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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02637687




Registration number
NCT02637687
Ethics application status
Date submitted
10/12/2015
Date registered
22/12/2015

Titles & IDs
Public title
A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children
Scientific title
A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors
Secondary ID [1] 0 0
LOXO-TRK-15003
Secondary ID [2] 0 0
20290
Universal Trial Number (UTN)
Trial acronym
SCOUT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumors Harboring NTRK Fusion 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Larotrectinib (Vitrakvi, BAY2757556)

Experimental: Phase 1 dose escalation - Patients will receive the different levels of dose on Day 1 (BID in accordance with the cohort assignment). Each cycle will consist of 28 days of continuous dosing.

Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)

Experimental: Phase 1 dose expansion - Patients who are enrolled in the expansion cohort, following the formal dose escalation phase of the study.

Distinct from the Phase 1 dose escalation cohort, the Phase 1 expansion cohort will enroll pediatric patients with advanced solid or primary CNS tumors with a documented NTRK gene fusion, or in the case of IFS, CMN or SBC with documented ETV6 rearrangement by FISH or RT-PCR or a documented NTRK fusion by NGS.

This expansion cohort will follow the same schedule of assessments as the dose escalation cohorts. (arm closed)

Experimental: Phase 2: Patients with tumors bearing NTRK fusions (IFS)_Cohort 1 - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.

Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)

Experimental: Phase 2: Other extra-cranial solid tumors_Cohort 2 - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.

Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. (arm closed)

Experimental: Phase 2: Primary CNS tumors_Cohort 3 - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.

Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation.

Experimental: Phase 2: Bone health assessment_sub-cohort - Patients will receive larotrectinib dose on Day 1 (BID in accordance with the cohort assignment) at the recommended Phase 2 dose as determined in the Phase 1 portion of this study. Each cycle will consist of 28 days of continuous dosing.

Individual patients will continue daily larotrectinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation.

Patients in this group will undergo bone health assessments in addition to all other efficacy and safety assessments.


Treatment: Drugs: Larotrectinib (Vitrakvi, BAY2757556)
BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
From Day 1 to Day 28 of Cycle 1 (1 Cycle=28 days)
Primary outcome [2] 0 0
Phase 1: Number of participants with TEAEs
Timepoint [2] 0 0
From first dose of larotrectinib up to 93 months
Primary outcome [3] 0 0
Phase 1: Severity of TEAEs
Timepoint [3] 0 0
From first dose of larotrectinib up to 93 months
Primary outcome [4] 0 0
Phase 2: Overall response rate (ORR) by IRRC
Timepoint [4] 0 0
From first dose of Larotrectinib to disease progression or subsequent therapy or surgical intervention or death, up to 76 months
Secondary outcome [1] 0 0
Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
Timepoint [1] 0 0
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 outcome [2] 0 0
Phase 1: Area under the concentration versus time curve from time 0 to t (AUC0-t) of larotrectinib in plasma
Timepoint [2] 0 0
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 outcome [3] 0 0
Phase 1: Oral clearance (CL/F)
Timepoint [3] 0 0
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 outcome [4] 0 0
Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
Timepoint [4] 0 0
C1D1 in conjunction with the post-dose 1-hour PK sample
Secondary outcome [5] 0 0
Phase 1: Maximum tolerated dose (MTD)
Timepoint [5] 0 0
From C1D1 to C1D28 of treatment of each participant in each of the assigned dose cohort, up to 16 months
Secondary outcome [6] 0 0
Phase 1: Recommended dose for Phase 2
Timepoint [6] 0 0
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 outcome [7] 0 0
Phase 1: Overall Response Rate (ORR)
Timepoint [7] 0 0
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 outcome [8] 0 0
Phase 1: Mean change from baseline in Pain scores as assessed by the Wong-Baker Faces scale
Timepoint [8] 0 0
Baseline and D1 of every cycle (1 Cycle=28 days), up to 93 months
Secondary outcome [9] 0 0
Phase 1: Mean change in Health-related quality of life scores by PedsQL-Core
Timepoint [9] 0 0
Baseline and D1 of every cycle (1 Cycle=28 days), Up to 93 months
Secondary outcome [10] 0 0
Phase 2: Best overall response (BOR)
Timepoint [10] 0 0
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 outcome [11] 0 0
Phase 2: Duration of response (DOR)
Timepoint [11] 0 0
From start of first objective response of confirmed CR or PR to progression or death (due to any cause), up to 76 months
Secondary outcome [12] 0 0
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
Timepoint [12] 0 0
From first dose of Larotrectinib, up to 76 months
Secondary outcome [13] 0 0
Phase 2: Progression-free survival (PFS)
Timepoint [13] 0 0
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 outcome [14] 0 0
Phase 2: Overall survival (OS)
Timepoint [14] 0 0
From first dose of Larotrectinib to death (due to any cause), up to 112 months
Secondary outcome [15] 0 0
Phase 2: Number of participants with Treatment emergent adverse events (TEAEs)
Timepoint [15] 0 0
From first dose of larotrectinib to discontinuation of treatment or death (due to any cayse), up to 112 months
Secondary outcome [16] 0 0
Phase 2: Severity of adverse events as assessed by NCI-CTCAE grading V 4.03
Timepoint [16] 0 0
From first dose of larotrectinib to discontinuation of treatment or death (due to any cause), up to 112 months
Secondary outcome [17] 0 0
Phase 2: Clinical Benefit Rate (CBR)
Timepoint [17] 0 0
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 outcome [18] 0 0
Phase 2: Concordance coefficient
Timepoint [18] 0 0
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 outcome [19] 0 0
Phase 2: Post-operative tumor staging
Timepoint [19] 0 0
From first dose of Larotrectinib to surgical intervention, up to 112 months
Secondary outcome [20] 0 0
Phase 2: Post-operative surgical margin assessment
Timepoint [20] 0 0
From first dose of Larotrectinib to surgical intervention, up to 112 months
Secondary outcome [21] 0 0
Phase 2: Pre-treatment surgical plan to preserve function and cosmetic outcome
Timepoint [21] 0 0
From first dose of Larotrectinib to surgical intervention, up to 112 months
Secondary outcome [22] 0 0
Phase 2: Post-treatment plans to conserve function and cosmetic outcome
Timepoint [22] 0 0
From surgical intervention to subsequent therapy, up to 112 months

