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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT02637687
Ethics application status
Date submitted
10/12/2015
Date registered
22/12/2015
Date last updated
1/07/2020

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 LOXO-101 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 (Vitravki, BAY2757556)

Experimental: Pediatric patients_Dose 1 - Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 50 mg twice daily (dose escalation cohort).

Experimental: Pediatric patients_Dose 2 - Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 75 mg twice daily (dose escalation cohort).

Experimental: Pediatric patients_Dose 3 - Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 100 mg twice daily (dose escalation cohort).

Experimental: Pediatric patients_Dose 4 - Pediatric cancer patients receiving BAY2757556 at an adult-equivalent dose of 150 mg twice daily (dose escalation cohort).

Experimental: Pediatric patients_Dose 5 - Pediatric cancer patients receiving BAY2757556 at dose of 100 mg/m2 twice daily (dose escalation cohort).

Experimental: Pediatric patients_Dose 6 - Pediatric cancer patients receiving BAY2757556 at dose of 150 mg/m2 twice daily (dose escalation cohort).

Experimental: Pediatric patients_Dose 7 - Pediatric cancer patients receiving BAY2757556 at dose of 200 mg/m2 twice daily (dose escalation cohort).

Experimental: Pediatric patients_Recommended dose - Pediatric cancer patients receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily as determined in the dose escalation part (dose expansion cohort, Phase 1).

Experimental: Pediatric patients_Fibrosarcoma - Pediatric patients with infantile fibrosarcoma (IFS) and documented ETV6 rearrangement or NTRK fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).

Experimental: Pediatric patients_Extracranial - Pediatric patients with other extra-cranial solid tumors and documented ETV6 rearrangement or NTRK fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).

Experimental: Pediatric patients_CNS tumors - Pediatric patients with primary central nervous system (CNS) tumors and documented ETV6 rearrangement or NTRK fusion receiving BAY2757556 at the recommended dose of 100 mg/m2 twice daily (efficacy cohort, Phase 2).


Treatment: Drugs: Larotrectinib (Vitravki, 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 with adverse events
Timepoint [1] 0 0
Up to 5 years
Primary outcome [2] 0 0
Phase 1: Severity of adverse events
Timepoint [2] 0 0
Up to 5 years
Primary outcome [3] 0 0
Phase 2: Overall response rate (ORR) by IRRC - Proportion of subjects with confirmed best overall response of complete response or partial response, assessed by an independent radiology review committee (IRRC) using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate.
Timepoint [3] 0 0
Up to 5 years
Secondary outcome [1] 0 0
Phase 1: Maximum concentration of larotrectinib in plasma (Cmax)
Timepoint [1] 0 0
Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Secondary outcome [2] 0 0
Phase 1: Area under the concentration versus time curve of larotrectinib in plasma (AUC)
Timepoint [2] 0 0
Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Secondary outcome [3] 0 0
Phase 1: Oral clearance (CL/F)
Timepoint [3] 0 0
Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Secondary outcome [4] 0 0
Phase 1: Cerebral spinal fluid/plasma ratio of larotrectinib
Timepoint [4] 0 0
Pre-dose, 1 hour and 4 hours after drug on Day 1 of Cycles 1 - 12
Secondary outcome [5] 0 0
Phase 1: Maximum tolerated dose (MTD)
Timepoint [5] 0 0
15 months
Secondary outcome [6] 0 0
Phase 1: Recommended dose for Phase 2
Timepoint [6] 0 0
15 months
Secondary outcome [7] 0 0
Phase 1: Overall response rate (ORR)
Timepoint [7] 0 0
15 months
Secondary outcome [8] 0 0
Phase 1: Pain level - Pain Status is assessed by the Wong-Baker Faces Scale giving a pain scale between 0 (no hurt) to 10 (hurts worst).
Timepoint [8] 0 0
Up to 5 years
Secondary outcome [9] 0 0
Phase 1: Health-related quality of life by PedsQL-Core - The health-related quality of life (HRQoL) is assessed with the Pediatrics Quality of Life - Core Module (PedsQL-Core) questionaire 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).
Timepoint [9] 0 0
Up to 5 years
Secondary outcome [10] 0 0
Phase 2: Overall Response Rate (ORR) by investigator - Proportion of subjects with confirmed best overall response of complete response or partial response, assessed by the treating investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate.
Timepoint [10] 0 0
Up to 5 years
Secondary outcome [11] 0 0
Phase 2: Duration of response (DOR) by IRRC - Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by an independent radiology review committee (IRRC).
Timepoint [11] 0 0
Up to 5 years
Secondary outcome [12] 0 0
Phase 2: Duration of response (DOR) by investigator - Duration of response is the number of months from the start of confirmed complete response or partial response to disease progression or death. Complete response, partial response and disease progression are assessed by the treating investigator.
Timepoint [12] 0 0
Up to 5 years
Secondary outcome [13] 0 0
Phase 2: Proportion of subjects with any tumor regression as a best response
Timepoint [13] 0 0
Up to 5 years
Secondary outcome [14] 0 0
Phase 2: Progression-free survival (PFS) after larotrectinib - Number of months from initiation of larotrectinib to either disease progression or death due to any cause.
Timepoint [14] 0 0
Up to 5 years
Secondary outcome [15] 0 0
Phase 2: Overall survival time - Number of months from the initiation of larotrectinib to the date of death due to any cause.
Timepoint [15] 0 0
Up to 5 years
Secondary outcome [16] 0 0
Phase 2: Number of participants with adverse events
Timepoint [16] 0 0
Up to 5 years
Secondary outcome [17] 0 0
Phase 2: Severity of adverse events
Timepoint [17] 0 0
Up to 5 years
Secondary outcome [18] 0 0
Phase 2: Clinical benefit rate (CBR) by IRRC - Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib, assessed by an independent radiology review committee (IRRC).
Timepoint [18] 0 0
Up to 5 years
Secondary outcome [19] 0 0
Phase 2: Clinical benefit rate (CBR) by investigator - Proportion of subjects with best overall response of complete response, partial response or stable disease lasting 16 or more weeks following the initiation of larotrectinib, assessed by investigator.
Timepoint [19] 0 0
Up to 5 years
Secondary outcome [20] 0 0
Phase 2: Concordance coefficient - Describes the concordance of prior molecular profiling that detected an NTRK fusion within the subject's tumor and a diagnostic test being evaluated by the sponsor.
Timepoint [20] 0 0
Up to 5 years
Secondary outcome [21] 0 0
Phase 2: Post-operative stage in patients treated with larotrectinib - Tumor stage is described according to the TNM Classification of malignant tumors of the Union for International Cancer Control (UICC).
Timepoint [21] 0 0
Up to 5 years
Secondary outcome [22] 0 0
Phase 2: Surgical margin status in patients treated with larotrectinib - Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3) Macroscopic residual tumor and 4) Distant metastatic tumor.
Timepoint [22] 0 0
Up to 5 years
Secondary outcome [23] 0 0
Phase 2: Descriptive analysis of pretreatment surgical plan
Timepoint [23] 0 0
Up to 5 years
Secondary outcome [24] 0 0
Phase 2: Descriptive analysis of post-treatment plans
Timepoint [24] 0 0
Up to 5 years

