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A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children

NCT02637687

Description:

The study is being done to test the safety of a cancer drug called larotrectinib in children. The cancer must have a change in a particular gene (NTRK1, NTRK2 or NTRK3). Larotrectinib blocks the actions of these NTRK genes in cancer cells and can therefore be used to treat cancer. The first study part (Phase 1) is done to determine what dose level of larotrectinib is safe for children, how the drug is absorbed and changed by their bodies and how well the cancer responds to the drug. The main purpose of the second study part (Phase 2) is to investigate how well and how long different cancer types respond to the treatment with larotrectininb.

Related Conditions:
  • Fibrosarcoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Oral TRK Inhibitor LOXO-101 (Larotrectinib) for Treatment of Advanced Pediatric Solid or Primary Central Nervous System Tumors
  • Official Title: A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 (Larotrectinib) in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors

Clinical Trial IDs

  • ORG STUDY ID: LOXO-TRK-15003
  • NCT ID: NCT02637687

Conditions

  • Neoplasms
  • Central Nervous System Neoplasms

Interventions

DrugSynonymsArms
LOXO-101 (larotrectinib)Treatment

Purpose

This is a multicenter, open label, Phase 1/2 study in pediatric patients with advanced solid or primary CNS tumors. LOXO‑101 (larotrectinib) will be administered orally (PO) twice daily (BID), with the dose adjusted by body surface area (BSA).

Detailed Description

      This is a multicenter, open label, Phase 1/2 study in pediatric patients with advanced solid
      or primary CNS tumors. LOXO‑101 (larotrectinib) will be administered orally (PO) twice daily
      (BID), with the dose adjusted by body surface area (BSA).

      Dose Escalation Phase has completed enrollment and it has been determined that the maximum
      dose for the Phase 1 Expansion and Phase 2 portions of the study will be no higher than the
      recommended Phase 2 dose of 100 mg BID in the adult Phase 2 trial, regardless of the
      patient's BSA.

      Phase 1 Expansion and Phase 2 portions of the study are currently enrolling.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalOpen Label LOXO-101 (larotrectinib)
  • LOXO-101 (larotrectinib)

Eligibility Criteria

        Inclusion Criteria:

          -  Pediatric patients ≥ 1 day old on Cycle 1 Day 1 (C1D1)

          -  Phase 1: Birth through 21 years of age at C1D1 with a locally advanced or metastatic
             solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to
             available therapies and for which no standard or available systemic curative therapy
             exists, or infants from birth and older with a diagnosis of malignancy and with a
             documented NTRK fusion that has progressed or was nonresponsive to available
             therapies, and for which no standard or available curative therapy exists, or patients
             with locally advanced infantile fibrosarcoma who would require, in the opinion of the
             Investigator, disfiguring surgery or limb amputation to achieve a complete surgical
             resection. The Phase I dose escalation cohorts are closed to enrollment. In addition
             to the above stated Inclusion Criteria, patients eligible for enrollment into this
             cohort must have a malignancy with a documented NTRK gene fusion with the exception of
             patients with infantile fibrosarcoma, congenital mesoblastic nephroma or secretory
             breast cancer. Patients with infantile fibrosarcoma, congenital mesoblastic nephroma
             or secretory breast cancer may enroll into this cohort with documentation of an ETV6
             rearrangement by FISH or RT-PCR or a documented NTRK fusion by NGS.

          -  Phase 2 only: Infants from birth and older at C1D1 with a locally advanced or
             metastatic infantile fibrosarcoma, patients with locally advanced infantile
             fibrosarcoma who would require, in the opinion of the Investigator, disfiguring
             surgery or limb amputation to achieve a complete surgical resection or birth through
             21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary
             CNS tumor that has relapsed, progressed or was nonresponsive to available therapies
             and for which no standard or available systemic curative therapy exists with a
             documented NTRK gene fusion (or in the case of infantile fibrosarcoma, congenital
             medoblastic nephroma or secretory breast cancer with documented ETV6 rearrangement by
             FISH or RT-PCR or a documented NTRK fusion by NGS) (identified through molecular
             assays as routinely performed at CLIA or other similarly-certified laboratories) or
             (including Expansion Phase) potential patients older than 21 years of age with a tumor
             diagnosis with histology typical of a pediatric patient and an NTRK fusion may be
             considered for enrollment following discussion between the local site Investigator and
             the Sponsor's Medical Monitor. Patients with NTRK-fusion positive benign tumors are
             also eligible.

          -  Karnofsky (those 16 years old or older) or Lansky (those younger than 16 years)
             performance score of at least 50

          -  Adequate hematologic function: Absolute neutrophil count (ANC) ≥ 1.0 109/L, platelet
             count ≥ 100.0 109/L and hemoglobin ≥ 8.0 g/dL (patients with bone marrow involvement
             will not be evaluable for hematologic DLT and can enroll with ANC ≥ 0.75 109/L,
             platelet count ≥ 50.0 109/L and hemoglobin ≥ 8.0 g/dL)

          -  Adequate hepatic function: Bilirubin (sum of conjugated + unconjugated) ≤ 2.5 upper
             limit of normal (ULN) for age (patients with documented Gilbert's Disease may be
             enrolled with Sponsor approval).

