A Phase 1/2 Trial of SRA737 in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer
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|ClinicalTrials.gov Identifier: NCT02797977|
Recruitment Status : Completed
First Posted : June 14, 2016
Last Update Posted : September 25, 2020
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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.
|Condition or disease||Intervention/treatment||Phase|
|Advanced Solid Tumors||Drug: SRA737, gemcitabine, cisplatin Drug: SRA737, gemcitabine||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||153 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||July 2016|
|Actual Primary Completion Date :||April 8, 2020|
|Actual Study Completion Date :||April 8, 2020|
Experimental: Standard-Dose Triplet Combination
SRA737 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.
Drug: SRA737, gemcitabine, cisplatin
Experimental: Low-Dose Gemcitabine Combination
SRA737 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.
Drug: SRA737, gemcitabine
- Number of subjects with adverse events as assessed by CTCAE4.03 [ Time Frame: Up to 30 days after last dose of SRA737 ]
- Maximum tolerated dose of SRA737 administered in combination with gemcitabine [ Time Frame: Cycle 1 (28 days) in the Dose Escalation Phase ]
- Recommended Phase 2 dose of SRA737 in combination with gemcitabine. [ Time Frame: Up to 30 days after last dose of SRA737 ]
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Key Inclusion Criteria:
- For Dose Escalation: subjects with locally advanced or metastatic, histologically or cytologically proven solid tumor, relapsed after or progressing despite conventional treatment
- Life expectancy of at least 12 weeks
- World Health Organization (WHO) performance status of 0-1
- Must meet select hematological and biochemical laboratory indices
- Archival tumor tissue or accessible tumor and willingness to consent to a biopsy
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
- Measurable disease per RECIST v1.1
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.
- 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. 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.
- 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:
Received the following prior or current anticancer therapy in the timeframes noted prior to receiving SRA737 and have recovered from toxicity:
- Radiotherapy, chemotherapy, PARP inhibitors, other targeted therapies, or other IMPs within 2 weeks
- Nitrosoureas or Mitomycin C within 6 weeks
- Any prior treatment with a Chk1 inhibitor at any point or prior treatment with an ATR inhibitor within 6 months
- No more than 3 previous treatment regimens for advanced disease (not applicable to HGSOC expansion cohort)
- Other malignancy within the past 2 years, except for adequately treated tumors
- If, in the opinion of the Investigator, the subject is highly likely to experience clinically significant myelosuppression
- Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1
- History of allergy to gemcitabine
- 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.
- High medical risk because of nonmalignant systemic disease
- Serologically positive for hepatitis B, hepatitis C or HIV
- 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.
- Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within the previous 8 weeks
- Peanut allergy
- QTcF > 450 msec in adult makes and > 470 msec in adult females
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of SRA737
- Inability to swallow capsules without chewing or crushing
- Is a participant or plans to participate in another interventional clinical trial
- Any other condition which in the Investigator's opinion would not make the subject a good candidate
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): NCT02797977
|Responsible Party:||Sierra Oncology, Inc.|
|Other Study ID Numbers:||
|First Posted:||June 14, 2016 Key Record Dates|
|Last Update Posted:||September 25, 2020|
|Last Verified:||September 2020|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
Advanced solid tumors
High grade serious ovarian cancer
Small cell lung cancer
Soft tissue sarcoma
Checkpoint Kinase 1
Molecular Mechanisms of Pharmacological Action