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

Solid Tumors Harboring NTRK Fusion Clinical Trial

— SCOUT  

Official title:

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

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
• Start date: December 16, 2015
• Est. completion date: September 22, 2026

Study information

• Verified date: March 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• 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.

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