(20290) A Phase 1/2 Study of the Oral TRK Inhibitor Larotrectinib in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors
- Trial ID
- 2022-502668-20-00
- Protocol
- 20290
- Sponsor
- Bayer Consumer Care AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** of oral larotrectinib, including dose-limiting toxicity (DLT), in pediatric patients with advanced solid or primary central nervous system (CNS) tumors. This is clinically relevant as it aims to establish a safe dosage regimen for larotrectinib, which is crucial for minimizing adverse effects and ensuring patient safety during treatment. Additionally, the study seeks to determine the overall response rate (ORR) in pediatric patients with advanced cancer harboring NTRK fusions, as assessed by an independent radiology review committee. This objective is significant for understanding the efficacy of larotrectinib in producing a complete or partial response in this patient population.
Secondary objectives include: - Phase 1: Characterizing the pharmacokinetic (PK) properties of larotrectinib, identifying the maximum tolerated dose (MTD) and/or recommended dose, describing the antitumor activity, and assessing pain and health-related quality of life (HRQoL) in pediatric patients. - Phase 2: Determining the ORR based on specific response criteria, evaluating the duration of response (DOR), estimating the proportion of patients with tumor regression, assessing progression-free survival (PFS) and overall survival (OS), and evaluating the safety profile and tolerability of larotrectinib. Additional objectives include evaluating the clinical benefit rate (CBR), concordance of prior molecular profiling with diagnostic tests, post-operative staging, surgical margin status, and the functional and cosmetic outcomes of surgical interventions following treatment with larotrectinib.
Participants
The clinical trial involves a total of **82 participants** diagnosed with **solid tumors harboring NTRK fusion**. The study population includes both male and female subjects, ranging from birth to 21 years of age, with a focus on pediatric patients. Participants are selected based on the presence of locally advanced or metastatic solid tumors or primary central nervous system (CNS) tumors that have relapsed, progressed, or were nonresponsive to available therapies, and for which no standard or available systemic curative therapy exists. The trial also considers patients with infantile fibrosarcoma (IFS) who would require disfiguring surgery or limb amputation to achieve complete surgical resection. The health status of participants is assessed to ensure adequate hematologic, hepatic, and renal function, with a performance score of at least 50 on the Karnofsky or Lansky scale, depending on age. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Participants are required to have a documented NTRK gene fusion, identified through molecular assays performed at certified laboratories.
Plans and Procedures
The clinical trial is designed as a **Phase 1/2** study to evaluate the safety and efficacy of the oral TRK inhibitor **larotrectinib** in pediatric patients with advanced solid or primary central nervous system tumors harboring **NTRK fusion**. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The estimated duration of the trial spans from December 15, 2015, to September 1, 2026, allowing for comprehensive data collection and analysis over an extended period.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, tumor type, and genetic markers. Following successful screening, participants will be enrolled in the trial and will attend regular follow-up visits to monitor safety, treatment response, and any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall response rate and other secondary endpoints.
The expected length of participant involvement varies depending on individual response to treatment and the occurrence of any dose-limiting toxicities. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Throughout the trial, the primary endpoints will focus on the number of subjects experiencing treatment-emergent adverse events and the overall response rate, while secondary endpoints will include pharmacokinetic parameters and quality of life assessments.
Treatment
The clinical trial involves the administration of **Larotrectinib Bayer**, an investigational medication, in pediatric patients with advanced solid or primary central nervous system tumors. The active substance in this medication is **larotrectinib sulfate**, which is of chemical origin. The pharmaceutical form of Larotrectinib Bayer is available as a **hard capsule** and an **oral solution**, both intended for **oral use**. The medication is not a pediatric formulation, and it is not classified as an orphan drug. The trial aims to evaluate the safety and efficacy of larotrectinib, with a focus on dose-limiting toxicity and overall response rate in patients with tumors harboring NTRK fusions.
The hard capsule form of Larotrectinib Bayer is designed for oral administration. The specific dosage and frequency of administration are determined based on the study protocol, which aims to assess the safety profile and therapeutic response in the target patient population. Compliance with the dosing schedule is monitored throughout the trial to ensure accurate assessment of the medication's effects.
The oral solution form of Larotrectinib Bayer provides an alternative route of administration for patients who may have difficulty swallowing capsules. This formulation is also administered orally, with dosing schedules tailored to the individual needs of the participants as outlined in the study protocol. Participant compliance is closely monitored to maintain the integrity of the trial data.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains on evaluating the investigational medication, Larotrectinib Bayer, in its various forms. The trial is conducted under the sponsorship of Bayer AG, with adherence to regulatory standards and ethical guidelines to ensure the safety and well-being of all participants.
