do_not_disturb_altRecruitment Complete

Solid tumors harboring NTRK fusion

A study to test the safety and efficacy of the drug larotrectinib for the treatment of tumors with NTRK-fusion in children

Trial 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.

Key Participants Requirements

Sex

All

Age

NaN - 21 Years
  • - 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
  • - 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.

Trial summary

Enrollment Goal
154
Trial Dates
December 2015 - September 2026
Phase
Phase 1/Phase 2
Could I Receive a placebo
No
Products
Vitrakvi (Larotrectinib, BAY2757556)
Accepts Healthy Volunteer
No

Where to participate

StatusInstitutionLocation
Active, not recruiting
Institut Curie - Ulm - ParisPARIS cedex 5, 75248, France
Active, not recruiting
Gustave Roussy - Departement Oncologie-RadiotherapieVILLEJUIF CEDEX, 94805, France
Completed
Uniwersyteckie Centrum KliniczneGdansk, 80-214, Poland
Active, not recruiting
Karolinska Universitetssjukhuset i SolnaStockholm, 171 76, Sweden
Active, not recruiting
Clalit Health Services Schneider Children's Medical CenterPetach Tikva, 4920235, Israel
Active, not recruiting
Sydney Children’s HospitalSydney, 2031, Australia
Completed
Royal Children's Hospital MelbourneParkville, 3052, Australia
Active, not recruiting
Universitätskinderspital ZürichZürich, 8032, Switzerland
Active, not recruiting
Rigshospitalet - Børn og UngeCopenhagen, 2100, Denmark
Completed
Nemours Children’s Hospital (Orlando)Orlando, 32827, United States
Active, not recruiting
Fondazione IRCCS Istituto Nazionale dei Tumori - S. C. Pediatria OncologicaMilano, 20133, Italy
Withdrawn
A.O.U. di PadovaPadova, 35128, Italy
Active, not recruiting
Royal Marsden NHS Trust (Surrey)Sutton, SM2 5PT, United Kingdom
Active, not recruiting
Children's Health Ireland CrumlinCrumlin, 12, Ireland
Active, not recruiting
University of Texas Southwestern Medical CenterDallas, 75390, United States
Active, not recruiting
Children's Hospital Los Angeles - Hematology/OncologyLos Angeles, 90027, United States
Active, not recruiting
Dana-Farber Cancer InstituteBoston, 02215, United States
Active, not recruiting
Memorial Sloan Kettering Cancer CenterNew York, 10021-0005, United States
Active, not recruiting
St. Jude Children's Research HospitalMemphis, 38105, United States
Active, not recruiting
Seattle Children's HospitalSeattle, 98105, United States
Completed
Cincinnati Children's Hospital Medical Center | Division of Nephrology and HypertensionCincinnati, 45229, United States
Active, not recruiting
UCLA Jonsson Comprehensive Cancer CenterLos Angeles, 90095-1781, United States
Completed
Lucille Packard Children's Hospital Stanford - Pediatric NephrologyPalo Alto, 94304, United States
Active, not recruiting
Tianjin Medical University Cancer Institute & HospitalTianjin, 300000, China
Active, not recruiting
Beijing Children's Hospital, Capital Medical UniversityBeijing, 100045, China
Withdrawn
Tohoku University HospitalSendai, 980-8574, Japan
Active, not recruiting
National Cancer Center HospitalChuo-ku, 104-0045, Japan
Active, not recruiting
Sun Yat-sen University Cancer CenterGuangzhou, 510000, China
Active, not recruiting
The Hospital for Sick Children (SickKids)Toronto, M5G 1X8, Canada
Active, not recruiting
CHU Sainte-JustineMontreal, H3T 1C5, Canada
Active, not recruiting
Charité - Campus Virchow-Klinikum (CVK), Klinik für Pädiatrie mit Schwerpunkt Onkologie und HämatologieBerlin, 13353, Germany
Active, not recruiting
KLINIKUM STUTTGART - Olgahospital | Paediatrie 5 (Onkologie, Haematologie, Immunologie)Stuttgart, 70174, Germany
Active, not recruiting
Universitaetsklinikum Heidelberg - KiTZ | Klinik für Paediatrische Onkologie, Haematologie, Immunologie und PneumologieHeidelberg, 69120, Germany
Active, not recruiting
Ciutat Sanitaria i Universitaria de la Vall d'HebronBarcelona, 08035, Spain
Active, not recruiting
Prinses Maxima CentrumUTRECHT, 3584 CS, Netherlands
Completed
Seoul National University HospitalSeoul, 3080, Korea,_republic_of
Active, not recruiting
Severance Hospital, Yonsei University Health SystemSeoul, 03722, Korea,_republic_of
Active, not recruiting
Kanagawa Children's Medical CenterYokohama, 252-8555, Japan
Withdrawn
Local Incorporated Administrative Agency Osaka City Hospital Organization Osaka City General HospitalOsaka, 534-0021, Japan
Completed
Kyushu University HospitalFukuoka, 812-8582, Japan
Active, not recruiting
BC Children's Hospital - Hematology/OncologyVancouver, V6H 3N1, Canada
Active, not recruiting
Children's Hospital of Philadelphia - Hematology/OncologyPhiladelphia, 19104, United States
Withdrawn
Alberta Childrens HospitalCalgary, T3B 6A8, Canada
Active, not recruiting
Fakultni nemocnice v MotolePraha 5, 150 06, Czech Republic
Completed
FN Brno - Detska nemocniceBrno, 613 00, Czech Republic
Active, not recruiting
Istanbul Universitesi Istanbul Tip FakultesiIstanbul, 34093, Turkey
Withdrawn
Center of Pediatric Hematology, Oncology and ImmunologyMoscow, 117997, Russian Federation
Active, not recruiting
Western Ukrainian Specialized Pediatric Medial Centre, Surgical DepartmentLviv, 79035, Ukraine
Completed
Governmental Noncommercial Institution "National Cancer InstituteKyiv, 03022, Ukraine
Withdrawn
Morozov Children's City Clinical HospitalMoscow, 119049, Russian Federation
Active, not recruiting
Women's and Children's HospitalNorth Adelaide, 5006, Australia

