Clinical Trials /

A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer

NCT02797964

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 and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

Related Conditions:
  • Colorectal Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer
  • Official Title: A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer

Clinical Trial IDs

  • ORG STUDY ID: SRA737-01
  • NCT ID: NCT02797964

Conditions

  • Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL)

Interventions

DrugSynonymsArms
SRA737Open label

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 and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

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
      FANCA), 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.

      This study has been designed to: establish the safety profile; determine the pharmacokinetic
      profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of
      activity; and evaluate SRA737's efficacy 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.

      This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort
      Expansion Phase 2 portion.

      In the Dose Escalation Phase 1 portion, cohorts consisting initially of a single subject will
      receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule
      in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation
      cohort during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose
      level cohorts will follow a rolling 6 design until the MTD has been identified.

      In the Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor
      genomic alterations linked to increased replication stress and that are hypothesized to be
      more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific
      cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or
      metastatic disease of one of the following types:

        -  castration-resistant prostate cancer (mCRPC);

        -  high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification;

        -  HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar
           functional effect);

        -  non-small cell lung cancer (NSCLC);

        -  head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus
           (SCCA); and

        -  colorectal cancer (mCRC).

      To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must
      have a confirmed combination of mutations which are expected to confer sensitivity to Chk1
      inhibition, determined by the Sponsor's review of genetic abnormalities detected in the
      following categories:

        -  Oncogenic drivers such as CCNE1 or MYC, etc.

        -  Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch
           repair (MMR) genetic alterations and/or high microsatellite instability.

        -  Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53,
           RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status
           is also considered for eligibility.

        -  Genetic indicators of replicative stress such as gain of function/amplification of
           CHEK1, ATR or other related genes.

      Tumor genetics will be prospectively determined using Next-Generation Sequencing.
    

Trial Arms

NameTypeDescriptionInterventions
Open labelExperimental
  • SRA737

Eligibility Criteria

        Key Inclusion Criteria:

          1. For Dose Escalation Only: any locally advanced or metastatic, histologically or
             cytologically proven solid tumor or NHL, 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. Any locally advanced or metastatic malignancy of the following types for which no
             other conventional therapy is considered appropriate:

               -  Metastatic Colorectal Cancer (CRC)

               -  Platinum-resistant or intolerant High Grade Serious Ovarian Cancer (HGSOC)

               -  Advanced Non-Small Cell Lung Cancer (NSCLC)

               -  Metastatic Castration-Resistant Prostate Cancer (mCRPC)

               -  Head and Neck Squamous Cell Carcinoma (HNSCC) or squamous cell carcinoma of the
                  anus (SCCA).

               -  Eligibility may be further restricted by the select number of prior regimens
                  specific to each indication

          2. Measurable disease per RECIST v1.1, or for mCRPC, evaluable disease per any of the
             following:

               -  Measurable disease per RECIST v1.1

               -  Increasing PSA

               -  Circulating tumor cell (CTC) count of 5 or more cells per 7.5 ml of blood

          3. Tumor tissue or ctDNA evidence that subject's tumor harbors a combination of mutations
             which are expected to confer sensitivity to Chk1 inhibition. Eligibility will be
             determined by the Sponsor's review of genetic abnormalities detected in genes in the
             following categories:

               -  Oncogenic drivers such as MYC, CCNE1, etc.

               -  Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as
                  RAD50, TP53, etc. For patients with NHSCC or SCCA, positive HPV status is also
                  considered for eligibility.

               -  The DDR pathway including BRCA1, BRCA2 and FANC. For patients with CRC, MMR
                  genetic alterations and/or high microsatellite instability are also considered
                  for eligibility.

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

        Key Exclusion Criteria:

          1. Received the following prior or current anticancer therapy:

               -  Radiotherapy within the last 6 weeks

               -  Endocrine therapy during the previous 4 weeks

               -  Chemotherapy during the previous 4 weeks

               -  Immunotherapy during the previous 6 weeks

               -  Nitrosoureas or Mitomycin C during the previous 6 weeks

               -  Other Investigational Medicinal Product during the 4 weeks before treatment

               -  Any prior treatment with a Chk1 inhibitor or prior treatment with an ATR
                  inhibitor within 6 months prior to receiving SRA737

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

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

          4. For Dose Escalation: new or progressing brain metastases. For Cohort Expansion:
             present or prior brain metastases

          5. High medical risk because of nonmalignant systemic disease

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

          7. 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

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

          9. Peanut allergy

         10. QTcF> 450 msec in adult males and > 470 msec in adult females

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

         12. Inability to swallow capsules without chewing or crushing

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

         14. 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 CTCAE 4.03
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:Active, not recruiting
Lead Sponsor:Sierra Oncology, Inc.

Trial Keywords

  • Replication stress
  • Advanced solid tumors
  • CCNE1
  • TP53
  • BRCA1
  • BRCA2
  • MYC
  • RAD50
  • Fanconi anemia
  • Cell cycle
  • Metastatic Colorectal Cancer
  • Platinum-Resistant or Intolerant High Grade Serious Ovarian Cancer
  • Advanced Non-Small Cell Lung Cancer
  • Metastatic Castration-Resistant Prostate Cancer
  • Head and Neck Squamous Cell Carcinoma
  • Squamous Cell Carcinoma of the Anus
  • Phase 1
  • Phase 2
  • Dose escalation
  • Chk1 inhibitor
  • Checkpoint kinase 1
  • Synthetic lethality
  • Next-Generation Sequencing
  • Genetic biomarkers

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