Efficacy
The efficacy of the clinical trial involving **larotrectinib** will be assessed through various primary and secondary endpoints. In Phase 1, the primary endpoints include the number of subjects experiencing treatment-emergent adverse events (TEAEs) by grade, as assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03, and the occurrence of dose-limiting toxicity (DLT). Phase 2 focuses on the overall response rate (ORR) as determined by an independent radiology review committee, measuring the proportion of patients achieving a complete response (CR) or partial response (PR) according to tumor response criteria.
Secondary endpoints in Phase 1 include pharmacokinetic parameters such as the maximum concentration of **larotrectinib** in plasma (Cmax), area under the concentration versus time curve (AUC0–t), oral clearance (CL/F), and cerebral spinal fluid/plasma ratio. Additionally, the maximum tolerated dose (MTD), recommended dose for Phase 2, and overall response rate (ORR) are evaluated. Patient-reported outcomes such as changes in pain scores using the Wong-Baker Faces scale and health-related quality of life scores via the Pediatrics Quality of Life - Core Module (PedsQL-Core) are also assessed.
In Phase 2, secondary endpoints include best overall response (BOR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and the clinical benefit rate (CBR). The trial also evaluates the proportion of patients with any tumor regression, severity of adverse events, concordance coefficient, post-operative tumor staging, surgical margin assessment, and plans to preserve function and cosmetic outcomes both pre- and post-treatment. These efficacy parameters are measured and analyzed at specified timepoints throughout the trial to determine the therapeutic impact of **larotrectinib** in pediatric patients with advanced solid or primary central nervous system tumors.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Phase 1 (Closed): Phase 1: Birth through 21 years of age at cycle 1 day 1 (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 neurotrophic tyrosine kinase receptor (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 (IFS) who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection. Phase 1 dose escalation cohorts are closed to enrollment. Phase 1 dose expansion: In addition to the above stated Inclusion Criteria, patients eligible for enrollment into this cohort must have a malignancy with a documented NTRK gene fusion with the exception of patients with IFS, congenital mesoblastic nephroma tumors (CMN) or secretory breast cancer (SBC). Patients with IFS, CMN or SBC may enroll into this cohort with documentation of an ETS variant gene 6 (ETV6) rearrangement by fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) or a documented NTRK fusion by next generation sequencing (NGS).
- Phase 2: Infants from birth and older at C1D1 with a locally advanced or metastatic IFS, patients with locally advanced IFS who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection withdocumented ETV6 rearrangement (or NTRK3 rearrangement after discussion with the Sponsor) by FISH or RT-PCR or a documented NTRK fusion by e.g., NGS. 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 e.g., by NGS, or in the case of IFS, CMN or SBC with documented ETV6 rearrangement (or NTRK3 rearrangement after discussion with the Sponsor) by FISH or RT-PCR. Documented NTRK fusion by NGS shall be identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. If CLIA or similar certification of the laboratory performing the molecular assay is not confirmed at the time of consent patients may be included after discussion with the Sponsor. Patients with NTRK-fusion positive benign tumors are also eligible. or: (including Expansion Phase) 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.
- Malabsorption syndrome or other condition affecting oral absorption.
- 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.
- Pregnancy or lactation.
- Phase 2 Only: Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK, including entrectinib, repotrectinib, crizotinib and lestaurtanib. Patients who received a TRK inhibitor for less than 28 days of treatment and discontinued because of intolerance remain eligible.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 15 Dec 2015 | 4 |
 Denmark | Not Recruiting | 15 Dec 2015 | 4 |
 France | Not Recruiting | 15 Dec 2015 | 18 |
 Germany | Not Recruiting | 15 Dec 2015 | 24 |
 Ireland | Not Recruiting | 15 Dec 2015 | 4 |
 Italy | Not Recruiting | 15 Dec 2015 | 4 |
 The Netherlands | Not Recruiting | 15 Dec 2015 | — |
 Spain | Not Recruiting | 15 Dec 2015 | 4 |
 Sweden | Not Recruiting | 15 Dec 2015 | 5 |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Larotrectinib Bayer | Test | ORAL SOLUTION | ORAL USE | — | — | PRD10414174 |
Larotrectinib Bayer | Test | CAPSULE, HARD | ORAL USE | — | — | PRD10414175 |
Larotrectinib Bayer | Test | CAPSULE, HARD | ORAL USE | — | — | PRD10414185 |