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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02637687
Registration number
NCT02637687
Ethics application status
Date submitted
10/12/2015
Date registered
22/12/2015
Date last updated
8/05/2024
Titles & IDs
Public title
A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children
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Scientific title
A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors
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Secondary ID [1]
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LOXO-TRK-15003
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Secondary ID [2]
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20290
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Universal Trial Number (UTN)
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Trial acronym
SCOUT
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Solid Tumors Harboring NTRK Fusion
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Condition category
Condition code
Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - Larotrectinib (Vitrakvi, BAY2757556)
Experimental: Phase 1 dose escalation - Patients will receive the different levels of dose on Day 1 (BID in accordance with the cohort assignment). Each cycle will consist of 28 days of continuous dosing.
Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
Experimental: Phase 1 dose expansion - Patients who are enrolled in the expansion cohort, following the formal dose escalation phase of the study.
Distinct from the Phase 1 dose escalation cohort, the Phase 1 expansion cohort will enroll pediatric patients with advanced solid or primary CNS tumors with a documented NTRK gene fusion, or in the case of IFS, CMN or SBC with documented ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by NGS.
This expansion cohort will follow the same schedule of assessments as the dose escalation cohorts. (arm closed)
Experimental: Phase 2: Patients with tumors bearing NTRK fusions (IFS)_Cohort 1 - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.
Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
Experimental: Phase 2: Other extra-cranial solid tumors_Cohort 2 - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.
Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)
Experimental: Phase 2: Primary CNS tumors_Cohort 3 - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.
Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation.
Experimental: Phase 2: Bone health assessment_sub-cohort - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.
Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation.
Patients in this group will undergo bone health assessments in addition to all other efficacy and safety assessments.
Treatment: Drugs: Larotrectinib (Vitrakvi, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Phase 1: Number of participants in an assigned dose cohort with treatment emergent adverse events (TEAEs) by grade assessed by NCI-CTCAE v 4.03 who experience a DLT
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Assessment method [1]
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DLT: Dose-limiting toxicity. NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events.
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Timepoint [1]
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From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)
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Primary outcome [2]
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Phase 1: Number of participants with TEAEs
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Assessment method [2]
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Timepoint [2]
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From first dose of larotrectinib up to 93 months
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Primary outcome [3]
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Phase 1: Severity of TEAEs
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Assessment method [3]
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Timepoint [3]
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From first dose of larotrectinib up to 93 months
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Primary outcome [4]
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Phase 2: Overall response rate (ORR) by IRRC
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Assessment method [4]
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Proportion of participants with a best overall response of complete response (CR) or partial response (PR) as determined by an independent radiology review committee (IRRC) based on Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, Response Assessment in Neuro Oncology (RANO) or International Neuroblastoma Response Criteria (INRC) as appropriate to tumor type who express NTRK gene fusions.
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Timepoint [4]
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From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months
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Secondary outcome [1]
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Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
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Assessment method [1]
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Timepoint [1]
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Cohort 1 and 2: Cycle 1 Day 1 (C1D1) at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose
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Secondary outcome [2]
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Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma
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Assessment method [2]
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Timepoint [2]
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Cohort 1 and 2: C1D1 at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dose
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Secondary outcome [3]
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Phase 1: Oral clearance (CL/F)
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Assessment method [3]
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Timepoint [3]
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Cohort 1 and 2: C1D1 at 1 and 4 hours post-dose and C2D1 at pre-dose, and at 1 and 4 hours post-dose; Cohort 3 and Dose Expansion Cohort: C1D1 at 1 and 4 hours post-dose and C4D1 at pre-dose, 1 and 4 hours post-dos
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Secondary outcome [4]
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Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
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Assessment method [4]
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Timepoint [4]
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C1D1 in conjunction with the post-dose 1-hour PK sample
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Secondary outcome [5]
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Phase 1: Maximum tolerated dose (MTD)
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Assessment method [5]
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Timepoint [5]
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From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months
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Secondary outcome [6]
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Phase 1: Recommended dose for Phase 2
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Assessment method [6]
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Timepoint [6]
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From the date a participants from assigned Cohort was administered the first dose to the date of the last dose for the last patient from the dose escalation phase, up to 16 months
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Secondary outcome [7]
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Phase 1: Overall Response Rate (ORR)
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Assessment method [7]
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Proportion of participants with best overall response (BOR) of CR and PR; PFS, CBR and maximum change in tumor burden as assessed based on RECIST 1.1, INRC or RANO as appropriate for tumor type by IRRC.
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Timepoint [7]
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From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 93 months
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Secondary outcome [8]
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Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale
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Assessment method [8]
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Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst).
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Timepoint [8]
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Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months
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Secondary outcome [9]
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Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core
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Assessment method [9]
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The health-related quality of life (HRQoL) is assessed with the Pediatrics Quality of Life - Core Module (PedsQL-Core) questionnaire 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).
