A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors

Study Overview
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Brief Summary
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This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric participants with an activating rearranged during transfection (RET) alteration and an advanced solid or primary CNS tumor.

Detailed Description
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This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, participants will be enrolled using a rolling 6 dose escalation scheme. The starting dose of LOXO-292 is equivalent to the adult recommended phase 2 dose of 160 milligrams (mg) twice a day (BID). Once the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is identified, participants will be enrolled to one of four phase 2 dose expansion cohorts depending on tumor histology and tumor genotype. Cycle length will be 28 days.

Official Title
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A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients With Advanced RET-Altered Solid or Primary Central Nervous System Tumors

Conditions
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Medullary Thyroid Cancer, Infantile Myofibromatosis, Infantile Fibrosarcoma, Papillary Thyroid Cancer, Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: LOXO-292


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced or metastatic solid or primary CNS tumor which has failed standard of care therapies Evidence of an activating RET gene alteration in the tumor and/or blood Measurable or non-measurable disease Karnofsky (participants 16 years and older) or Lansky (participants younger than 16) performance score of at least 50 Participant with primary CNS tumors or cerebral metastases must be neurologically stable for 7 days prior and must not have required increasing doses of steroids within the last 7 days Adequate hematologic, hepatic and renal function. Ability to receive study drug therapy orally or via gastric access Willingness of men and women of reproductive potential to observe conventional and effective birth control Exclusion Criteria: Major surgery within two weeks prior to planned start of LOXO-292 Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 Active uncontrolled systemic bacterial, viral, fungal or parasitic infection Clinically significant active malabsorption syndrome Pregnancy or lactation Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant required a modification to current thyroid medication in the 7 days before start of LOXO-292) Uncontrolled symptomatic hypercalcemia or hypocalcemia Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s])

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LOXO-292<br>Phase 1- Dose Escalation and determination of MTD; multiple dose levels of LOXO-292 to be evaluated; Phase 2 - The MTD/recommended dose from Phase 1 | Drug: LOXO-292<br>* Oral LOXO-292<br>* Other names: LY3527723;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Safety of Oral LOXO-292 in Pediatric Participants with Advanced Solid Tumors: Dose Limiting Toxicities (DLTs) | For Phase 1 | During the first 28-day cycle of LOXO-292 treatment | 
| To Determine the Safety of Oral LOXO-292 in Pediatric Participants with Primary CNS Tumors: DLTs | For Phase 1 | During the first 28-day cycle of LOXO-292 treatment | 
| Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per Independent Review Committee (IRC) | For Phase 2 | Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) | 
| ORR Based on Response Assessment in Neuro-Oncology (RANO) per IRC | For Phase 2 | Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of LOXO-292 | Phase 1 | Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) | 
| Area Under the Concentration-Time Curve from 0 to 24 hours (AUC0-24) of LOXO-292 | Phase 1 and Phase 2 | Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) | 
| Maximum Concentration (Cmax) of LOXO-292 | Phase 1 and Phase 2 | Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) | 
| Time to Maximum Concentration (Tmax) of LOXO-292 | Phase 1 and Phase 2 | Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days) | 
| Recommended LOXO-292 Dose for Phase 2 (MTD) | For Phase 1 | Cycle 1 (28 days) | 
| To Assess the Preliminary Anti-Tumor Activity of LOXO-292 in Pediatric Participants with Tumors Harboring an Activating RET Alteration as Determined by ORR Based on RECIST v1.1 | For Phase 1 | Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months) | 
| Changes from Baseline in Pain Measures as Measured by Wong Baker Faces scales. Wong-Baker Faces Pain Scale includes pictures of facial expressions with correlating scores of 0 being 'no hurt' and 10 being 'hurts worst'. | For Phase 1 | Up to 24 months | 
| Changes from Baseline in Health Related Quality of Life Measures as Measured by Pediatric Quality of Life (PedsQoL) Inventory Core. PedsQoL includes a list of problems with scores of 0 being 'never a problem' and 4 being 'almost always a problem'. | For Phase 1 | Up to 24 months | 
| Objective Response Rate as Assessed by RECIST v1.1, as Assessed by Investigator | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Objective Response Rate as Assessed by RANO, as Assessed by Investigator | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Duration of Response (DOR) as Assessed by Investigator | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Duration of Response (DOR) as Assessed by the IRC | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Progression Free Survival (PFS) as Assessed by Investigator | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| PFS as Assessed by IRC | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Overall survival (OS) | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Clinical Benefit Rate (by Investigator) | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Clinical Benefit Rate (by IRC) | For Phase 2 | Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed. | 
| Frequency of Adverse Events (AEs) | For Phase 2 | From the time of informed consent, for approximately 24 months (or earlier if the participants discontinues from the study), and through Safety Follow-up (28 days after the last dose) | 
| To Evaluate the Concordance of Prior Molecular that Detected a RET Alteration within the Participant's Tumor with Diagnostic Tests Being Evaluated by Sponsor | For Phase 2 | 6 months | 
| Phase 2: Post-Operative Stage on Participants Treated with LOXO-292 | Tumor stage is described according to the Tumor, Node, Metastasis (TNM)Classification of malignant tumors of the Union for International Cancer Control (UICC) | Up to 3 years | 
| Phase 2: Surgical Margin Status in Participants Treated with LOXO-292 | Tumor margins after surgery are classified into four groups using the International Cancer Control (UICC)-R classification and the Intergroup Rhabdomyosarcoma Staging (IRS) systems: 1) Complete tumor resection with histologically free margins, 2) Macroscopic resection but invaded margins on histology, 3)Macroscopic residual tumor and 4) Distant metastatic tumor. | Up to 3 years | 
| Descriptive Analysis of Pretreatment Surgical Plan | For Phase 2 | Up to 3 years | 
| Descriptive Analysis of Post-Treatment Plans | For Phase 2 | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNS tumor, Loxo, LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Adenoma, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, Primary CNS tumor, Colonic Neoplasms, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, Soft tissue sarcoma, Infantile Myofibromatosis, Infantile Fibrosarcoma