Eligibility
Key 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
Minimum age
No limit
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
16/12/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/09/2026
Actual
Sample size
Target
Accrual to date
Final
154
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Sydney
Recruitment hospital [2] 0 0
Women's and Children's Hospital - North Adelaide
Recruitment hospital [3] 0 0
Royal Children's Hospital Melbourne - Parkville
Recruitment postcode(s) [1] 0 0
2031 - Sydney
Recruitment postcode(s) [2] 0 0
5006 - North Adelaide
Recruitment postcode(s) [3] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
Ohio
Country [6] 0 0
United States of America
State/province [6] 0 0
Pennsylvania
Country [7] 0 0
United States of America
State/province [7] 0 0
Tennessee
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Washington
Country [10] 0 0
Canada
State/province [10] 0 0
British Columbia
Country [11] 0 0
Canada
State/province [11] 0 0
Ontario
Country [12] 0 0
Canada
State/province [12] 0 0
Quebec
Country [13] 0 0
China
State/province [13] 0 0
Guangdong
Country [14] 0 0
China
State/province [14] 0 0
Beijing
Country [15] 0 0
China
State/province [15] 0 0
Tianjin
Country [16] 0 0
Czechia
State/province [16] 0 0
Brno
Country [17] 0 0
Czechia
State/province [17] 0 0
Praha 5
Country [18] 0 0
Denmark
State/province [18] 0 0
Copenhagen
Country [19] 0 0
France
State/province [19] 0 0
PARIS cedex 5
Country [20] 0 0
France
State/province [20] 0 0
Villejuif Cedex
Country [21] 0 0
Germany
State/province [21] 0 0
Baden-Württemberg
Country [22] 0 0
Germany
State/province [22] 0 0
Berlin
Country [23] 0 0
Ireland
State/province [23] 0 0
Dublin
Country [24] 0 0
Israel
State/province [24] 0 0
Petach Tikva
Country [25] 0 0
Italy
State/province [25] 0 0
Lombardia
Country [26] 0 0
Japan
State/province [26] 0 0
Kanagawa
Country [27] 0 0
Japan
State/province [27] 0 0
Tokyo
Country [28] 0 0
Japan
State/province [28] 0 0
Fukuoka
Country [29] 0 0
Korea, Republic of
State/province [29] 0 0
Seoul Teugbyeolsi
Country [30] 0 0
Korea, Republic of
State/province [30] 0 0
Seoul
Country [31] 0 0
Netherlands
State/province [31] 0 0
Utrecht
Country [32] 0 0
Poland
State/province [32] 0 0
Gdansk
Country [33] 0 0
Spain
State/province [33] 0 0
Barcelona
Country [34] 0 0
Sweden
State/province [34] 0 0
Stockholm
Country [35] 0 0
Switzerland
State/province [35] 0 0
Zürich
Country [36] 0 0
Turkey
State/province [36] 0 0
Istanbul
Country [37] 0 0
Ukraine
State/province [37] 0 0
Kyiv
Country [38] 0 0
Ukraine
State/province [38] 0 0
Lviv
Country [39] 0 0
United Kingdom
State/province [39] 0 0
Surrey

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Bayer
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT02637687