Gastrointestinal Stromal Tumors
Conditions
Brief summary
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.
Interventions
DRUGPimitespib
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.
DRUGImatinib
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.
DRUGSunitinib
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.
Sponsors
Taiho Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provided written informed consent * Histologically confirmed GIST * Has radiographic progression based on RECIST 1.1 during or within 6 months of the last imatinib administration at enrollment. If surgery/radiotherapy has been performed, radiographic progression based on RECIST 1.1 with imatinib must have been observed after the last surgery /radiotherapy * Has at least one measurable lesion based on the RECIST version 1.1, except lymph nodes (not dependent on size), which should be chosen as nontarget lesions; * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Exclusion criteria
* Corrected visual acuity \< 0.5 (using the International Visual Acuity Measurement Standard) for both eyes * Received treatment with any other line of therapy besides imatinib for advanced GIST * History of total gastrectomy and/or whole resection of the small intestine * 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. However, any previous cancer curatively treated \> 5 years before the enrollment can be eligible * Pregnancy or lactation (including lactation interruption)
Design outcomes
Primary
| Measure | 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
| Measure | 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) |
Countries
Australia, China, Japan, Singapore, Taiwan
Contacts
STUDY_DIRECTORTaiho Pharmaceutical Co., Ltd.
Taiho Pharmaceutical Co., Ltd.
Outcome results
None listed