A Study of Repotrectinib in Combination With Chemotherapy in Children and Young Adults With Solid Tumor Cancer

NCT05004116 | Recruiting Phase 1 FDA Drug

• 1 other identifier: 21-156
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 1

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.

Conditions

Advanced Cancer; Metastatic Solid Tumor

Keywords

Repotrectinib; 21-156

Outcome Measures

Primary Outcomes (2)

• incidence of Dose Limiting Toxicity (DLTs) (phase I)

  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.

  8 weeks following the start of treatment

• Maximum tolerated dose (MTD) (phase I)

  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).

  1 year

Study Arms (5)

Phase I portion

EXPERIMENTAL

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.

Drug: Repotrectinib; Drug: Irinotecan and temozolomide

Phase II, ALK-mutated neuroblastoma Cohort (THIS IS CLOSED)

EXPERIMENTAL

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

Drug: Repotrectinib; Drug: Irinotecan and temozolomide

Phase II, Molecularly defined DSRCT Cohort

EXPERIMENTAL

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

Drug: Repotrectinib; Drug: Irinotecan and temozolomide

Phase II, Exploratory Cohort

EXPERIMENTAL

Phase II, Exploratory Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1

Drug: Repotrectinib; Drug: Irinotecan and temozolomide

Phase II, DIPG Cohort

EXPERIMENTAL

Patients with DIPG will enroll in cohort 4 and receive TPX-0005 (Repotrectinib) monotherapy at the pediatric recommended phase 2 dose

Drug: Repotrectinib; Drug: Irinotecan and temozolomide

Interventions

Repotrectinib DRUG

TPX-0005 (Repotrectinib) will be taken orally twice daily in 28-day cycles without regard to food and will be administered orally before administration of irinotecan and temozolomide (exception: C1, TPX-0005 (Repotrectinib) will be administered once daily x 14 days, then twice daily D15-D28).

Also known as: TPX-0005

Phase I portion; Phase II, ALK-mutated neuroblastoma Cohort (THIS IS CLOSED); Phase II, DIPG Cohort; Phase II, Exploratory Cohort; Phase II, Molecularly defined DSRCT Cohort

Irinotecan and temozolomide DRUG

Irinotecan and temozolomide will be given as per institutional standard.

Phase I portion; Phase II, ALK-mutated neuroblastoma Cohort (THIS IS CLOSED); Phase II, DIPG Cohort; Phase II, Exploratory Cohort; Phase II, Molecularly defined DSRCT Cohort

Eligibility Criteria

• Age: 1 Year - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Prior Therapy: Patients must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy prior to study enrollment. Patients must not have received the therapies indicated below for the specified time period prior to the first day of administration of protocol therapy on this study:
• Myelosuppressive chemotherapy: Last dose was given at least 21 days before the start date for protocol therapy.
• Biologic (anti-neoplastic agent including retinoids): Last dose given at least 7 days prior to the start date for protocol therapy.
• Monoclonal antibodies: Last dose of any monoclonal antibodies must have received at least 7 days or 3 half-lives, whichever is longer, prior to the start date for protocol therapy.
• Radiation Therapy: Patients must not have received radiation for a minimum of two weeks prior to first dose of the drug for small port. If extensive bone marrow radiation, at least 42 days must have elapsed.
• Palliative radiotherapy on study is permitted for the treatment of painful bony lesions providing the lesions were known at the time of study entry and the Investigator clearly indicates that the need for palliative radiotherapy is not indicative of disease progression. In view of the current lack of data about the interaction of repotrectinib with radiotherapy, repotrectinib treatment should be interrupted during palliative radiotherapy, stopping 1 day before palliative radiotherapy and resuming treatment 1 day after completion of palliative radiotherapy and recovery from any acute radiation toxicities to baseline.
• Hematopoietic Stem Cell Transplant (HSCT): Patients are eligible 12 weeks after date of autologous hematopoietic stem cell infusion following myeloablative therapy (timed from first day of this protocol therapy). Patients who have received an autologous hematopoietic stem cell infusion to support non- myeloablative therapy (such as \^131 I-MIBG) are eligible at any time as long as they meet the other criteria for eligibility.
• \^131 I-MIBG therapy: A minimum of 6 weeks must have elapsed after \^131 I-MIBG therapy prior to start of protocol therapy.
• Growth factors: Patients are eligible 14 days after last dose of long-acting growth factor (ex: peg-GCSF) or 7 days after short acting growth factor.
• Any investigational agent or anticancer therapy other than chemotherapy and not otherwise noted: Not within 2 weeks prior to planned start of TPX-0005 (Repotrectinib) or 5 half-lives, whichever is shorter. Full recovery of clinically significant toxicities from that therapy must be evident.
• Any prior treatment with a tyrosine kinase inhibitor (TKI) of ALK/ROS/NTRK does NOT exclude patient from study (Patients are eligible for study at least 7 days or 5 half-lives, whichever is shorter, after last dose)
• Disease Status
• Patients must have relapsed or refractory disease despite standard therapy.
• Phase 1: Patients must have evaluable or measurable disease
• Phase 2: All patients must have measurable disease (per Appendices 1-3) at time of enrollment

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead

Study Sites (1)

Memorial Sloan Kettering Cancer Center (All Protocol Activities)

New York, New York, 10065, United States

RECRUITING

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

repotrectinib; Irinotecan; Temozolomide

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Emily Slotkin, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Emily Slotkin, MD

CONTACT

1-833-675-5437; slotkine@mskcc.org

Fiorella Iglesias Cardenas, MD,MS

CONTACT

1-833-675-5437

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a single institution phase 1/2 study of TPX-0005 (Repotrectinib) (capsule) when given in combination with irinotecan and temozolomide in pediatric and young adult patients (≥12 years old) with relapsed/refractory solid tumors, followed by a single institution phase 2 study to determine the overall response rate at the recommended phase 2 dose in primarily neuroblastoma and DSRCT patients.

Study Record Dates

• First Submitted: August 9, 2021
• First Posted: August 13, 2021
• Study Start: August 9, 2021
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028
• Last Updated: March 4, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)