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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 1 Year - 25 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria (ALL Patients) :

  • - Weight >50kg (until Part B plan submitted via amendment) - 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.
  • - Immunotherapy (ex: tumor vaccine): Patient is eligible after 42 days of completion.
Steroids are excluded from inclusion in immunotherapy.
  • - Radiation Therapy: Patients must not have received radiation for a minimum of two weeks prior to study enrollment 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.
  • - Exception: Neuroblastoma patients are permitted to have evaluable disease only (ex: bone disease only, evaluable by MIBG or FDG PET/CT) - Biopsy Requirement.
°Archived tissue must be available for analysis, but no fresh biopsy is required (exception: patients with DIPG do not require archived tissue).
  • - Patients with Primary CNS Tumors: - Patients with primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment.
  • - Archived tissue and histologic verification requirement are waived for patients with diffuse intrinsic pontine glioma (DIPG) - Performance Score: Patients must have a Lansky (< 16 years age) or Karnofsky (≥ 16 years age) score of at least 50.
Patients who are unable to walk because of paralysis or tumor pain, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • - No bone marrow involvement.
  • - Absolute Neutrophil Count ≥1000/mm^3 (1 x 10^9/L) - Platelet Count ≥100,000/mm ^3 (100 x 10^9/L); transfusions allowed.
  • - Hemoglobin ≥ 8.0 g/dL, transfusions are allowed.
  • - Known bone marrow involvement (applicable for phase 2 only) - Absolute Neutrophil Count ≥750/mm 3 (1.5 x 109/L) - Platelet Count ≥50,000/mm^3 (100 x 10^9/L), transfusions allowed.
  • - Hemoglobin ≥ 8.0 g/dL, transfusions are allowed.
  • - Serum Creatinine or Creatinine Clearance*Creatinine within normal limits for age/gender (see table below) or creatinine clearance or nuclear GFR ≥ 60 mL/min/1.73m^2.
  • - Total Serum Bilirubin <2.5 x ULN for age/gender.
  • - Liver Transaminases (AST/ALT) <2.5 x ULN for age/gender; < 5 x ULN for age/gender if liver metastasis is present.
  • - Alkaline phosphatase <2.5 x ULN for age/gender; < 5 x ULN for age/gender if bone metastases are present.
  • - Serum calcium, magnesium and potassium Normal for age/gender or ≤ CTCAE Grade 1 with or without supplementation.
  • - Cardiac Function Echocardiogram with left ventricular shortening fraction >25% and QTc
  • - AST/ALT = aspartate aminotransferase/alanine aminotransferase, ULN = upper limit of normal.
  • - Adequate Renal Function using the Schwartz formula for estimating GFR Schwartz et al.
J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
  • - Females of Childbearing potential: Must have negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation.
Females of childbearing potential must agree to avoid pregnancy during the study and agree to the use of 2 effective contraceptive methods (hormonal and barrier method of birth control) prior to study entry, for the duration of study participation, and in the following 1 month after discontinuation of study treatment. Men with partner(s) of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 6 months after discontinuation of study treatment and to use appropriate barrier contraception or abstinence.
  • - Ability to comply with outpatient visits, laboratory testing, and study procedures during study participation.
  • - The patient, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
  • - Age: - Phase 1A: 12-25 years (age at C1D1) - Phase 1B: 1 year to 11.99 years (age at C1D1) - Phase 2: 1 year to 25 years.
  • - Disease: - Phase 1: Pediatric patients with ALK, ROS1, NTRK1-3 fusion negative relapsed/refractory solid tumors (including primary CNS tumors).
Other ALK, ROS1, or NTRK1-3 aberrations (point mutation, amplification, etc.) are permitted to enroll in this cohort. Patients with tumors not characterized by any ALK/ROS/NTRK aberration are also permitted to enroll in this cohort.
  • - DSRCT patients may be enrolled onto phase 1 once at least 2 other patients have been enrolled.
  • - Phase 2.
  • - Cohort 1: Patients with relapsed/refractory neuroblastoma with documented ALK activating SNV (including F1174, F1245, R1275, and other SNVs deemed activating by the primary investigator).
  • - Cohort 2: Patients with molecularly defined desmoplastic small round cell tumor (DSRCT) - Cohort 3: Exploratory cohort of patients with relapsed or refractory solid tumor characterized by ALK, ROS1, NTRK1-3 aberrations not otherwise specified above, including: - Non-neuroblastoma patients with ALK activating point mutation.
  • - Patients with ALK amplification (defined as greater than 10-fold increase in the ALK signal number as compared to reference signal number on chromosome 2q arm) - Patients with ROS1 point mutations.
  • - Patients with NTRK1-3 point mutations.
  • - Patients treated in Phase 1 at RP2D will be evaluable in the Phase 2 cohort if they meet all other inclusion criteria for the specified cohort.
Patients receiving oral capsule OR oral suspension can be included in Phase 2 cohort. Enrollment of patients of at least 12 years old can begin treatment in Phase 2 once TPX-0005 (Repotrectinib) combination therapy RP2D is defined in Phase 1A (even if Phase 1B is not yet completed)
  • - Tissue Analysis.
  • - Phase 1: All patients must have archived tissue available for analysis (exception: DIPG patients), but ALK/ROS/NTRK status verification is not required prior to enrollment.
  • - Phase 2: Prior to enrollment, all patients must have ALK/ROS/NTRK status evaluated in CLIA lab or equivalent by any nucleic acid-based diagnostic testing method (e.g., next-generation sequencing [NGS], Sanger sequencing, reverse transcription-polymerase chain reaction).
Exception: Patients with molecularly defined DSRCT do not require ALK/ROS/NTRK status confirmed prior to enrollment.

Exclusion Criteria:

  • - Phase 1- patients with known bone marrow disease.
  • - Concurrent participation in another therapeutic clinical trial.
  • - Neuroblastoma patients with only bone marrow disease evaluable only by bone marrow aspiration.
  • - 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 infections requiring ongoing treatment (bacterial, fungal, viral including human immunodeficiency virus positivity).
  • - 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT05004116
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Memorial Sloan Kettering Cancer Center
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Tara O'Donohue, MD
Principal Investigator Affiliation Memorial Sloan Kettering Cancer Center
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Advanced Cancer, Metastatic Solid Tumor
Study Website: View Trial Website
Additional Details

Part A (patients 12-25 years old, >50kg): 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. 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. Dosing will depend on: 1. Pediatric RP2D of TPX-0005 (Repotrectinib) administered as monotherapy to children less than 12 years old (per IRB # 20-077) 2. Pediatric RP2D of TPX-0005 (Repotrectinib) administration in combination with chemotherapy as will be determined in Part A of this trial. An amendment to this trial will be submitted once these data are available for review. 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) Cohort 2 (Desmoplastic Small Round Cell Tumor) Cohort 3 (Exploratory)

Arms & Interventions

Arms

Experimental: Repotrectinib

Phase 1: Part A (patients 12-25 years old, >50kg): 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. 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.

Interventions

Drug: - Repotrectinib

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).

Drug: - Irinotecan and temozolomide

Irinotecan and temozolomide will be given as per institutional standard.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

New York, New York

Status

Recruiting

Address

Memorial Sloan Kettering Cancer Center (All Protocol Activities)

New York, New York, 10065

Site Contact

Tara O'Donohue, MD

odonohut@mskcc.org

833-675-5437