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

NCT02797964 | Completed Phase 1 Results

• 1 other identifier: SRA737-01
• Study Type: interventional
• Target: 107
• Locations: 1 country
• Sites: 15

Brief Summary

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.

Conditions

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

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

Outcome Measures

Primary Outcomes (7)

• 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

• 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

• 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

• 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.

• 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.

• 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.

• 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.

Study Arms (1)

Open label

EXPERIMENTAL

Drug: SRA737

Interventions

SRA737 DRUG

SRA737 will be administered orally on each day of a 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.

Open label

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For Dose Escalation Only: any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, 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
• Expansion Only:
• 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
• Measurable disease per RECIST v1.1, or for mCRPC, evaluable disease per any of the following:
• Measurable disease per RECIST v1.1

You may not qualify if:

• 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
• Other malignancy within the past 2 years, except for adequately treated tumors
• Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1
• For Dose Escalation: new or progressing brain metastases. For Cohort Expansion: present or prior brain metastases
• 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
• Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within 8 weeks

Sponsors & Collaborators

• Sierra Oncology LLC - a GSK company: lead

Study Sites (15)

Royal Marsden Hospital

Sutton, London, SM2 5PT, United Kingdom

Location

Belfast City Hospital

Belfast, Northern Ireland, BT9 7AB, United Kingdom

Location

Oxford University Hospitals

Headington, Oxford, OX3 7LE, United Kingdom

Location

Velindre Cancer Centre - Cardiff

Cardiff, Whitchurch, CF14 2TL, United Kingdom

Location

The Clatterbridge Cancer Centre

Bebington, Wirral, CH63 4JY, United Kingdom

Location

Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

Location

The Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

The Leeds Teaching Hospitals of St James University Hospital

Leeds, LS9 7TF, United Kingdom

Location

University Hospitals of Leicester

Leicester, LE1 5WW, United Kingdom

Location

Guy's and St. Thomas

London, SE1 9RT, United Kingdom

Location

Sarah Cannon Research Institute

London, W1G 6AD, United Kingdom

Location

University College London Hospitals

London, W1T 7HA, United Kingdom

Location

The Christie

Manchester, M20 4BX, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Sheffield Teaching Hospitals

Sheffield, S10 2SJ, United Kingdom

Location

Related Publications (2)

• Kristeleit R, Plummer R, Jones R, Carter L, Blagden S, Sarker D, Arkenau T, Evans TRJ, Danson S, Symeonides SN, Veal GJ, Klencke BJ, Kowalski MM, Banerji U. A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. Br J Cancer. 2023 Jul;129(1):38-45. doi: 10.1038/s41416-023-02279-x. Epub 2023 Apr 29.

  PMID: 37120671 DERIVED

• Jin T, Xu L, Wang P, Hu X, Zhang R, Wu Z, Du W, Kan W, Li K, Wang C, Zhou Y, Li J, Liu T. Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile. J Med Chem. 2021 Oct 28;64(20):15069-15090. doi: 10.1021/acs.jmedchem.1c00994. Epub 2021 Oct 19.

  PMID: 34665631 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Fanconi Anemia; Colorectal Neoplasms; Squamous Cell Carcinoma of Head and Neck; Anus Neoplasms

Interventions

SRA737

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Hematologic Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Rectal Neoplasms; Anus Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2016
• First Posted: June 14, 2016
• Study Start: July 1, 2016
• Primary Completion: October 28, 2019
• Study Completion: October 28, 2019
• Last Updated: June 18, 2023
• Results First Posted: March 10, 2022

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (15)