A Study of Pimitespib in Combination With Imatinib in Patients With GIST (CHAPTER-GIST-101)

Study Overview
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Brief Summary
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This study consists of Dose escalation part and Expansion part. In Dose Escalation Part, the maximum tolerated dose of combination of pimitespib and imatinib in patients with gastrointestinal stromal tumors (GIST) who are judged to be refractory to imatinib, estimate the recommended dose, evaluate safety and pharmacokinetics, and observe the antitumor effect. Expansion part consists of 3 arms. In Arm A, the efficacy and safety will be evaluated, which of the combination of pimitespib and imatinib in patients with GIST who have failed imatinib at doses below the MTD determined in Dose Escalation Part. In Arm B, the efficacy and safety of pimitespib monotherapy will be evaluated and the therapeutic effect of imatinib administration after pimitespib will be evaluated in an exploratory manner. In Arm C, the efficacy and safety of sunitinib monotherapy will be evaluated as reference data.

Official Title
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A Phase 1 Study of TAS-116 (Pimitespib) in Combination With Imatinib in Patients With Advanced Gastrointestinal Stromal Tumor

Conditions
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Gastrointestinal Stromal Tumors

Intervention / Treatment
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* Drug: Pimitespib
* Drug: Imatinib
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provided written informed consent Histologically confirmed GIST Progressed on the basis of imaging during or within 6 months of the last imatinib administration at enrollment Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: Received treatment with any other line of therapy besides imatinib for advanced GIST; including local surgery and radiotherapy A serious illness or medical condition Previous or concurrent cancer that is distinct in primary disease or histology from cancer that is being evaluated in this study Pregnancy or lactation (including lactation interruption)

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Part<br>Pimitespib in combination with imatinib | Drug: Pimitespib<br>* Pimitespib will be administered orally in 5 consecutive days followed by 2 days off treatment (QD 5) on an empty stomach at least 1 hour before or 2 hours after a meal. The doses in the Dose Escalation Part will be 80, 120 (starting dose), and 160 mg. The doses used in Arm A will be MTD or recommended dose (RD) based on the information, including the safety and the pharmacokinetics (PK) data in the Dose Escalation Part. In Expansion Part-B, pimitespib will be administered with the starting dose of 160 mg daily.<br>* Other names: TAS-116;Drug: Imatinib<br>* Imatinib will be administered orally, after a meal and large glass of water QD. The doses in Dose Escalation Part will be 400 mg or 300 mg (De-escalation). The doses used in Expansion Part-A will be MTD or RD based on information, including the safety and PK data in the Dose Escalation Part. In Expansion Part-B, imatinib will be administered post after pimitespib discontinuation with the starting dose of 400 mg daily.<br>|
| Experimental: Expansion Part-A<br>Pimitespib in combination with imatinib | Drug: Pimitespib<br>* Pimitespib will be administered orally in 5 consecutive days followed by 2 days off treatment (QD 5) on an empty stomach at least 1 hour before or 2 hours after a meal. The doses in the Dose Escalation Part will be 80, 120 (starting dose), and 160 mg. The doses used in Arm A will be MTD or recommended dose (RD) based on the information, including the safety and the pharmacokinetics (PK) data in the Dose Escalation Part. In Expansion Part-B, pimitespib will be administered with the starting dose of 160 mg daily.<br>* Other names: TAS-116;Drug: Imatinib<br>* Imatinib will be administered orally, after a meal and large glass of water QD. The doses in Dose Escalation Part will be 400 mg or 300 mg (De-escalation). The doses used in Expansion Part-A will be MTD or RD based on information, including the safety and PK data in the Dose Escalation Part. In Expansion Part-B, imatinib will be administered post after pimitespib discontinuation with the starting dose of 400 mg daily.<br>|
| Experimental: Expansion Part-B<br>Pimitespib followed by imatinib | Drug: Pimitespib<br>* Pimitespib will be administered orally in 5 consecutive days followed by 2 days off treatment (QD 5) on an empty stomach at least 1 hour before or 2 hours after a meal. The doses in the Dose Escalation Part will be 80, 120 (starting dose), and 160 mg. The doses used in Arm A will be MTD or recommended dose (RD) based on the information, including the safety and the pharmacokinetics (PK) data in the Dose Escalation Part. In Expansion Part-B, pimitespib will be administered with the starting dose of 160 mg daily.<br>* Other names: TAS-116;Drug: Imatinib<br>* Imatinib will be administered orally, after a meal and large glass of water QD. The doses in Dose Escalation Part will be 400 mg or 300 mg (De-escalation). The doses used in Expansion Part-A will be MTD or RD based on information, including the safety and PK data in the Dose Escalation Part. In Expansion Part-B, imatinib will be administered post after pimitespib discontinuation with the starting dose of 400 mg daily.<br>|
| Experimental: Expansion Part-C<br>Sunitinib | Drug: Sunitinib<br>* Sunitinib will be administered orally QD with a starting dose of 50 mg, on a schedule of 4 weeks on treatment followed by 2 weeks off, and will be taken with or without a meal in Expansion Part-C.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) of pimitespib in combination with imatinib |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Maximum tolerable dose (MTD) of pimitespib in combination with imatinib |  | At the end of Cycle 1 (each cycle is 28 days) | 
| Progression-free survival (PFS) |  | approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | approximately 2 years | 
| Overall response rate (ORR) |  | approximately 2 years | 
| Disease control rate (DCR) |  | approximately 2 years | 
| Duration of response (DoR) |  | approximately 2 years | 
| Adverse event (AE) |  | approximately 2 years | 
| Adverse drug reaction (ADR) |  | approximately 2 years | 
| Maximum plasma concentration (Cmax) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Time to reach maximum plasma concentration (Tmax) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Under the plasma concentration-time curve up to the last observable concentration (AUC0-last) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| λz |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Half-life (T1/2) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Oral clearance (CL/F) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Apparent volume of distribution (Vz/F) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Mean residence time (MRT) |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Accumulation ratio |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) | 
| Metabolite ratio |  | Multiple time points on Day 1 and Day5 or Day12 of Cycle 1 (each cycle is 28 days) |