Larotrectinib for Childhood Cancer

(SCOUT Trial)

Not currently recruiting at 81 trial locations

Overseen By Bayer Clinical Trials Contact

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bayer

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Major surgery, Cardiovascular disease, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a cancer drug called larotrectinib in children. The drug targets cancers with specific changes in the NTRK genes, which can promote cancer growth. Larotrectinib blocks these gene changes to slow or stop the cancer. Children with advanced or hard-to-treat cancers that have these specific gene changes may be suitable for the trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Do I need to stop my current medications for the trial?

The trial requires that you do not take strong CYP3A4 inhibitors or inducers. However, enzyme-inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases are allowed if on a stable dose.

Is there any evidence suggesting that larotrectinib is likely to be safe for children?

Research has shown that larotrectinib is generally safe for both children and adults with TRK fusion cancers. In studies involving children, this drug not only helped combat cancer but also maintained a good safety profile, with most patients experiencing no serious side effects.

Additional studies support these findings, highlighting larotrectinib's long-lasting effects and survival benefits, indicating its effectiveness over time. Although approved for other conditions, this trial focuses on ensuring its safety for children with specific genetic changes in their cancer.

While this treatment is in the early stages for this specific use, existing data on larotrectinib's safety in other contexts is promising. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for childhood cancer?

Researchers are excited about larotrectinib because it specifically targets a genetic feature known as NTRK gene fusions, which are often found in various childhood cancers. Unlike standard treatments like chemotherapy and radiation that attack cancer cells and can affect healthy cells too, larotrectinib precisely aims at these gene fusions, potentially offering a more effective and less toxic option. This precision targeting means larotrectinib could lead to better outcomes with fewer side effects, making it a promising new approach in the fight against childhood cancer.

What evidence suggests that larotrectinib might be an effective treatment for childhood cancer?

Research has shown that larotrectinib effectively treats cancers with specific gene changes called NTRK fusions. This drug blocks these genes in cancer cells, preventing their growth. Studies have found larotrectinib particularly effective for both adults and children with these gene changes, and it is approved for use in these cases. In this trial, children with TRK fusion cancers will receive larotrectinib. Early results suggest it can significantly shrink tumors in patients with these gene changes. Overall, this treatment holds strong potential to help children with certain types of cancer. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for children and young adults up to age 21 with advanced or metastatic solid tumors, including CNS tumors that have not responded to other treatments. Eligible patients must have a specific gene change (NTRK fusion) in their cancer cells. Those with certain heart conditions, active infections, or recent major surgery are excluded.

Inclusion Criteria

Phase 1 (Closed): Patients birth through 21 years of age 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 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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Determine safe dose level of larotrectinib, assess drug absorption and response

28 days per cycle, multiple cycles

Daily dosing

Phase 1: Dose Expansion

Enroll pediatric patients with specific tumor types to further assess safety and efficacy

28 days per cycle, multiple cycles

Daily dosing

Phase 2: Treatment

Investigate response of different cancer types to larotrectinib at recommended dose

28 days per cycle, up to 93 months

Daily dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 112 months

What Are the Treatments Tested in This Trial?

Interventions

• Larotrectinib

Trial Overview

The drug larotrectinib is being tested for safety and effectiveness in treating cancers with NTRK gene changes. The study has two parts: Phase 1 determines the safe dose for children and how they respond; Phase 2 examines the treatment's response duration across different cancer types.

How Is the Trial Designed?

Group I: Phase 2: Primary CNS tumors_Cohort 3 Experimental Treatment 1 Intervention

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.

Group II: Phase 2: Patients with tumors bearing NTRK fusions (IFS)_Cohort 1 Experimental Treatment 1 Intervention

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)

Group III: Phase 2: Other extra-cranial solid tumors_Cohort 2 Experimental Treatment 1 Intervention

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)

Group IV: Phase 2: Bone health assessment_sub-cohort Experimental Treatment 1 Intervention

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.

Group V: Phase 1 dose expansion Experimental Treatment 1 Intervention

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)

Group VI: Phase 1 dose escalation Experimental Treatment 1 Intervention

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)

Larotrectinib is already approved in United States, European Union for the following indications:

Approved in United States as Vitrakvi for:

• Solid tumors with NTRK gene fusions

Approved in European Union as Vitrakvi for:

• Solid tumors with NTRK gene fusions

Who Is Running the Clinical Trial?

