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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors

Conditions
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Solid Tumors Harboring NTRK Fusion

Intervention / Treatment
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* Drug: Larotrectinib (Vitrakvi, BAY2757556)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 dose escalation<br>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) | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Phase 1 dose expansion<br>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) | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Phase 2: Patients with tumors bearing NTRK fusions (IFS)_Cohort 1<br>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) | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Phase 2: Other extra-cranial solid tumors_Cohort 2<br>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) | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Phase 2: Primary CNS tumors_Cohort 3<br>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. | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Phase 2: Bone health assessment_sub-cohort<br>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. | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | DLT: Dose-limiting toxicity. NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events. | From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days) | 
| Phase 1: Number of participants with TEAEs |  | From first dose of larotrectinib up to 93 months | 
| Phase 1: Severity of TEAEs |  | From first dose of larotrectinib up to 93 months | 
| Phase 2: Overall response rate (ORR) by IRRC | 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. | From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum concentration of larotrectinib in plasma (Cmax) |  | 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: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma |  | 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: Oral clearance (CL/F) |  | 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 1: Cerebral spinal fluid/plasma ratio of larotrectinib |  | C1D1 in conjunction with the post-dose 1-hour PK sample | 
| Phase 1: Maximum tolerated dose (MTD) |  | From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months | 
| Phase 1: Recommended dose for Phase 2 |  | 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 1: Overall Response Rate (ORR) | 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. | 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: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale | Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst). | Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months | 
| Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core | 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). | Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months | 
| Phase 2: Best overall response (BOR) | 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 | 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: Duration of response (DOR) | DOR determined by 1) an independent radiology review committee and 2) the treating Investigator. | From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 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 |  | From first dose of Larotrectinib, up to 76 months | 
| Phase 2: Progression-free survival (PFS) |  | From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 112 months | 
| Phase 2: Overall survival (OS) |  | From first dose of Larotrectinib to death (due to any cause), up to 112 months | 
| Phase 2: Number of participants with Treatment emergent adverse events (TEAEs) |  | From first dose of larotrectinib to discontinuation of treatment or death (due to any cayse), up to 112 months | 
| Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03 |  | From first dose of larotrectinib to discontinuation of treatment or death (due to any cause), up to 112 months | 
| Phase 2: Clinical Benefit Rate (CBR) | 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. | 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: Concordance coefficient | Concordance coefficient of intra-patient molecular profile | 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: Post-operative tumor staging | Post-operative stage in patients treated with larotrectinib according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC). | From first dose of Larotrectinib to surgical intervention, up to 112 months | 
| Phase 2: Post-operative surgical margin assessment | Surgical margin status in patients treated with larotrectinib using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems. | From first dose of Larotrectinib to surgical intervention, up to 112 months | 
| Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome | Descriptive analysis of pretreatment surgical plan. | From first dose of Larotrectinib to surgical intervention, up to 112 months | 
| Phase 2: Post-treatment plans to conserve function and cosmetic outcome | Descriptive analysis of post-treatment plans | From surgical intervention to subsequent therapy, up to 112 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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