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

Phase 2Active Not RecruitingNCT02637687

Bayer154 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

154

Conditions

Solid Tumors Harboring NTRK Fusion

Interventions

Eligibility

Sex: ALLMax age: 21 Years

Medical Language ↔ Plain English

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.

Locations (45)

Children's Hospital Los Angeles - Hematology/Oncology

Los Angeles, California, United States

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, California, United States

Lucille Packard Children's Hospital Stanford - Pediatric Nephrology

Palo Alto, California, United States

Nemours Children's Hospital - Florida - Hematology / Oncology

Orlando, Florida, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

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.

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

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.

Time frame: From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months

Secondary Outcomes

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: 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: Oral clearance (CL/F)

Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib

Time frame: C1D1 in conjunction with the post-dose 1-hour PK sample

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 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 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.

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: 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).

Time frame: 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).

Time frame: 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

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: Duration of response (DOR)

DOR determined by 1) an independent radiology review committee and 2) the treating Investigator.

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 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: 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

Phase 2: Overall survival (OS)

Time frame: 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)

Time frame: 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

Time frame: 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.

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: Concordance coefficient

Concordance coefficient of intra-patient molecular profile

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: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: From surgical intervention to subsequent therapy, up to 112 months