A Study of Repotrectinib in Combination With Chemotherapy in Children and Young Adults With Solid Tumor Cancer
- Conditions
- Advanced CancerMetastatic Solid Tumor
- Interventions
- Registration Number
- NCT05004116
- Lead Sponsor
- Memorial Sloan Kettering Cancer Center
- Brief Summary
This study will test the safety of the study drug, repotrectinib, in combination with chemotherapy (irinotecan and temozolomide) in children and young adults who have advanced or metastatic solid tumors. We researchers will try to find the highest dose of the study drug that causes few or mild side effects in study participants. When the researchers find this dose, we will evaluate it in a different group of participants to find out whether repotrectinib in combination with chemotherapy is an effective treatment for children and young adults who have advanced/metastatic solid tumors. Another purpose of the study is to look at the way the body absorbs, distributes, and gets rid of repotrectinib.
- Detailed Description
Part A : TPX-0005 (Repotrectinib) will be given orally (without regard to food) once daily for 14 days, then increased to twice daily for remainder of cycles and concurrently administered with chemotherapy backbone described below. If a patient is enrolled on DL3, cycle length will be 21 days, repotrectinib will be administered once daily x 14 days followed by twice daily if tolerated for remainder of therapy. For patients less than 12 years old or less than 50kg, adult equivalent dosing (AED) will be used Approximately 4-24 pediatric subjects will be enrolled into 2-4 dose levels (pending if DL-1 or DL-1b are utilized), with maximum of 6 subjects per dose level according to the 'rolling 6' design. Starting dose of TPX-0005 (Repotrectinib) will begin at dose level (DL) 1.
Part B (PK expansion cohort for patients \<12 years old): Up to six patients \<12 years old will be included in a PK expansion cohort after the maximum tolerated dose in Part A has been determined. The number of patients included in part B will be based on the the number of patients \<12 years old enrolled on part A. A minimum of 6 patients \<12 will be included in parts A and B combined.
Phase 2: Patients will be enrolled into one of the following 3 cohorts and will be treated at the RP2D of TPX-0005 (Repotrectinib) plus chemotherapy as determined in Phase 1.
Cohort 1 (Neuroblastoma ALK point mutation) THIS COHORT IS CLOSED Cohort 2 (Desmoplastic Small Round Cell Tumor) Cohort 3 (Exploratory)
Of note for patients enrolled to Dose Level 3 (21 day cycles), there will be no D22 assessements performed.
Enrollment to Phase 2 cohort 3 will occur concurrently with Phase 1 Part B (PK expansion cohort) since cohort 3 patients are being treated at the RP2D of TPX-0005 (Repotrectinib) monotherapy.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 77
Not provided
- Phase 1- patients with known bone marrow disease
- Concurrent participation in another therapeutic clinical trial
- Major surgery within 14 days (2 weeks) prior to C1D1. Central venous access (Broviac, MediPort) placement does not meet criteria for major surgery.
- Pregnancy or lactation
- Known active systemic infections requiring ongoing treatment (bacterial, fungal, viral including human immunodeficiency virus positivity). Skin or other superficial infections requiring topical treatment only are not an exclusion.
- Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
- Peripheral neuropathy CTCAE grade ≥ 3.
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study, or could compromise protocol objectives in the opinion of the Investigator and/or Turning Point Therapeutics.
- Current use or anticipated need for drugs that are known to be strong CYP3A4 inhibitors or inducers
- Disease progression while on treatment with irinotecan/temozolomide.
- Gilbert Syndrome or Crigler-Najjar
- Prolonged QTc: 450m/s for male patients and 470ms for female patients.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase I portion Repotrectinib Phase 1: Part A : TPX-0005 (Repotrectinib) will be given orally (without regard to food) once daily for 14 days, then increased to twice daily for remainder of cycles and concurrently administered with chemotherapy backbone described below. For patients less than 12 years old or less than 40kg, adult equivalent dosing (AED) will be used. Approximately 4-24 pediatric subjects will be enrolled into 2-4 dose levels (pending if DL-1 or DL-1b are utilized), with maximum of 6 subjects per dose level according to the 'rolling 6' design. Starting dose of TPX-0005 (Repotrectinib) will begin at dose level (DL) 1. Part B (combination therapy; patients less than 12 years old or ≤ 50kg): For 6 additional patients, a safety run-in will be conducted with TPX-0005 (Repotrectinib) and chemotherapy. Phase I portion Irinotecan and temozolomide Phase 1: Part A : TPX-0005 (Repotrectinib) will be given orally (without regard to food) once daily for 14 days, then increased to twice daily for remainder of cycles and concurrently administered with chemotherapy backbone described below. For patients less than 12 years old or less than 40kg, adult equivalent dosing (AED) will be used. Approximately 4-24 pediatric subjects will be enrolled into 2-4 dose levels (pending if DL-1 or DL-1b are utilized), with maximum of 6 subjects per dose level according to the 'rolling 6' design. Starting dose of TPX-0005 (Repotrectinib) will begin at dose level (DL) 1. Part B (combination therapy; patients less than 12 years old or ≤ 50kg): For 6 additional patients, a safety run-in will be conducted with TPX-0005 (Repotrectinib) and chemotherapy. Phase II, ALK-mutated neuroblastoma Cohort (THIS IS CLOSED) Repotrectinib Phase II, ALK-mutated neuroblastoma Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1 Phase II, ALK-mutated neuroblastoma Cohort (THIS IS CLOSED) Irinotecan and temozolomide Phase II, ALK-mutated neuroblastoma Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1 Phase II, Molecularly defined DSRCT Cohort Repotrectinib Phase II, Molecularly defined DSRCT Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1 Phase II, Molecularly defined DSRCT Cohort Irinotecan and temozolomide Phase II, Molecularly defined DSRCT Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1 Phase II, Exploratory Cohort Repotrectinib Phase II, Exploratory Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1 Phase II, Exploratory Cohort Irinotecan and temozolomide Phase II, Exploratory Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1 Phase II, DIPG Cohort Repotrectinib Patients with DIPG will enroll in cohort 4 and receive TPX-0005 (Repotrectinib) monotherapy at the pediatric recommended phase 2 dose Phase II, DIPG Cohort Irinotecan and temozolomide Patients with DIPG will enroll in cohort 4 and receive TPX-0005 (Repotrectinib) monotherapy at the pediatric recommended phase 2 dose
- Primary Outcome Measures
Name Time Method incidence of Dose Limiting Toxicity (DLTs) (phase I) 8 weeks following the start of treatment DLTs will be defined as any of the following events that are possibly, probably or definitely attributable to TPX-0005 (Repotrectinib) given in combination with chemotherapy and occurring. Grading will be evaluated according to National Cancer Institute CTCAE v5.0.
Maximum tolerated dose (MTD) (phase I) 1 year MTD will be defined for TPX-0005 (Repotrectinib) in combination with chemotherapy. The MTD is the highest dose level of TPX-0005 (Repotrectinib) expected to cause a DLT in not more than 1/6 treated subjects. The dose escalation will follow a standard rolling 6 design (an algorithm-based extension of a standard 3+3 design).
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
Memorial Sloan Kettering Cancer Center (All Protocol Activities)
🇺🇸New York, New York, United States