Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL) Clinical Trial
Official title:
A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer
| Verified date | June 2023 |
| Source | Sierra Oncology LLC - a GSK company |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 107 |
| Est. completion date | October 28, 2019 |
| Est. primary completion date | October 28, 2019 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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 |
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | The Clatterbridge Cancer Centre | Bebington | Wirral |
| United Kingdom | Belfast City Hospital | Belfast | Northern Ireland |
| United Kingdom | Velindre Cancer Centre - Cardiff | Cardiff | Whitchurch |
| United Kingdom | Western General Hospital | Edinburgh | |
| United Kingdom | The Beatson West of Scotland Cancer Centre | Glasgow | |
| United Kingdom | Oxford University Hospitals | Headington | Oxford |
| United Kingdom | The Leeds Teaching Hospitals of St James University Hospital | Leeds | |
| United Kingdom | University Hospitals of Leicester | Leicester | |
| United Kingdom | Guy's and St. Thomas | London | |
| United Kingdom | Sarah Cannon Research Institute | London | |
| United Kingdom | University College London Hospitals | London | |
| United Kingdom | The Christie | Manchester | |
| United Kingdom | Freeman Hospital | Newcastle upon Tyne | |
| United Kingdom | Sheffield Teaching Hospitals | Sheffield | |
| United Kingdom | Royal Marsden Hospital | Sutton | London |
| Lead Sponsor | Collaborator |
|---|---|
| Sierra Oncology LLC - a GSK company |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Number of Subjects With Adverse Events as Assessed by CTCAE 4.03 | Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first. | Up to 30 days after last dose of SRA737 | |
| Primary | Maximum Tolerated Dose of SRA737 | The highest dose at which = 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects. | Cycle 1 (28 days) in the Dose Escalation Phase | |
| Primary | Recommended Phase 2 Dose of SRA737 | The RP2D and schedule were defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account. The RP2D was to be a dose equal to or less than the MTD for the selected schedule. | Up to 30 days after last dose of SRA737 | |
| Primary | Disease Control Rate (DCR) of SRA737 | The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD. | Radiographic tumor assessments were performed every 2 cycles of therapy. | |
| Primary | Time to Progression (TTP) | Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K-M method. | Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy. | |
| Primary | Progression Free Survival (PFS) | Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. Censoring rules are defined in the SAP. PFS was analyzed using the K-M method. | Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy. | |
| Primary | Overall Survival (OS) | Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K-M method. | Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy. |