(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors

Study Overview
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Brief Summary
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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 426 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 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.

Official Title
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A Phase 3 Randomized, Open-Label, Multicenter Clinical Study of CGT9486+Sunitinib vs. Sunitinib in Subjects With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumors

Conditions
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Advanced Gastrointestinal Stromal Tumors, Metastatic Cancer

Intervention / Treatment
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* Drug: CGT9486 plus sunitinib
* Drug: CGT9486
* Drug: Sunitinib
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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. Documented disease progression on or intolerance to imatinib Subjects must have received the following treatment: 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 Have at least 1 measurable lesion according to mRECIST v1.1 ECOG - 0 to 2 Have clinically acceptable local laboratory screening results (clinical chemistry and hematology) within certain limits Key Exclusion Criteria: Known PDGFR driving mutations or known succinate dehydrogenase deficiency Clinically significant cardiac disease Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug Gastrointestinal abnormalities including, but not limited to, significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption Any active bleeding excluding hemorrhoidal or gum bleeding Seropositive for HIV 1 or 2, or positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody. Active, uncontrolled, systemic bacterial, fungal, or viral infections at Screening Received strong CYP3A4 inhibitors or inducers Received sunitinib within 3 weeks (Part 1a, Part 1b)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a<br>CGT9486 plus sunitinib 37.5 mg QD | Drug: CGT9486 plus sunitinib<br>* Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.<br>|
| Experimental: Part 2 - Experimental Group<br>CGT9486 plus sunitinib 37.5 mg QD | Drug: CGT9486 plus sunitinib<br>* Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.<br>|
| Active Comparator: Part 2 - Control Group<br>sunitinib 37.5 mg QD | Drug: Sunitinib<br>* Participants will receive sunitinib orally until study stopping rules are met.<br>* Other names: sunitinib - Part 2;|
| Experimental: Part 1b - DDI Cohort 1<br>CGT9486 plus sunitinib 37.5 mg QD | Drug: CGT9486<br>* Participants will receive CGT9486 until steady state then both CGT9486 and sunitinib orally until study stopping rules are met.<br>|
| Experimental: Part 1b - DDI Cohort 2<br>sunitinib 37.5 mg QD plus CGT9486 | Drug: Sunitinib<br>* Participants will receive sunitinib until steady state then both sunitinib and CGT9486 orally until study stopping rules are met.<br>* Other names: sunitinib - Part 1b;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1a - pharmacokinetics - Cmax | Maximum plasma concentration (Cmax) | 16 days | 
| Part 1a - pharmacokinetics - AUC | Area under the plasma concentration-time curve (AUC) | 16 days | 
| Part 1b - pharmacokinetics - Cmax | Maximum plasma concentration (Cmax) | 14 days | 
| Part 1b - pharmacokinetics - AUC | Area under the plasma concentration-time curve (AUC) | 14 days | 
| Part 1b - pharmacokinetics - Tmax | Time to maximum observed plasma concentration (Tmax) | 14 days | 
| Part 2 - Progression Free Survival (PFS) | Time from first dose to documented disease progression or death due to any cause, whichever occurs first | Approximately 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Study Parts - observing the safety of each treatment regimen. | Incidence and severity of Adverse Events from first dose of study drug | Approximately 48 months | 
| All Study Parts - observing the safety of each treatment regimen. | Incidence and severity of Serious Adverse Events from first dose of study drug | Approximately 48 months | 
| All Study Parts - observing the safety of each treatment regimen. | Incidence of Adverse Events leading to dose modifications from first dose of study drug | Approximately 48 months | 
| All Study Parts - observing the safety of each treatment regimen. | Change from baseline in laboratory results | Approximately 48 months | 
| All Study Parts - Overall Survival (OS) | Time from first dose to death due to any cause | Approximately 48 months | 
| All Study Parts - Objective Response Rate (ORR) | 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 | Approximately 48 months | 
| All Study Parts - Disease Control Rate (DCR) | Percentage of subjects who achieved CR + PR + stable disease (SD) at 16 weeks | Approximately 48 months | 
| All Study Parts - Time to response (TTR) | Time from first dose to first documented response based on modified Response Evaluation Criteria in Solid Tumors Version 1.1 | Approximately 48 months | 
| All Study Parts - Duration of Response (DOR) | Time from first response (CR or PR) to the date of progression or death from any cause, whichever occurs first | Approximately 48 months | 
| Part 2 Only - European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30) | 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. | Approximately 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sunitinib, Solid Tumors, Gastrointestinal Stromal Tumors, Gastrointestinal, KIT, Kinase Inhibitors, Growth Inhibitors, CGT9486, Unresectable, Metastatic, GIST, Bezuclastinib, PLX9486