Advanced Gastrointestinal Stromal Tumors, Metastatic Cancer
Conditions
Keywords
Sunitinib, Solid Tumors, Gastrointestinal Stromal Tumors, Gastrointestinal, KIT, Kinase Inhibitors, Growth Inhibitors, CGT9486, Unresectable, Metastatic, GIST, Bezuclastinib, PLX9486, Midazolam, Drug-drug interaction
Brief summary
This is a Phase 3, open-label, international, multicenter study of CGT9486 in combination with sunitinib. This is a multi-part study that will enroll approximately 482 patients. Part 1 consists of two evaluations: 1) confirming the dose of an updated formulation of CGT9486 to be used in subsequent parts in approximately 20 patients who have received at least one prior line of therapy for GIST and 2) evaluating the potential for drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who have received at least two prior tyrosine kinase inhibitors (TKIs) for GISTs. The second part of the study will enroll approximately 388 patients who are intolerant to, or who failed prior treatment with imatinib only and will compare the efficacy of CGT9486 plus sunitinib to sunitinib alone with patients being randomized in a 1:1 manner. This study also contains two substudies: 1) a drug-drug interactions substudy will investigate the potential for CGT9486 to be a CYP3A4 inducer in approximately 16 patients who have received at least one prior line of therapy for GIST and 2) a substudy intended to test the efficacy of bezuclastinib and sunitinib as first-line treatment of GIST in approximately 40 participants with KIT exon 9 mutations and no prior systemic therapy (with the exception of up to 10 subjects with ongoing imatinib therapy of ≤4 weeks).
Interventions
DRUGCGT9486 plus sunitinib
Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.
DRUGCGT9486
Participants will receive CGT9486 until steady state then both CGT9486 and sunitinib orally until study stopping rules are met.
DRUGSunitinib
Participants will receive sunitinib until steady state then both sunitinib and CGT9486 orally until study stopping rules are met.
DRUGMidazolam
Participants will receive a single-dose of midazolam on Day 1 and Day 16
Sponsors
Cogent Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a multi-part study: Part 1a is a single-arm design, Part 1b is a two-arm parallel design drug-drug interaction evaluation in the first treatment cycle and single-arm design in subsequent treatment cycles, and Part 2 is a randomized two-arm parallel comparator study. The DDI substudy is a single-arm, fixed-sequence, crossover design to investigate the potential for CGT9486 to be a CYP3A4 inducer. The GIST 1L substudy is a single-arm study of bezuclastinib+sunitinib exploring efficacy in a 1L setting.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Histologically confirmed locally advanced, metastatic, and/or unresectable GIST. Molecular pathology report must be available for Part 2; if molecular pathology report is unavailable or inadequate, an archival or fresh tumor tissue sample will be required to evaluate mutational status prior to randomization. (GIST 1L Substudy: must have documented mutation in KIT Exon 9 with an available molecular pathology report; archival or fresh tumor tissue sample will be required) 2. Documented disease progression on or intolerance to imatinib (Part 1a, Part 1b, Part 2, DDI Substudy) 3. Subjects must have received the following treatment: * DDI Substudy/Part 1a: Treatment with ≥1 prior lines of therapy for GIST * Part 1b: Treatment with ≥2 prior TKI for GISTs * Part 2: Prior treatment with imatinib only * GIST 1L Substudy: No prior systemic therapy for GIST including adjuvant therapy. Exception: up to 10 subjects with ongoing imatinib therapy of ≤4 weeks 4. Have at least 1 measurable lesion according to mRECIST v1.1 (Part1a, Part 1b, Part 2, GIST 1L Substudy) 5. ECOG * 0 to 2 (Part 1a, Part 1b, Part 2, DDI Substudy) * 0 to 1 (GIST 1L Substudy) 6. Have clinically acceptable local laboratory screening results (clinical chemistry and hematology) within certain limits Key
Exclusion criteria
1. Known PDGFR driving mutations or known succinate dehydrogenase deficiency (Part 1a, Part 1b, Part 2, DDI Substudy) 2. Clinically significant cardiac disease 3. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug (Part 1a, Part 1b, Part 2, DDI Substudy) 4. Gastrointestinal abnormalities including, but not limited to, significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption 5. Any active bleeding excluding hemorrhoidal or gum bleeding 6. Seropositive for HIV 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody. 7. Active, uncontrolled, systemic bacterial, fungal, or viral infections at Screening 8. Received strong CYP3A4 inhibitors or inducers (Part 1a, Part 1b, Part 2, DDI Substudy) 9. Received sunitinib within 3 weeks (Part 1a, Part 1b, DDI Substudy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1a - pharmacokinetics - Cmax | 16 days | Maximum plasma concentration (Cmax) |
| Part 1a - pharmacokinetics - AUC | 16 days | Area under the plasma concentration-time curve (AUC) |
| Part 1b - pharmacokinetics - Cmax | 14 days | Maximum plasma concentration (Cmax) |
| Part 1b - pharmacokinetics - AUC | 14 days | Area under the plasma concentration-time curve (AUC) |
| Part 1b - pharmacokinetics - Tmax | 14 days | Time to maximum observed plasma concentration (Tmax) |
| Part 2 - Progression Free Survival (PFS) | Approximately 48 months | Time from first dose to documented disease progression or death due to any cause, whichever occurs first |
| DDI Substudy - pharmacokinetics - AUC | 16 days | Area under the plasma concentration-time curve (AUC) |
| DDI Substudy - pharmacokinetics - Cmax | 14 days | Maximum plasma concentration (Cmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Study Parts - observing the safety of each treatment regimen. | Approximately 48 months | Incidence and severity of Adverse Events from first dose of study drug |
| Part 1a, Part 1b, Part 2 - Overall Survival (OS) | Approximately 48 months | Time from first dose to death due to any cause |
| Part 1a, Part 1b, Part 2 - Objective Response Rate (ORR) | Approximately 48 months | Percentage of subjects who achieved documented complete response (CR) + confirmed partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Part 1a, Part 1b, Part 2 - Disease Control Rate (DCR) | Approximately 48 months | Percentage of subjects who achieved CR + PR + stable disease (SD) at 16 weeks |
| Part 1a, Part 1b. Part 2 - Time to response (TTR) | Approximately 48 months | Time from first dose to first documented response based on modified Response Evaluation Criteria in Solid Tumors Version 1.1 |
| Part 1a, Part 1b, Part 2 - Duration of Response (DOR) | Approximately 48 months | Time from first response (CR or PR) to the date of progression or death from any cause, whichever occurs first |
| Part 2 Only - European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30) | Approximately 48 months | Change in individual scores in patients with locally advanced, unresectable, or metastatic GIST treated with CGT9486 in combination with sunitinib compared with patients treated with sunitinib monotherapy. The scale comprises 30 questions, 24 of which are aggregated into 9 multi-item scales, to include 5 functioning scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting) and 1 global health status scale. The remaining 6 single-item scales assess symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea and the financial impact). All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms. |
Countries
Argentina, Australia, Brazil, Canada, Chile, Czechia, Denmark, France, Germany, Hong Kong, Hungary, Italy, Mexico, Netherlands, Norway, Poland, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Outcome results
None listed