          -  Adequate renal function: Estimated glomerular filtration rate ≥ 30 mL/minute using the
             Cockroft-Gault formula or: a serum creatinine based on age/gender as outlined in the
             protocol

          -  Requirement of highly effective birth control methods with a failure rate of less than
             1% per year for male subjects. Also defined sexual abstinence as a birth control
             method per CTFG guidelines.

        Exclusion Criteria:

          -  Investigational agent, anticancer therapy, or major surgery within 14 days (2 weeks)
             prior to C1D1

          -  Clinically significant active cardiovascular disease or history of prolonged QT
             interval corrected for heart rate (QTc)

          -  Current treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor or inducer (EIAEDs
             and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed)

          -  Phase 2 Only: Prior progression while receiving approved or investigational tyrosine
             kinase inhibitors targeting TRK, including entrectinib, crizotinib and lestaurtanib.
             Patients who received a TRK inhibitor for less than 28 days of treatment and
             discontinued because of intolerance remain eligible.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: To determine the safety of oral LOXO-101 (larotrectinib) in pediatric patients with advanced solid or primary central nervous system (CNS) tumors. Phase 2: To determine the overall response rate (ORR).
Time Frame:6 Months
Safety Issue:
Description:Phase 1: To determine the safety of oral LOXO-101 (larotrectinib), including dose-limiting toxicity (DLT), in pediatric patients with advanced solid or primary central nervous system (CNS) tumors. Phase 2: To determine the overall response rate (ORR) as determined by an independent radiology review committee and measured by the proportion of subjects with best overall confirmed response of complete response (CR) or partial response (PR) by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate, following treatment with LOXO-101 (larotrectinib) in pediatric subjects with an advanced cancer harboring a fusion involving NTRK1, NTRK2, or NTRK3 (collective referred to as neurotrophic tyrosine kinase receptor [NTRK] fusions)

Secondary Outcome Measures

Measure:To characterize the pharmacokinetic (PK) properties of LOXO-101 (larotrectinib) in pediatric patients with advanced solid or primary CNS tumors
Time Frame:6 Months
Safety Issue:
Description:
Measure:To identify the recommended maximum tolerated dose and/or the appropriate dose of LOXO‑101 (larotrectinib) for further clinical investigation in this patient population
Time Frame:6 Months
Safety Issue:
Description:
Measure:To describe the antitumor activity of LOXO-101 (larotrectinib) in pediatric patients with advanced solid or primary CNS tumors
Time Frame:6 Months
Safety Issue:
Description:
Measure:To describe pain and health related quality of life (HRQOL) in pediatric patients with advanced solid or primary CNS tumors treated with LOXO-101 (larotrectinib)
Time Frame:6 Months
Safety Issue:
Description:
Measure:To assess the safety profile and tolerability of LOXO-101 (larotrectinib)
Time Frame:6 Months
Safety Issue:
Description:
Measure:To evaluate the concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor with diagnostic tests being evaluated by the Sponsor
Time Frame:6 Months
Safety Issue:
Description:
Measure:To characterize post-operative staging and surgical margin status in patients who have definitive surgery following treatment with LOXO-101 (larotrectinib)
Time Frame:6 Months
Safety Issue:
Description:
Measure:To describe the putitive pretreatment surgical plan and capture the post treatment actual approach with an emphasis on the functional and cosmetic outcome
Time Frame:6 Months
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Loxo Oncology, Inc.

Trial Keywords

  • Pediatric
  • NTRK1
  • NTRK2
  • NTRK3
  • Fusion
  • Tumors
  • Solid Tumors
  • CNS Tumors
  • Central Nervous System Tumors
  • NTRK Fusion Positive
  • TRKA
  • TRKB
  • TRKC
  • Infantile Fibrosarcoma
  • NTRK Gene Rearrangements
  • TRK Fusion
  • NTRK1 fusion
  • NTRK2 fusion
  • NTRK3 fusion
  • NTRK1 gene rearrangement
  • NTRK2 gene rearrangement
  • NTRK3 gene rearrangement
  • ETV6-NTRK3
  • ETV6
  • ETV6 fusion
  • ETV6 gene rearrangement
  • Solid CNS tumor
  • Primary CNS tumor
  • Advanced CNS tumor
  • Metastatic CNS tumor
  • Metastatic infantile fibrosarcoma
  • Advanced infantile fibrosarcoma
  • Fibrosarcoma
  • Congenital mesoblastic nephroma
  • Congenital nephroma
  • Thyroid
  • Larotrectinib
  • Solid tumors Cancer of Unknown primary

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