Digestive System Disease, Gastrointestinal Diseases, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumor (GIST), Metastatic Cancer
Conditions
Keywords
GIST, IDRX, IDRX-42, Strate, StrateGIST, StrateGIST 1, GSK6042981
Brief summary
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
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. The study consists of 2 parts. Phase 1 comprises dose escalation to assess clinical and pharmacologic profile and safety/tolerability after failure of at least prior imatinib and support choice of the recommended phase 1b dose(s) and schedule(s) (RP1bDs)). Phase 1b expansion will enroll separate cohorts of participants defined by numbers of lines of prior GIST therapy at the selected RP1bD(s) to assess the preliminary antitumor effect of IDRX-42 and further characterize the safety profile of IDRX-42 at the RP1bD(s). In addition, a Concentration-QTc (C-QTc) substudy will be conducted in a subset of participants enrolled at selected sites in the study to characterize the effects of IDRX-42 on QTc and other ECG parameters in GIST patients.
Interventions
DRUGIDRX-42
Administered at assigned doses and schedules once or twice daily in continuous cycles of 28 days each.
Sponsors
IDRX, Inc., a wholly owned subsidiary of GSK, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phase 1 1. Male or female participants ≥18 years of age 2. Histologically or cytologically confirmed metastatic and/or surgically unresectable GIST 3. Documented progression on imatinib (Phase 1) 4. Documented pathogenic mutation in KIT OR any PDGFRA mutation other than exon 18 mutations, determined through local testing 5. At least one measurable lesion by mRECIST v1.1 for participants with GIST 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 7. 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. 8. 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 1. For Cohort 1, progressed on imatinib only (second line therapy) and refused or are ineligible for other standard of care (SOC) therapies. 2. 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) or progressed on imatinib, sunitinib, regorafenib, and ripretininb (fifth line or greater therapy) 3. For Cohort 3 \[US, UK, China, and Japan only\], treatment naïve (first line therapy) and refused or are ineligible for other standard of care (SOC) therapies. 4. For Cohort 4, met the same criteria as Cohort 2 (third line or greater) and have also had prior treatment with investigational agents NB003 or THE-630 or a line of therapy of bezuclastinib plus sunitinib combination.
Exclusion criteria
1. Any prior exposure to the following investigational agents NB003 or THE-630 or bezuclastinib plus sunitinib combination (except for participants treated in Cohort 4 of Phase 1b). 2. GIST with no documented mutation in both KIT and PDGFRA genes. 3. Primary brain malignancy or known untreated or active central nervous system metastases. 4. Has an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics. 5. Has significant, uncontrolled, or active cardiovascular disease.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1 (Dose Escalation) - C-QTc sub-study: QTcF - concentration response analysis | At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days) |
| Phase 1b-Number of participants with TEAEs and with laboratory test results | Approximately 18 months |
| Phase 1b - Objective Response Rate (ORR) mRESIST v1.1 | Approximately 18 months |
| Phase 1b - C-QTcF sub-study: QTcF - concentration response analysis | 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) - Safety and Tolerability (Nature, incidence, and severity of any DLTs) | When participant completes 1 cycle (28 days) treatment with safety and tolerability assessment by investigators |
| Phase 1 (Dose Escalation) - Determination of the MTD and/or RP1bD(s) of orally administered IDRX-42 | Approximately 18 months from first participant enrolled |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Phase 1b C-QTc sub-study: QTcF, heart rate, PR, QRS interval at baseline, post baseline and change from baseline. | 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)- 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) - C-QTcF sub-study: QTcF, heart rate, PR, QRS interval at baseline, post baseline and change from baseline. | 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) - 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) |
Countries
Belgium, China, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, United Kingdom, United States
Outcome results
None listed