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

• Register: ClinicalTrials.gov
• Last refreshed on: 1 April 2024
• Main ID: NCT02637687
• Date of registration: 10/12/2015
• Prospective Registration: Yes
• Primary sponsor: Bayer
• Public title: A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children SCOUT
• 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
• Date of first enrolment: December 16, 2015
• Target sample size: 154
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02637687
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

Australia, Canada, China, Czechia, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Sweden, Switzerland, Turkey, Ukraine, United Kingdom, United States

Key inclusion & exclusion 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. 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 lestaurtinib.
Patients who received a TRK inhibitor for less than 28 days of treatment and
discontinued because of intolerance remain eligible.



Age minimum: N/A
Age maximum: 21 Years
Gender: All

Health Condition(s) or Problem(s) studied

Solid Tumors Harboring NTRK Fusion

Intervention(s)

Drug: Larotrectinib (Vitrakvi, BAY2757556)

Primary Outcome(s)

Phase 2: Overall response rate (ORR) by IRRC [Time Frame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months]

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 [Time Frame: From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)]

Phase 1: Number of participants with TEAEs [Time Frame: From first dose of larotrectinib up to 93 months]

Phase 1: Severity of TEAEs [Time Frame: From first dose of larotrectinib up to 93 months]

Secondary Outcome(s)

Phase 1: Maximum tolerated dose (MTD) [Time Frame: From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months]

Phase 2: Post-operative surgical margin assessment [Time Frame: From first dose of Larotrectinib to surgical intervention, up to 112 months]

Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma [Time Frame: 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]

Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core [Time Frame: Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months]

Phase 1: Overall Response Rate (ORR) [Time Frame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 93 months]

Phase 1: Recommended dose for Phase 2 [Time Frame: 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]

Phase 2: Concordance coefficient [Time Frame: 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]

Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome [Time Frame: From first dose of Larotrectinib to surgical intervention, up to 112 months]

Phase 2: Post-operative tumor staging [Time Frame: From first dose of Larotrectinib to surgical intervention, up to 112 months]

Phase 1: Maximum concentration of larotrectinib in plasma (Cmax) [Time Frame: 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]

Phase 1: Oral clearance (CL/F) [Time Frame: 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]

Phase 2: Duration of response (DOR) [Time Frame: From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 months]

Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib [Time Frame: C1D1 in conjunction with the post-dose 1-hour PK sample]

Phase 2: Clinical Benefit Rate (CBR) [Time Frame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months]

Phase 2: Best overall response (BOR) [Time Frame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months]

Phase 2: Number of participants with Treatment emergent adverse events (TEAEs) [Time Frame: From first dose of larotrectinib to discontinuation of treatment or death (due to any cayse), up to 112 months]

Phase 2: Post-treatment plans to conserve function and cosmetic outcome [Time Frame: From surgical intervention to subsequent therapy, up to 112 months]

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 [Time Frame: From first dose of Larotrectinib, up to 76 months]

Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03 [Time Frame: From first dose of larotrectinib to discontinuation of treatment or death (due to any cause), up to 112 months]

Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale [Time Frame: Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months]

Phase 2: Overall survival (OS) [Time Frame: From first dose of Larotrectinib to death (due to any cause), up to 112 months]

Phase 2: Progression-free survival (PFS) [Time Frame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 112 months]

Secondary ID(s)

LOXO-TRK-15003

2016-003498-16

2022-502668-20-00

20290

Source(s) of Monetary Support

Please refer to primary and secondary sponsors