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

Sponsor

Bayer (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02637687

Collaborator

(none)

155

Enrollment

Locations

Arms

129.2

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors Harboring NTRK Fusion	Drug: Larotrectinib (Vitrakvi, BAY2757556)	Phase 1/Phase 2

Detailed Description

The primary objectives are to determine the safety and efficacy of oral larotrectinib in pediatric patients with advanced solid or primary central nervous system (CNS) tumors.

The secondary objectives comprise e.g. the determination of the pharmacokinetic properties, the maximum tolerated dose/ recommended dose and the tumor-type specific efficacy of larotrectinib. In addition, pain status and health-related quality of life of the pediatric patients will be assessed.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

155 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 16, 2015

Anticipated Primary Completion Date :

Jul 1, 2026

Anticipated Study Completion Date :

Sep 22, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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 [From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)]
DLT: Dose-limiting toxicity. NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events.
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 [From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months]
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.

Secondary Outcome Measures

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) [From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 93 months]
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.
Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale [Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months]
Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst).
Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core [Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months]
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).
Phase 2: Best overall response (BOR) [From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months]
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
Phase 2: Duration of response (DOR) [From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 months]
DOR determined by 1) an independent radiology review committee and 2) the treating Investigator.
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) [From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death (due to any cause), up to 76 months]
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.
Phase 2: Concordance coefficient [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]
Concordance coefficient of intra-patient molecular profile
Phase 2: Post-operative tumor staging [From first dose of Larotrectinib to surgical intervention, up to 112 months]
Post-operative stage in patients treated with larotrectinib according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).
Phase 2: Post-operative surgical margin assessment [From first dose of Larotrectinib to surgical intervention, up to 112 months]
Surgical margin status in patients treated with larotrectinib using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems.
Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome [From first dose of Larotrectinib to surgical intervention, up to 112 months]
Descriptive analysis of pretreatment surgical plan.
Phase 2: Post-treatment plans to conserve function and cosmetic outcome [From surgical intervention to subsequent therapy, up to 112 months]
Descriptive analysis of post-treatment plans

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 or a documented NTRK fusion by next generation sequencing) (identified through molecular assays as routinely performed at CLIA or other similarly certified laboratories). 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
2	UCLA Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
3	Lucille Salter Packard Children's Hospital at Stanford	Palo Alto	California	United States	94304
4	Nemours Children's Hospital (Orlando)	Orlando	Florida	United States	32827
5	Boston hildren's Hospital	Boston	Massachusetts	United States	02115
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Cincinnati Children's Hospital and Medical Center	Cincinnati	Ohio	United States	45229-3039
8	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
9	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
10	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75235
11	Seattle Children's Hospital	Seattle	Washington	United States	98105
12	Sydney Children's Hospital	Sydney	New South Wales	Australia	2031
13	Women's and Children's Hospital	North Adelaide	South Australia	Australia	5006
14	Royal Children's Hospital Melbourne	Parkville	Victoria	Australia	3052
15	Alberta Childrens Hospital	Calgary	Alberta	Canada	T3B 6A8
16	British Columbia Childrens Hospital	Vancouver	British Columbia	Canada	V6H 3V4
17	The Hospital for Sick Children (SickKids)	Toronto	Ontario	Canada	M5G 1X8
18	CHU Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
19	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong	China	510060
20	Beijing Children's Hospital, Capital Medical University	Beijing		China	100045
21	Tianjin Medical University Cancer Institiute & Hospital	Tianjin		China	300060
22	FN Brno - Detska nemocnice	Brno		Czechia	625 00
23	Fakultni nemocnice v Motole	Praha 5		Czechia	150 06
24	Rigshospitalet, Dept Pediatrics & Adelescent Med.	Copenhagen		Denmark	2100
25	Institut Curie - Ulm - Paris	PARIS cedex 5		France	75248
26	Institut Gustave Roussy	Villejuif Cedex		France	94805
27	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg	Germany	69120
28	Olgahospital	Stuttgart	Baden-Württemberg	Germany	70174
29	Charité - Campus Virchow-Klinikum (CVK)	Berlin		Germany	13353
30	Our Lady's Hospital For Sick Children	Crumlin	Dublin	Ireland	12
31	Clalit Health Services Schneider Children's Medical Center	Petach Tikva		Israel	4920235
32	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia	Italy	20133
33	A.O.U. di Padova	Padova	Veneto	Italy	35128
34	Kanagawa Children's Medical Center	Yokohama	Kanagawa	Japan	232-8555
35	Tohoku University Hospital	Sendai	Miyagi	Japan	980-8574
36	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
37	Kyushu University Hospital	Fukuoka		Japan	812-8582
38	Osaka City Hospital Organization Osaka City General Hospital	Osaka		Japan	534-0021
39	Seoul National University Hospital	Seoul	Seoul Teugbyeolsi	Korea, Republic of	03080
40	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
41	Prinses Maxima Centrum	Utrecht		Netherlands	3584 CS
42	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-952
43	Center of Pediatric Hematology, Oncology and Immunology	Moscow		Russian Federation	117997
44	Morozov Children's City Clinical Hospital	Moscow		Russian Federation	119049
45	Ciutat Sanitària i Universitaria de la Vall d'Hebron	Barcelona		Spain	08035
46	Karolinska Universitetssjukhuset i Solna	Stockholm		Sweden	171 76
47	Universitätskinderspital Zürich	Zürich		Switzerland	8032
48	Istanbul Universitesi Istanbul Tip Fakultesi	Istanbul		Turkey	34093
49	National Cancer Institute-Ukraine	Kiev		Ukraine	03022
50	Western Ukrainian Specialized Pediatric Medical Centre	Lviv		Ukraine	79035
51	Royal Marsden NHS Trust (Surrey)	Sutton	Surrey	United Kingdom	SM2 5PT