Phase 1/2 Evaluation of Selpercatinib in Pediatric Patients with Advanced RET-Altered Solid or Primary CNS Tumors
- Trial ID
- 2023-507703-63-00
- Protocol
- LOXO-RET-18036
- Sponsor
- Loxo Oncology Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 1/2 study is to evaluate the **safety profile** of the oral RET inhibitor Selpercatinib in pediatric patients with advanced RET-altered solid or primary central nervous system tumors. In Phase 1, the focus is on identifying dose-limiting toxicities (DLTs) to ensure the treatment's safety. In Phase 2, the study aims to determine the objective response rate (ORR) as assessed by an Independent Review Committee (IRC). This is measured by the proportion of patients achieving a best overall confirmed response of complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v 1.1), or the Response Assessment in Neuro-Oncology (RANO) criteria, as applicable. These objectives are clinically relevant as they provide critical insights into the therapeutic potential and safety of Selpercatinib in a pediatric population with challenging tumor profiles.
Participants
The clinical trial involves a total of **65 participants** who are pediatric patients with advanced **RET-altered solid or primary central nervous system tumors**. The study population includes both male and female subjects, aged between **12 and 21 years**. Participants were selected based on their diagnosis of locally advanced or metastatic solid or primary 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 includes individuals who are able to comply with outpatient treatment, laboratory monitoring, and required clinic visits. Participants must have adequate hematologic, hepatic, pancreatic, and renal function, and must be able to swallow capsules, liquid suspension, or have gastric access. The study population is considered vulnerable, given the pediatric nature of the participants. Lifestyle considerations such as diet and physical activity are not specified in the available data. Key inclusion criteria include evidence of an activating RET gene alteration in tumor and/or blood, and a performance score of at least 50 on the Karnofsky or Lansky scale, depending on age. The sponsor has not provided additional information regarding lifestyle or other demographic factors.
Plans and Procedures
The clinical trial is designed to evaluate the safety and efficacy of **selpercatinib**, an oral RET inhibitor, in pediatric patients with advanced RET-altered solid or primary central nervous system tumors. This study is structured as a Phase 1/2 trial, employing a randomized, double-blind, and controlled methodology to ensure robust and unbiased results. The trial is expected to span from February 28, 2019, to October 28, 2024, encompassing both recruitment and follow-up periods.
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 organ function. Following successful screening, participants will enter the treatment phase, where they will receive selpercatinib in one of its pharmaceutical forms: oral solution, tablet, or capsule. The trial includes regular follow-up visits to monitor safety, assess treatment response, and manage 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 treatment outcomes.
The expected length of participant involvement varies, depending on individual response and tolerance to the treatment. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to discontinue participation. Additionally, any significant protocol deviations or non-compliance with study procedures may also result in early termination from the trial. The primary endpoints include the frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) in Phase 1, and the objective response rate (ORR) in Phase 2, as determined by an Independent Review Committee using RECIST v1.1 or RANO criteria, as appropriate.
Treatment
The clinical trial involves the administration of **Selpercatinib**, a chemical entity, as the experimental medication. Selpercatinib is provided in multiple pharmaceutical forms, including a hard capsule, oral solution, and tablet. The hard capsule form of Selpercatinib is administered orally. The manufacturing process for the drug substance used in clinical trials and commercial use is consistent, ensuring comparable quality and safety. The oral solution and tablet forms of Selpercatinib are also administered orally, with the active substance being chemically derived. The sponsor product code for these forms is LY3527723, and they are produced by ELI LILLY AND COMPANY LIMITED. The trial does not involve a pediatric formulation, and the drug is not classified as an orphan drug.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The dosing schedule and frequency of administration for Selpercatinib are not detailed in the provided data. Participant compliance with the medication regimen will be monitored throughout the trial to ensure adherence to the protocol. The primary objective of the trial is to assess the safety profile and determine the objective response rate of Selpercatinib in pediatric patients with advanced RET-altered solid or primary central nervous system tumors.
Efficacy
The efficacy of the clinical trial involving the oral RET inhibitor **Selpercatinib** will be assessed through specific endpoints tailored to the trial's phases. In Phase 1, the primary focus is on determining the safety profile, including dose-limiting toxicities (DLTs) in pediatric patients. For Phase 2, the primary efficacy endpoint is the objective response rate (ORR), which will be evaluated by an Independent Review Committee (IRC). This assessment will be based on the proportion of patients achieving a best overall confirmed response of complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v 1.1), or the Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate for the tumor type.
