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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT02637687
Other study ID # 20290
Secondary ID LOXO-TRK-1500320
Status Active, not recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date December 16, 2015
Est. completion date September 22, 2026

Study information

Verified date May 2024
Source Bayer
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 154
Est. completion date September 22, 2026
Est. primary completion date July 25, 2024
Accepts healthy volunteers No
Gender All
Age group N/A to 21 Years
Eligibility 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.

Study Design


Related Conditions & MeSH terms

  • Neoplasms
  • Solid Tumors Harboring NTRK Fusion

Intervention

Drug:
Larotrectinib (Vitrakvi, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.

Locations

Country Name City State
Australia Women's and Children's Hospital North Adelaide South Australia
Australia Royal Children's Hospital Melbourne Parkville Victoria
Australia Sydney Children's Hospital Sydney New South Wales
Canada CHU Sainte-Justine Montreal Quebec
Canada The Hospital for Sick Children (SickKids) Toronto Ontario
Canada British Columbia Childrens Hospital Vancouver British Columbia
China Beijing Children's Hospital, Capital Medical University Beijing
China Sun Yat-sen University Cancer Center Guangzhou Guangdong
China Tianjin Medical University Cancer Institute & Hospital Tianjin
Czechia Fakultni nemocnice v Motole Praha 5
Denmark Rigshospitalet, Dept Pediatrics & Adelescent Med. Copenhagen
France Institut Curie - Ulm - Paris PARIS cedex 5
France Institut Gustave Roussy - Département de Médecine Oncologique Villejuif Cedex
Germany Charité - Campus Virchow-Klinikum (CVK) Berlin
Germany Universitätsklinikum Heidelberg Heidelberg Baden-Württemberg
Germany KLINIKUM STUTTGART - Olgahospital | Paediatrie 5 (Onkologie, Haematologie, Immunologie) Stuttgart Baden-Württemberg
Ireland Our Lady's Hospital For Sick Children Crumlin Dublin
Israel Clalit Health Services Schneider Children's Medical Center Petach Tikva
Italy Fondazione IRCCS Istituto Nazionale dei Tumori Milano Lombardia
Japan National Cancer Center Hospital Chuo-ku Tokyo
Japan Kyushu University Hospital Fukuoka
Japan Kanagawa Children's Medical Center Yokohama Kanagawa
Korea, Republic of Seoul National University Hospital Seoul Seoul Teugbyeolsi
Netherlands Prinses Maxima Centrum Utrecht
Poland Uniwersyteckie Centrum Kliniczne Gdansk
Spain Ciutat Sanitaria i Universitaria de la Vall d'Hebron Barcelona
Sweden Karolinska Universitetssjukhuset i Solna Stockholm
Switzerland Universitätskinderspital Zürich Zürich
Turkey Istanbul Universitesi Istanbul Tip Fakultesi Istanbul
Ukraine Western Ukrainian Specialized Pediatric Medical Centre Lviv
United Kingdom Royal Marsden NHS Trust (Surrey) Sutton Surrey
United States Boston Children's Hospital Boston Massachusetts
United States Cincinnati Children's Hospital and Medical Center Cincinnati Ohio
United States University of Texas Southwestern Medical Center Dallas Texas
United States Children's Hospital of Los Angeles Los Angeles California
United States UCLA Jonsson Comprehensive Cancer Center Los Angeles California
United States St. Jude Children's Research Hospital Memphis Tennessee
United States Memorial Sloan Kettering Cancer Center New York New York
United States Nemours Children's Hospital (Orlando) Orlando Florida
United States Lucille Salter Packard Children's Hospital at Stanford Palo Alto California
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States Seattle Children's Hospital Seattle Washington

Sponsors (1)

Lead Sponsor Collaborator
Bayer

Countries where clinical trial is conducted

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

Outcome

Type Measure Description Time frame Safety issue
Primary 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)
Primary Phase 1: Number of participants with TEAEs From first dose of larotrectinib up to 93 months
Primary Phase 1: Severity of TEAEs From first dose of larotrectinib up to 93 months
Primary 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 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
Secondary 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
Secondary 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
Secondary Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib C1D1 in conjunction with the post-dose 1-hour PK sample
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary Phase 2: Overall survival (OS) From first dose of Larotrectinib to death (due to any cause), up to 112 months
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
Secondary 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
See also
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Active, not recruiting NCT02576431 - A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors Phase 2
Completed NCT02122913 - A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer Phase 1
Completed NCT03215511 - A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer Phase 1
Completed NCT04275960 - Study in Healthy Adult Male Participants to Gather Information How the Human Body Absorbs, Distributes and Excretes the Study Drug Selitrectinib Including the Effect of the Interaction of Food With the Study Drug on the Human Body Phase 1
Completed NCT04771390 - Study to Compare How the Body Absorbs, Distributes and Excretes the Drug Selitrectinib (BAY2731954) Given as Two Different Tablet Formulations or as Liquid Formulations Including the Effect of Food on the Absorption, Distribution or Excretion of the Different Formulations in Healthy Participants Phase 1
Completed NCT05192642 - A Study Called VICTORIA to Learn More About How Well Larotrectinib Works in Adults With TRK Fusion-positive Cancer by Comparing Larotrectinib Data From Clinical Studies With Data of Other Treatments From Actual Practice
No longer available NCT03206931 - Expanded Access to Provide Selitrectinib for the Treatment of Cancers With a NTRK Gene Fusion