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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:
  • Congenital Mesoblastic Nephroma
  • Infantile Fibrosarcoma
  • Malignant Solid Tumor
  • Secretory Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children
  • Official Title: A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors

Clinical Trial IDs

  • ORG STUDY ID: 20290
  • SECONDARY ID: LOXO-TRK-15003
  • SECONDARY ID: 2016-003498-16
  • NCT ID: NCT02637687

Conditions

  • Solid Tumors Harboring NTRK Fusion

Interventions

DrugSynonymsArms
Larotrectinib (Vitravki, BAY2757556)LOXO-101Pediatric patients_CNS tumors

Purpose

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.

Detailed Description

      The primary objectives are to determine the safety and efficacy of oral larotrectinib in
      pediatric patients with advanced solid or primary central nervous system (CNS) tumors.

      The secondary objectives comprise e.g. the determination of the pharmacokinetic properties,
      the maximum tolerated dose/ recommended dose and the tumor-type specific efficacy of
      larotrectinib. In addition, pain status and health-related quality of life of the pediatric
      patients will be assessed.
    

Trial Arms

NameTypeDescriptionInterventions
Pediatric patients_Dose 1ExperimentalPediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 50 mg twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Dose 2ExperimentalPediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 75 mg twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Dose 3ExperimentalPediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 100 mg twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Dose 4ExperimentalPediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 150 mg twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Dose 5ExperimentalPediatric cancer patients receiving BAY2757556 at dose of 100 mg/m2 twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Dose 6ExperimentalPediatric cancer patients receiving BAY2757556 at dose of 150 mg/m2 twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Dose 7ExperimentalPediatric cancer patients receiving BAY2757556 at dose of 200 mg/m2 twice daily (dose escalation cohort).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_Recommended doseExperimentalPediatric cancer patients receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily as determined in the dose escalation part (dose expansion cohort, Phase 1).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_FibrosarcomaExperimentalPediatric patients with infantile fibrosarcoma (IFS) and documented ETV6 rearrangement or NTRK fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_ExtracranialExperimentalPediatric patients with other extra-cranial solid tumors and documented ETV6 rearrangement or NTRK fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).
  • Larotrectinib (Vitravki, BAY2757556)
Pediatric patients_CNS tumorsExperimentalPediatric patients with primary central nervous system (CNS) tumors and documented ETV6 rearrangement or NTRK fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).
  • Larotrectinib (Vitravki, BAY2757556)

Eligibility Criteria

        Inclusion Criteria:

          -  Phase 1 (Closed):

               -  Dose escalation: 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. Phase I dose escalation
                  cohorts are closed to enrollment.

               -  Dose expansion: In addition to the above stated inclusion criteria, patients 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 next generation sequencing.

          -  Phase 2:

               -  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
                  mesoblastic nephroma or secretory breast cancer with documented ETV6
                  rearrangement (or NTRK3 rearrangement after discussion with the sponsor) by FISH
                  or RT-PCR or a documented NTRK fusion by next generation sequencing) (identified
                  through molecular assays as routinely performed at CLIA or other similarly
                  certified laboratories). Patients with NTRK-fusion positive benign tumors are
                  also eligible; OR 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.

          -  Patients with primary CNS tumors or cerebral metastasis

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

          -  Adequate hematologic function

          -  Adequate hepatic and renal function

        Exclusion Criteria:

          -  Major surgery within 14 days (2 weeks) prior to C1D1

          -  Clinically significant active cardiovascular disease or history of myocardial
             infarction within 6 months prior to C1D1, ongoing cardiomyopathy; current prolonged
             QTc interval > 480 milliseconds

          -  Active uncontrolled systemic bacterial, viral, or fungal infection

          -  Current treatment with a strong CYP3A4 inhibitor or inducer. Enzyme-inducing
             anti-epileptic drugs (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: Number of participants with adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Proportion of subjects with confirmed best overall response of complete response or partial response, assessed by an independent radiology review committee (IRRC) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate.

