A FIRST-IN-HUMAN (FIH) STUDY OF IDRX-42 IN PARTICIPANTS WITH METASTATIC AND/OR UNRESECTABLE GASTROINTESTINAL STROMAL TUMORS (GIST)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 276
- 试验地点
- 32
- 主要终点
- Phase 1 (Dose Escalation) - Safety and Tolerability (Nature, incidence, and severity of any DLTs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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) and refused or are ineligible for other standard of care (SOC) therapies.
- •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)
- •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.
- •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.
排除标准
- •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).
- •GIST with no documented mutation in both KIT and PDGFRA genes.
- •Primary brain 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.
研究组 & 干预措施
Dose Escalation (Phase I)
Participants should have advanced (metastatic and/or surgically unresectable) GIST, following failure of at least prior imatinib therapy due to progression of GIST.
干预措施: IDRX-42 (Drug)
(Phase 1b): Cohort 3 - Participants with GIST who are treatment naïve
Participants with metastatic and/or surgically unresectable GIST who are treatment naïve (first line therapy) and refused or are ineligible for other standard of care (SOC) therapies.
干预措施: IDRX-42 (Drug)
(Phase 1b) Cohort 1 - Participants with GIST progression after first-line imatinib therapy
Participants with advanced GIST who have had GIST progression after first-line imatinib only (second line therapy setting) and refused or are ineligible for other standard of care (SOC) therapies.
干预措施: IDRX-42 (Drug)
(Phase 1b): Cohort 4
Participants with GIST progression who meet the same criteria as Cohort 2 (third line or greater TKI therapy) and have had prior treatment with investigational agents NB003 or THE-630 or a line of therapy of bezuclastinib plus sunitinib combination.
干预措施: IDRX-42 (Drug)
(Phase 1b): Cohort 2 - Participants with GIST progression after 2 or more lines of TKI therapy
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) OR after imatinib, sunitinib, regorafenib, and ripretinib (5th line or greater therapy).
干预措施: IDRX-42 (Drug)
结局指标
主要结局
Phase 1 (Dose Escalation) - Safety and Tolerability (Nature, incidence, and severity of any DLTs)
时间窗: When participant completes 1 cycle (28 days) treatment with safety and tolerability assessment by investigators
Phase 1b - Objective Response Rate (ORR) mRESIST v1.1
时间窗: Approximately 18 months
Phase 1b-Number of participants with TEAEs and with laboratory test results
时间窗: Approximately 18 months
Phase 1 (Dose Escalation) - Safety and Tolerability (Nature, incidence, and severity of any DLTs)
时间窗: Approximately 18 months from first participant enrolled
Phase 1 (Dose Escalation) - Determination of the MTD and/or RP1bD(s) of orally administered IDRX-42
时间窗: Approximately 18 months from first participant enrolled
Phase 1 (Dose Escalation) - C-QTc sub-study: QTcF - concentration response analysis
时间窗: At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days)
Phase 1b - C-QTcF sub-study: QTcF - concentration response analysis
时间窗: At the end of Cycle 1 Day 1 and at the end of Cycle 2 Day 1 (each cycle is 28 days)
次要结局
- 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 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 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)
- 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))