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

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ClinicalTrials.gov Identifier: NCT02637687

Recruitment Status : Active, not recruiting

First Posted : December 22, 2015

Last Update Posted : May 8, 2024

View this study on the modernized ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Bayer

Tracking Information

First Submitted Date ^ICMJE

December 10, 2015

First Posted Date ^ICMJE

December 22, 2015

Last Update Posted Date

May 8, 2024

Actual Study Start Date ^ICMJE

December 16, 2015

Estimated Primary Completion Date

July 25, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

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 [ Time Frame: 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 [ Time Frame: From first dose of larotrectinib up to 93 months ]
Phase 1: Severity of TEAEs [ Time Frame: From first dose of larotrectinib up to 93 months ]
Phase 2: Overall response rate (ORR) by IRRC [ Time Frame: 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.

Original Primary Outcome Measures ^ICMJE

Determine dose-limiting toxicity (DLT), in pediatric patients with advanced solid or primary central nervous system (CNS) tumors, as assessed by CTCAE v4.0 [ Time Frame: 6 Months ]

Change History

Current Secondary Outcome Measures ^ICMJE

Phase 1: Maximum concentration of larotrectinib in plasma (Cmax) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: C1D1 in conjunction with the post-dose 1-hour PK sample ]
Phase 1: Maximum tolerated dose (MTD) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: From first dose of Larotrectinib, up to 76 months ]
Phase 2: Progression-free survival (PFS) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From surgical intervention to subsequent therapy, up to 112 months ]
Descriptive analysis of post-treatment plans

Original Secondary Outcome Measures ^ICMJE

To characterize the pharmacokinetic (PK) properties of LOXO-101 in pediatric patients with advanced solid or primary CNS tumors including Peak Plasma Concentration (Cmax), following BID dosing [ Time Frame: 6 Months ]
To characterize the pharmacokinetic (PK) properties of LOXO-101 in pediatric patients with advanced solid or primary CNS tumors including Time (TMax) at which the Peak Plasma Concentration (Cmax) is observed, following BID dosing [ Time Frame: 6 Months ]
To characterize the pharmacokinetic (PK) properties of LOXO-101 in pediatric patients with advanced solid or primary CNS tumors including the Half Life of LOXO-101, following BID dosing [ Time Frame: 6 Months ]
To characterize the pharmacokinetic (PK) properties of LOXO-101 in pediatric patients with advanced solid or primary CNS tumors including Area under the plasma concentration versus time curve (AUC) following BID dosing [ Time Frame: 6 Months ]
To identify the recommended Phase 2 Dose (RP2D) of LOXO-101 for further clinical investigation in this patient population [ Time Frame: 6 Months ]
Proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by the Investigator. [ Time Frame: 6 Months ]
Change From Baseline in Pain Scores on the Visual Analog Scale based on final assessment [ Time Frame: 6 Months ]

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

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

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.

Detailed Description

Not Provided

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 1
Phase 2

Study Design ^ICMJE

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Solid Tumors Harboring NTRK Fusion

Intervention ^ICMJE

Drug: Larotrectinib (Vitrakvi, BAY2757556)

BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.

Other Name: LOXO-101

Study Arms ^ICMJE

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)

Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
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)

Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
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)

Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
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)

Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
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.

Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)
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.

Intervention: Drug: Larotrectinib (Vitrakvi, BAY2757556)

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Active, not recruiting

Actual Enrollment ^ICMJE

154

Original Estimated Enrollment ^ICMJE

Estimated Study Completion Date ^ICMJE

September 22, 2026

Estimated Primary Completion Date

July 25, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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.

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

up to 21 Years (Child, Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ^ICMJE

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

Removed Location Countries

Russian Federation

Administrative Information

NCT Number ^ICMJE

NCT02637687

Other Study ID Numbers ^ICMJE

20290
LOXO-TRK-15003 ( Other Identifier: Loxo Oncology, Inc )
2022-502668-20-00 ( Other Identifier: CTIS (EU) )
2016-003498-16 ( EudraCT Number )

Has Data Monitoring Committee

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

IPD Sharing Statement ^ICMJE

Plan to Share IPD:

Plan Description:

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.

Current Responsible Party

Bayer

Original Responsible Party

Loxo Oncology, Inc.

Current Study Sponsor ^ICMJE

Bayer

Original Study Sponsor ^ICMJE

Loxo Oncology, Inc.

Collaborators ^ICMJE

Not Provided

Investigators ^ICMJE

Not Provided