Bayer

Lead Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Published Research Related to This Trial

Larotrectinib, a selective TRK inhibitor, has shown to be effective and well tolerated in treating infantile fibrosarcoma (IFS) in a newborn, indicating its potential for use in very young patients.

The patient exhibited a rapid clinical and radiographic response to larotrectinib, suggesting that this treatment could be a promising option for IFS when surgical resection is not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib. Caldwell, KJ., De La Cuesta, E., Morin, C., et al.[2021]

Larotrectinib, an FDA-approved treatment for certain cancers, is significantly affected by transporters like ABCB1 and ABCG2, which limit its oral availability and ability to penetrate the brain and testis, potentially impacting its therapeutic effectiveness.

The study found that the uptake transporter OATP1A/1B and the enzyme CYP3A also restrict larotrectinib's systemic exposure and oral availability, suggesting that understanding these mechanisms could enhance its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation. Wang, Y., Sparidans, RW., Li, W., et al.[2022]

Elacridar significantly increases the oral availability and brain penetration of larotrectinib, suggesting it could enhance the drug's therapeutic effects in treating NTRK fusion-positive cancers.

Both rifampin and ritonavir also improve the systemic exposure of larotrectinib, indicating that these drugs can be used to optimize larotrectinib's effectiveness by inhibiting specific transporters and enzymes involved in its metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib. Wang, Y., Sparidans, RW., Wang, J., et al.[2022]

Larotrectinib (VITRAKVI®) is a targeted therapy specifically designed to inhibit tropomyosin receptor kinases (TRK) in patients with cancers that have neurotrophic receptor tyrosine kinase (NTRK) gene fusions, making it a promising option for both adults and children.

Approved in November 2018 in the USA, larotrectinib is indicated for metastatic solid tumors with NTRK gene fusions when no other satisfactory treatments are available, highlighting its role as a critical option for patients with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Larotrectinib: First Global Approval. Scott, LJ.[2020]

Larotrectinib (VITRAKVI) is a highly effective treatment for patients with Trk fusion-positive cancers, showing a remarkable response rate of 75% regardless of cancer type, age, or gender.

The study developed a new LC-MS/MS method for accurately measuring Larotrectinib levels and assessing its metabolic stability, revealing a moderate extraction ratio and a half-life of approximately 48.8 minutes in human liver microsomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry. Attwa, MW., Kadi, AA., Darwish, HW.[2022]

Larotrectinib shows promising efficacy for treating solid tumors with NTRK gene fusions, with a 12-month progression-free survival (PFS) rate of 66.6% consistent between 2018 predictions and 2020 observed data from 102 patients across 15 tumor types.

While long-term PFS predictions varied due to differences in tumor responses, the overall survival (OS) predictions were reliable, with a 48-month OS rate of 67.2% aligning closely with observed data, indicating larotrectinib's potential for sustained effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study. Briggs, A., Paracha, N., Rosettie, K., et al.[2022]

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A Study to Test the Safety and Efficacy of the Drug ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9159442/

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NTRK gene fusions have been identified in a variety of adult and pediatric tumors and are estimated to occur in up to 1% of all solid tumors.

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esmoopen.com

esmoopen.com/article/S2059-7029(25)00979-2/fulltext

Efficacy and safety of larotrectinib as first-line treatment for ...

Larotrectinib is a highly selective TRK inhibitor approved for tumour-agnostic use in patients with TRK fusion cancer.

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clinicaltrials.bayer.com

clinicaltrials.bayer.com/study/20290

Solid tumors harboring NTRK fusion | Study 20290

A study to test the safety and efficacy of the drug larotrectinib for the treatment of tumors with NTRK-fusion in children.

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ascopubs.org

ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.10010

Larotrectinib efficacy and safety in pediatric TRK fusion ...

Results: As of July 30, 2018, 38 children and adolescents < 18 y with TRK fusion cancer were enrolled. Median age was 2.3 y (range 0.1–14.0); 14 (37%) were < 1 ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40408921/

Efficacy and safety of larotrectinib as first-line treatment for ...

Larotrectinib achieved extremely durable responses, extended survival and had a favourable safety profile in treatment-naïve patients with TRK fusion cancers.

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02637687

NCT02637687 | A Study to Test the Safety and Efficacy of ...

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 ...

8.

vitrakvi-us.com

vitrakvi-us.com/

VITRAKVI® (larotrectinib) | Official Patient Website

VITRAKVI is a prescription medicine that is used to treat adults and children with solid tumors (cancer) that: are caused by certain abnormal neurotrophic ...