The primary endpoints for Phase 1 include the frequency, severity, and relatedness of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), including DLTs, in pediatric patients receiving **Selpercatinib**. In Phase 2, the ORR will be determined based on RECIST v 1.1 or RANO criteria, as appropriate to the tumor type, as assessed by the IRC. These efficacy parameters will be collected and analyzed to provide a comprehensive understanding of the treatment's impact on the targeted patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Pediatric patients ≥ 12 years of age and ≤ 21 years of age at Cycle 1 Day 1 (C1D1) with a locally advanced or metastatic solid or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and/or for which no standard or available systemic curative therapy exists. a) Patients with locally advanced disease who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection, are also eligible. b) In geographies where a selective RET-inhibitor is approved, patients may enroll without prior systemic treatment.
- Evidence of an activating RET gene alteration in tumor and/or blood as identified through molecular assays, as performed for clinical evaluation.
- Patients with primary CNS tumors or cerebral metastasis: a) Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment b) Must have not required increasing doses of steroids within the 7 days prior to enrollment to manage CNS symptoms
- Imaging study must be performed within 28 days of C1D1 while on stable dose steroid medication (if needed) for at least 7 days immediately before the imaging study.
- Histologic verification of malignancy at original diagnosis or relapse, except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebral spinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or betahuman chorionic gonadotropin (HCG).
- Must have measurable or non-measurable but evaluable disease.
- Karnofsky (patients 16 years and older) or Lansky (patients younger than 16 years) performance score of at least 50.
- Must have fully recovered from the acute toxic effects of all prior anti- cancer chemotherapy to CTCAE (v5.0) Grade ≤ 2.
- An archival (FFPE or fresh frozen) or fresh tumor tissue sample must be available (refer to Section 7.5 of the protocol).
- Adequate hematologic/pancreatic status, defined as: a) Absolute neutrophil count (ANC) ≥ 1.0× 10^9/L not requiring growth factor support for at least 7 days prior to treatment. b) Platelet count ≥ 75 × 10^9/L not requiring transfusion support for at least 7 days prior to treatment. c) Hb ≥ 8 mg/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment.
- Adequate hepatic/pancreatic function, defined as: a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN) or ≤ 5 × ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor), and b) Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement (patients with Gilbert's Disease may be enrolled with prior Sponsor approval)
- Adequate renal function, defined as: a) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 based on local institutional practice for determination, or a maximum serum creatinine by age and gender as presented in Synopsis Table 2.
- Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
- Willingness of male and female patients with reproductive potential to utilize double effective birth control methods
- Ability to swallow capsules, liquid suspension, or gastric access via a naso- or gastric tube.
- The patient and, when applicable, the parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study Informed Consent Form (ICF) and applicable Pediatric Assent Form before initiation of any protocol-related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent.
Exclusion Criteria
- Major surgery within 2 weeks prior to C1D1
- Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1; ongoing cardiomyopathy; or current prolonged QT interval corrected for heart rate (QTc) interval > 440 milliseconds for patients ≤ 15 years old and > 470 milliseconds for patients > 15 years old. For patients ≤ 15 years old, Bazett's Formula will be utilized to determine QTc. For patients > 15 years old, either method, Fridericia or Bazett's Formula may be applied.
- Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator makes the risk: benefit ratio for the patient to participate in the trial unfavorable.
- Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
- Pregnancy or lactation.
- Uncontrolled hypotension or hypertension ≥ Grade 3 CTCAE (v 5.0).
- Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the patient required a modification to current thyroid medication in the 7 days before start of selpercatinib).
- Uncontrolled symptomatic hypercalcemia or hypocalcemia.
- Known hypersensitivity to any of the components of the investigational agent, selpercatinib or Ora-Sweet® SF and OraPlus®, for patients who will receive selpercatinib suspension.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 28 Feb 2019 | 3 |
 France | Not Recruiting | 28 Feb 2019 | 10 |
 Germany | Not Recruiting | 28 Feb 2019 | 5 |
 Italy | Not Recruiting | 28 Feb 2019 | 2 |
 Spain | Not Recruiting | 28 Feb 2019 | 5 |
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 |
|---|---|---|---|---|---|---|
SELPERCATINIB | Test | — | ORAL USE | — | — | SUB193120 |
Selpercatinib | Test | TABLET | ORAL USE | — | — | PRD11200318 |
Selpercatinib | Test | ORAL SOLUTION | ORAL USE | — | — | PRD11200322 |
SELPERCATINIB | Test | — | ORAL USE | — | — | SUB193120 |
Selpercatinib | Test | TABLET | ORAL USE | — | — | PRD11200321 |