malignancy within the past 2 years, except for adequately treated tumors

          4. If, in the opinion of the Investigator, the subject is highly likely to experience
             clinically significant myelosuppression

          5. Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1

          6. History of allergy to gemcitabine

          7. New or progressing brain metastases. Subjects with brain metastases that have been
             asymptomatic and radiologically stable over an 8-week period and have not been treated
             with steroids during that time may be included with approval from the sponsor.

          8. High medical risk because of nonmalignant systemic disease

          9. Serologically positive for hepatitis B, hepatitis C or HIV

         10. Serious cardiac condition, left ventricular ejection fraction < 45% at baseline,
             history of cardiac ischemia within the past 6 months, or prior history of cardiac
             arrhythmia requiring treatment, unless approved by the sponsor.

         11. Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone
             marrow within the previous 8 weeks

         12. Peanut allergy

         13. QTcF > 450 msec in adult makes and > 470 msec in adult females

         14. Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of SRA737

         15. Inability to swallow capsules without chewing or crushing

         16. Is a participant or plans to participate in another interventional clinical trial

         17. Any other condition which in the Investigator's opinion would not make the subject a
             good candidate
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of subjects with adverse events as assessed by CTCAE4.03
Time Frame:Up to 30 days after last dose of SRA737
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sierra Oncology, Inc.

Trial Keywords

  • Replication Stress
  • Advanced solid tumors
  • CCNE1
  • TP53
  • BRCA1
  • BRCA2
  • MYC
  • RAD50
  • Fanconi anemia
  • Cell Cycle
  • High grade serious ovarian cancer
  • Small cell lung cancer
  • Soft tissue sarcoma
  • Cervical/anogenital cancer
  • Phase 1
  • Phase 2
  • Dose escalation
  • Chk1 inhibitor
  • Checkpoint Kinase 1
  • Synthetic lethality
  • Next-Generation Sequencing
  • Genetic biomarkers

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