Larotrectinib for Childhood Cancer

(SCOUT Trial)

Recruiting at 71 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

154 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Larotrectinib for childhood cancer?

Larotrectinib has been shown to be effective in treating cancers with NTRK gene fusions in both adults and children, including a case where a newborn with a rare cancer called infantile fibrosarcoma responded well to the drug. It is a targeted therapy that works by blocking specific proteins involved in cancer growth. ^{1 2 3 4 5}

Is larotrectinib safe for children?

Larotrectinib has been shown to be well tolerated in children, including those as young as 1-month old, and is used to treat certain types of cancer with specific gene fusions. ^{1 2 3 4 6}

How is the drug larotrectinib unique for treating childhood cancer?

Larotrectinib is unique because it is an oral drug specifically designed to target and inhibit TRK proteins in cancers with NTRK gene fusions, regardless of the cancer type or patient's age. This makes it a precision treatment option for rare cancers like infantile fibrosarcoma, where traditional surgical options may not be feasible. ^{3 4 6 7 8}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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, 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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Tumour-agnostic drugs in paediatric cancers. [2021]

2. England 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. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Larotrectinib: First Global Approval. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

A newborn with a large NTRK fusion positive infantile fibrosarcoma successfully treated with larotrectinib. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study. [2022]