A First-in-human (FIH) Study of IDRX-42 in Participants With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) [Study ID: StrateGIST1]

Study Overview
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Brief Summary
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This is the first clinical trial of IDRX-42. The study is designed to evaluate the safety, tolerability, PK, and preliminary antitumor activity of IDRX-42 in adult participants with advanced (metastatic and/or surgically unresectable) GIST.

Detailed Description
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This is a Phase 1/1b open-label, first-in-human FIH study of IDRX-42, an orally administered small molecule tyrosine kinase inhibitor. Eligible participants will have metastatic and/or surgically unresectable GIST, after failure of at least imatinib due to progression of GIST. The study consists of 2 parts. Phase 1 comprises dose escalation to assess clinical and pharmacologic profile, safety/tolerability, and support choice of the recommended phase 2 dose and schedule (RP2DS). Phase 1b expansion will enroll separate cohorts of participants defined by numbers of lines of prior GIST therapy at the selected RP2DS to assess the preliminary antitumor effect of IDRX-42 and further characterize the safety profile of IDRX-42 at the RP2DS.

Official Title
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A First-in-human (FIH) Study of IDRX-42 in Participants With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) [Study ID: StrateGIST1]

Conditions
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Gastrointestinal Stromal Tumor (GIST), Digestive System Disease, Gastrointestinal Diseases, Metastatic Cancer

Intervention / Treatment
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* Drug: IDRX-42
* Drug: IDRX-42


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1 Male or female participants ≥18 years of age Histologically or cytologically confirmed metastatic and/or surgically unresectable GIST Documented progression on imatinib (Phase 1) Documented pathogenic mutation in KIT OR any PDGFRA mutation other than exon 18 mutations, determined through local testing At least one measurable lesion by mRECIST v1.1 for participants with GIST Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Resolution of any toxicities from prior treatment(s) to ≤ Grade 1 by NCI CTCAE v5.0 criteria, or have resolved to baseline, at the time of first dose of study drug. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions. Additional for Phase 1b Exploratory Cohorts For Cohort 1, progressed on imatinib only (second line therapy) For Cohort 2, progressed on both imatinib and sunitinib (third line therapy) or progressed on imatinib, sunitinib, and an additional agent (i.e., regorafenib or ripretinib) (fourth line therapy) For Cohort 3, progressed on at all U.S. -approved TKI therapies for KIT-mutant GIST [imatinib, sunitinib, regorafenib, and ripretinib] (fifth line or greater therapy) Exclusion Criteria: Any prior exposure to the following investigational agents NB003 or THE-630 or bezuclastinib plus sunitinib combination. GIST with no documented mutation in both KIT and PDGFRA genes. Any prior primary CNS malignancy or known untreated or active central nervous system metastases. Has an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics. Has significant, uncontrolled, or active cardiovascular disease.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Phase I)<br>Participants should have advanced (metastatic and/or surgically unresectable) GIST, following failure of at least prior imatinib therapy due to progression of GIST. | Drug: IDRX-42<br>* IDRX-42 will be administered at assigned doses and schedules once daily in continuous cycles of 28 days each.<br>|
| Experimental: (Phase 1b) Cohort 1 - Participants with GIST progression after first-line imatinib therapy<br>Participants with advanced GIST who have had GIST progression only after first-line imatinib only (second line therapy setting). | Drug: IDRX-42<br>* IDRX-42 will be administered at RP2DS once daily in continuous cycles of 28 days each.<br>|
| Experimental: (Phase 1b): Cohort 2 - Participants with GIST progression after 2nd OR 3rd line TKI therapy<br>Participants with metastatic and/or surgically unresectable GIST following progression EITHER after sequential imatinib then sunitinib (third-line therapy setting) OR after imatinib, sunitinib, and then an additional TKI agent (i.e., regorafenib or ripretinib) (fourth-line therapy setting). | Drug: IDRX-42<br>* IDRX-42 will be administered at RP2DS once daily in continuous cycles of 28 days each.<br>|
| Experimental: (Phase 1b): Cohort 3 - Participants with GIST progression after 4th or greater lines of TKI therapy<br>Participants with advanced GIST who have had GIST progression after 4th line or greater lines of TKI therapy (failure due to progression of all available agents (imatinib, sunitinib, regorafenib, ripretinib, and possibly others (> 5th line therapy setting) | Drug: IDRX-42<br>* IDRX-42 will be administered at RP2DS once daily in continuous cycles of 28 days each.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 (Dose Escalation) - Safety and Tolerability (Nature, incidence, and severity of any DLTs) |  | When participant completes 1 cycle (28days) treatment with safety and tolerability assessment by investigators | 
| Phase 1 (Dose Escalation) - Safety and Tolerability (Nature, incidence, and severity of any DLTs) |  | Approximately18 months from first participant enrolled | 
| Phase 1 (Dose Escalation) - Determination of the MTD and/or RP2DS of orally administered IDRX-42 |  | Approximately18 months from first participant enrolled | 
| Phase 1b-Number of participants with TEAEs and with laboratory test results |  | Approximately18 months | 
| Phase 1b - Objective Response Rate (ORR) mRESIST v1.1 |  | Approximately 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 (Dose Escalation)- Number of participants with non-DLT TEAEs and with laboratory test results |  | 6 months | 
| Phase 1 (Dose Escalation) - ORR per mRECIST v1.1 |  | 6 months | 
| Phase 1 (Dose Escalation) - Cmax; Maximum Observed Concentration of IDRX-42 |  | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) | 
| Phase 1 (Dose Escalation) - Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of IDRX-42 |  | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) | 
| Phase 1 (Dose Escalation) - AUC 0-24; Area Under the Concentration-time Curve from Time Zero to 24 hours for IDRX-42 |  | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) | 
| Phase 1 (Dose Escalation) - Duration of response (DOR) per mRECIST v1.1 |  | 6 months | 
| Phase 1 (Dose Escalation) - Time to response (TTR) per mRECIST v1.1 |  | 6 months | 
| Phase 1 (Dose Escalation) - Progression-free survival (PFS), per mRECIST v1.1 |  | 6 months | 
| Phase 1b- Duration of response (DOR) per mRECIST v1.1 |  | 18 months | 
| Phase 1b - PFS per mRECIST v1.1 |  | 18 months | 
| Phase 1b - Clinical benefit rate (CBR) per mRECIST v1.1 |  | 18 months | 
| Phase 1b - TTR per mRECIST v1.1 |  | 18 months | 
| Phase 1b - Cmax; Maximum Observed Concentration of IDRX-42 |  | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) | 
| Phase 1b - Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of IDRX-42 |  | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) | 
| Phase 1b - AUC 0-24; Area Under the Concentration-time Curve from Time Zero to 24 hours for IDRX-42 |  | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) | 
| Phase 1b - Overall survival |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIST, IDRX, IDRX-42