Primary Outcome

  • 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.
    date_rangeTime Frame:
    From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)
  • Phase 1: Number of participants with TEAEs
    date_rangeTime Frame:
    From first dose of larotrectinib up to 93 months
  • Phase 1: Severity of TEAEs
    date_rangeTime 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.
    date_rangeTime Frame:
    From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months

Secondary Outcome

  • Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
    date_rangeTime 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
    date_rangeTime 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)
    date_rangeTime 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 1: Cerebral spinal fluid/plasma ratio of larotrectinib
    date_rangeTime Frame:
    C1D1 in conjunction with the post-dose 1-hour PK sample
  • Phase 1: Maximum tolerated dose (MTD)
    date_rangeTime 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
    date_rangeTime 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.
    date_rangeTime 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).
    date_rangeTime 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).
    date_rangeTime 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
    date_rangeTime 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.
    date_rangeTime 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
    date_rangeTime Frame:
    From first dose of Larotrectinib, up to 76 months
  • Phase 2: Progression-free survival (PFS)
    date_rangeTime 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)
    date_rangeTime 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)
    date_rangeTime 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
    date_rangeTime 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.
    date_rangeTime 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
    date_rangeTime 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).
    date_rangeTime 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.
    date_rangeTime 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.
    date_rangeTime 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
    date_rangeTime Frame:
    From surgical intervention to subsequent therapy, up to 112 months

Trial design

A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors
Trial Type
Interventional
Intervention Type
Drug
Trial Purpose
Treatment
Allocation
Non-randomized
Blinding
N/A
Assignment
Parallel Assignment
Trial Arms
6