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 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
Minimum age
No limit
Maximum age
21 Years
Gender
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 lestaurtanib.
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/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Sydney
Recruitment hospital [2] 0 0
Royal Children's Hospital Melbourne - Parkville
Recruitment postcode(s) [1] 0 0
2031 - Sydney
Recruitment postcode(s) [2] 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
Tennessee
Country [7] 0 0
United States of America
State/province [7] 0 0
Texas
Country [8] 0 0
United States of America
State/province [8] 0 0
Washington
Country [9] 0 0
Canada
State/province [9] 0 0
British Columbia
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Canada
State/province [11] 0 0
Quebec
Country [12] 0 0
China
State/province [12] 0 0
Guangdong
Country [13] 0 0
China
State/province [13] 0 0
Beijing
Country [14] 0 0
China
State/province [14] 0 0
Tianjin
Country [15] 0 0
Denmark
State/province [15] 0 0
Copenhagen
Country [16] 0 0
France
State/province [16] 0 0
PARIS cedex 5
Country [17] 0 0
France
State/province [17] 0 0
Villejuif Cedex
Country [18] 0 0
Germany
State/province [18] 0 0
Baden-Württemberg
Country [19] 0 0
Germany
State/province [19] 0 0
Berlin
Country [20] 0 0
Ireland
State/province [20] 0 0
Dublin
Country [21] 0 0
Israel
State/province [21] 0 0
Petach Tikva
Country [22] 0 0
Italy
State/province [22] 0 0
Lombardia
Country [23] 0 0
Italy
State/province [23] 0 0
Veneto
Country [24] 0 0
Japan
State/province [24] 0 0
Kanagawa
Country [25] 0 0
Japan
State/province [25] 0 0
Miyagi
Country [26] 0 0
Japan
State/province [26] 0 0
Tokyo
Country [27] 0 0
Japan
State/province [27] 0 0
Fukuoka
Country [28] 0 0
Japan
State/province [28] 0 0
Osaka
Country [29] 0 0
Korea, Republic of
State/province [29] 0 0
Seoul
Country [30] 0 0
Netherlands
State/province [30] 0 0
Utrecht
Country [31] 0 0
Poland
State/province [31] 0 0
Gdansk
Country [32] 0 0
Spain
State/province [32] 0 0
Barcelona
Country [33] 0 0
Sweden
State/province [33] 0 0
Stockholm
Country [34] 0 0
Switzerland
State/province [34] 0 0
Zürich
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Surrey

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

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02637687
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
Bayer Clinical Trials Contact
Address 0 0
Country 0 0
Phone 0 0
(+)1-888-84 22937
Fax 0 0
Email 0 0
clinical-trials-contact@bayer.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02637687