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Timepoint [9]
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Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months
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Secondary outcome [10]
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Phase 2: Best overall response (BOR)
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Assessment method [10]
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Participants with best overall response (BOR) of either CR or PR determined by Investigator's or IRC's response assessment based on RANO, INRC and RECIST 1.1 as appropriate for tumor type
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Timepoint [10]
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From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months
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Secondary outcome [11]
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Phase 2: Duration of response (DOR)
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Assessment method [11]
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DOR determined by 1) an independent radiology review committee and 2) the treating Investigator.
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Timepoint [11]
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From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 months
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Secondary outcome [12]
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Phase 2: Proportion of patients with any tumor regression (i.e., any decrease from baseline of the longest diameters of target lesions) as a best response
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Assessment method [12]
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Timepoint [12]
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From first dose of Larotrectinib, up to 76 months
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Secondary outcome [13]
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Phase 2: Progression-free survival (PFS)
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Assessment method [13]
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Timepoint [13]
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From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 112 months
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Secondary outcome [14]
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Phase 2: Overall survival (OS)
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Assessment method [14]
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Timepoint [14]
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From first dose of Larotrectinib to death (due to any cause), up to 112 months
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Secondary outcome [15]
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Phase 2: Number of participants with Treatment emergent adverse events (TEAEs)
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Assessment method [15]
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Timepoint [15]
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From first dose of larotrectinib to discontinuation of treatment or death (due to any cayse), up to 112 months
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Secondary outcome [16]
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Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03
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Assessment method [16]
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Timepoint [16]
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From first dose of larotrectinib to discontinuation of treatment or death (due to any cause), up to 112 months
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Secondary outcome [17]
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Phase 2: Clinical Benefit Rate (CBR)
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Assessment method [17]
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CBR (i.e., best overall response of CR, PR or SD lasting 16 weeks or more as determined by 1) an independent radiology review committee (IRC) and 2) by the treating Investigator.
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Timepoint [17]
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From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months
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Secondary outcome [18]
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Phase 2: Concordance coefficient
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Assessment method [18]
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Concordance coefficient of intra-patient molecular profile
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Timepoint [18]
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From baseline/screening and if feasible end of treatment (EOT) and or PD and or at re-start of study treatment following a "drug holiday" and disease recurrence, up to 112 months
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Secondary outcome [19]
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Phase 2: Post-operative tumor staging
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Assessment method [19]
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Post-operative stage in patients treated with larotrectinib according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).
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Timepoint [19]
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From first dose of Larotrectinib to surgical intervention, up to 112 months
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Secondary outcome [20]
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Phase 2: Post-operative surgical margin assessment
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Assessment method [20]
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Surgical margin status in patients treated with larotrectinib using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems.
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Timepoint [20]
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From first dose of Larotrectinib to surgical intervention, up to 112 months
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Secondary outcome [21]
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Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome
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Assessment method [21]
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Descriptive analysis of pretreatment surgical plan.
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Timepoint [21]
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From first dose of Larotrectinib to surgical intervention, up to 112 months
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Secondary outcome [22]
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Phase 2: Post-treatment plans to conserve function and cosmetic outcome
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Assessment method [22]
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Descriptive analysis of post-treatment plans
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Timepoint [22]
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From surgical intervention to subsequent therapy, up to 112 months
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Eligibility
Key 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. 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
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Minimum age
No limit
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Maximum age
21
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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 lestaurtinib.
Patients who received a TRK inhibitor for less than 28 days of treatment and
discontinued because of intolerance remain eligible.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
16/12/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
22/09/2026
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Actual
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Sample size
Target
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Accrual to date
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Final
154
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
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Recruitment hospital [1]
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Sydney Children's Hospital - Sydney
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Recruitment hospital [2]
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Women's and Children's Hospital - North Adelaide
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Recruitment hospital [3]
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Royal Children's Hospital Melbourne - Parkville
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Recruitment postcode(s) [1]
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2031 - Sydney
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Recruitment postcode(s) [2]
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5006 - North Adelaide
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Recruitment postcode(s) [3]
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3052 - Parkville
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Recruitment outside Australia
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United States of America
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California
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United States of America
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Florida
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United States of America
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Massachusetts
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United States of America
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New York
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United States of America
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Ohio
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United States of America
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Pennsylvania
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United States of America
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Tennessee
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United States of America
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Texas
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United States of America
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Washington
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Canada
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British Columbia
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Canada
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Ontario
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Canada
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Quebec
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China
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Guangdong
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China
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Beijing
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China
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Tianjin
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Czechia
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Praha 5
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Denmark
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Copenhagen
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France
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PARIS cedex 5
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France
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Villejuif Cedex
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Germany
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Baden-Württemberg
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Germany
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Berlin
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Ireland
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Dublin
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Israel
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Petach Tikva
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Italy
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Lombardia
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Japan
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Kanagawa
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Japan
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Tokyo
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Japan
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Fukuoka
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Korea, Republic of
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Seoul Teugbyeolsi
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Netherlands
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Utrecht
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Poland
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Gdansk
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Spain
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Barcelona
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Sweden
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Stockholm
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Switzerland
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Zürich
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Turkey
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Istanbul
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Ukraine
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Lviv
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United Kingdom
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Surrey
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Bayer
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02637687
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02637687
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