Secondary Outcome Measures

Measure:Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
Time Frame:Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Safety Issue:
Description:
Measure:Phase 1: Area under the concentration versus time curve of larotrectinib in plasma (AUC)
Time Frame:Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Safety Issue:
Description:
Measure:Phase 1: Oral clearance (CL/F)
Time Frame:Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Safety Issue:
Description:
Measure:Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
Time Frame:Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Safety Issue:
Description:
Measure:Phase 1: Maximum tolerated dose (MTD)
Time Frame:15 months
Safety Issue:
Description:
Measure:Phase 1: Recommended dose for Phase 2
Time Frame:15 months
Safety Issue:
Description:
Measure:Phase 1: Overall response rate (ORR)
Time Frame:15 months
Safety Issue:
Description:
Measure:Phase 1: Pain level
Time Frame:Up to 5 years
Safety Issue:
Description:Pain Status is assessed by the Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst).
Measure:Phase 1: Health-related quality of life by PedsQL-Core
Time Frame:Up to 5 years
Safety Issue:
Description:The health-related quality of life (HRQoL) is assessed with the Pediatrics Quality of Life - Core Module (PedsQL-Core) questionaire that consists of various age-related items regarding physical, emotional, social and school functioning and gives an overall score between 0 (highest HRQoL) and 144 (lowest HRQoL).
Measure:Phase 2: Overall Response Rate (ORR) by investigator
Time Frame:Up to 5 years
Safety Issue:
Description:Proportion of subjects with confirmed best overall response of complete response or partial response, assessed by the treating investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate.
Measure:Phase 2: Duration of response (DOR) by IRRC
Time Frame:Up to 5 years
Safety Issue:
Description:Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by an independent radiology review committee (IRRC).
Measure:Phase 2: Duration of response (DOR) by investigator
Time Frame:Up to 5 years
Safety Issue:
Description:Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by the treating investigator.
Measure:Phase 2: Proportion of subjects with any tumor regression as a best response
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Phase 2: Progression-free survival (PFS) after larotrectinib
Time Frame:Up to 5 years
Safety Issue:
Description:Number of months from initiation of larotrectinib to either disease progression or death due to any cause.
Measure:Phase 2: Overall survival time
Time Frame:Up to 5 years
Safety Issue:
Description:Number of months from the initiation of larotrectinib to the date of death due to any cause.
Measure:Phase 2: Number of participants with adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Phase 2: Severity of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Phase 2: Clinical benefit rate (CBR) by IRRC
Time Frame:Up to 5 years
Safety Issue:
Description:Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib, assessed by an independent radiology review committee (IRRC).
Measure:Phase 2: Clinical benefit rate (CBR) by investigator
Time Frame:Up to 5 years
Safety Issue:
Description:Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib, assessed by investigator.
Measure:Phase 2: Concordance coefficient
Time Frame:Up to 5 years
Safety Issue:
Description:Describes the concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor and a diagnostic test being evaluated by the sponsor.
Measure:Phase 2: Post-operative stage in patients treated with larotrectinib
Time Frame:Up to 5 years
Safety Issue:
Description:Tumor stage is described according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).
Measure:Phase 2: Surgical margin status in patients treated with larotrectinib
Time Frame:Up to 5 years
Safety Issue:
Description:Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3) Macroscopic residual tumor and 4) Distant metastatic tumor.
Measure:Phase 2: Descriptive analysis of pretreatment surgical plan
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Phase 2: Descriptive analysis of post-treatment plans
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bayer

Trial Keywords

  • Advanced solid tumors
  • Central nervous system (CNS) tumor
  • Extra-cranial tumor
  • Infantile fibrosarcoma (IFS)
  • Neurotrophic tyrosine receptor kinase (NTRK)
  • NTRK1
  • NTRK2
  • NTRK3
  • Fusion Positive
  • TRK fusion
  • TRKA
  • TRKB
  • TRKC
  • ETV6

Last Updated

June 29, 2020