A Study of Selpercatinib (LY3527723) in Participants With RET-Mutant Medullary Thyroid Cancer

Study Overview
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Brief Summary
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The reason for this study is to see if the study drug selpercatinib is safe and more effective compared to a standard treatment in participants with rearranged during transfection (RET)-mutant medullary thyroid cancer (MTC) that cannot be removed by surgery or has spread to other parts of the body. Participants who are assigned to the standard treatment and discontinue due to progressive disease have the option to potentially crossover to selpercatinib.

Detailed Description
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Adaptive sample size re-estimation will be performed at interim analysis. The sample size could be increased from approximately 250 to 400 depending on the results of interim analysis.

Official Title
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A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians Choice of Cabozantinib or Vandetanib in Patients With Progressive, Advanced, Kinase Inhibitor Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531)

Conditions
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Medullary Thyroid Cancer

Intervention / Treatment
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* Drug: Selpercatinib
* Drug: Cabozantinib
* Drug: Vandetanib


Participation Criteria
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Eligibility Criteria
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At least 18 years of age (participants as young as 12 years of age will be allowed if permitted by local regulatory authorities). Histologically or cytologically confirmed, unresectable, locally advanced and/or metastatic MTC and no prior history of treatment with kinase inhibitors for advanced/metastatic disease. Radiographic progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at screening compared with a previous image taken within the prior 14 months as assessed by the BICR. Participants with measurable or non-measurable but evaluable disease are eligible; however, participants with non-measurable disease may not have disease limited to bone sites only. A defined/acceptable RET gene alteration identified in a tumor, germline deoxyribonucleic acid (DNA) or blood sample. Tumor tissue in sufficient quantity to allow for retrospective central analysis of RET mutation status Eastern Cooperative Oncology Group performance status score of 0 to 2. Adequate hematologic, hepatic, and renal function and electrolytes. Men and women of childbearing potential must agree to use a highly effective contraceptive method during treatment with study drug and for 4 months following the last dose of study drug. Ability to swallow capsules. Exclusion Criteria: An additional validated oncogenic driver in MTC if known that could cause resistance to selpercatinib treatment. Examples include, but are not limited to RAS or BRAF gene mutations and NTRK gene fusions. Symptomatic central nervous system (CNS) metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months, history of Torsades de pointes, or prolongation of the QTcF >470 milliseconds on more than one electrocardiogram (ECG) during screening. Participants who are intended to receive vandetanib if randomized to the control arm are ineligible if QTcF is >450 milliseconds. Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing uncontrolled intercurrent illness. Active hemorrhage or at significant risk for hemorrhage. Other malignancy unless nonmelanoma skin cancer, carcinoma in situ or malignancy diagnosed ≥2 years previously and not currently active. Participants with multiple endocrine neoplasia type 2 (MEN2) associated pheochromocytoma may be eligible.

Ages Eligible for Study
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Minimum Age: 12 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selpercatinib<br>Selpercatinib given orally. | Drug: Selpercatinib<br>* Administered orally<br>* Other names: LOXO-292;|
| Active Comparator: Cabozantinib or Vandetanib<br>Cabozantinib or vandetanib given orally. | Drug: Cabozantinib<br>* Administered orally<br>Drug: Vandetanib<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by BICR | PFS by BICR | Baseline to Progressive Disease or Death from Any Cause (Estimated at up to 30 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Failure-Free Survival (TFFS) by Blinded Independent Committee Review (BICR) | TFFS by BICR | Baseline to Progressive Disease, Unacceptable Toxicity or Death from Any Cause (Estimated at up to 30 Months) | 
| Overall Response Rate (ORR): Percentage of Participants with Complete Response (CR) or Partial Response (PR) by BICR | ORR: Percentage of Participants with CR or PR by BICR | Baseline through Disease Progression or Death (Estimated at up to 30 Months) | 
| Duration of Response (DoR) by BICR | DoR by BICR | Date of CR or PR to Date of Disease Progression or Death Due to Any Cause (Estimated at up to 30 Months) | 
| Overall Survival (OS) | OS | Baseline to Date of Death from Any Cause (Estimated at up to 60 Months) | 
| PFS2 by Investigator | PFS2 by Investigator | Baseline to Second Disease Progression or Death from Any Cause (Estimated at up to 48 Months) | 
| Comparative Tolerability: Percentage of Time with High Side Effect Bother Based on the Functional Assessment of Cancer Therapy-Side Effects (FACT-GP5) | FACT-G is a validated instrument used to measure quality of life (QOL) in participants with cancer. The single FACT-G item, GP5, I am bothered by side effects of treatment, is a summary measure of the overall impact of treatment toxicity, based upon its association with the number and degree of adverse events in clinical trials. It uses a 5-point rating scale (0=not at all and 4=equals very much). Higher GP5 scores indicates more bother from side effects | Baseline to Progressive Disease, Unacceptable Toxicity or Death from Any Cause (30 months) | 
| The Concordance of the Local Lab and the Central Lab RET Results: Percentage of Participants with RET-Positive Specimens as Called by the Central Lab, which is also RET-Positive as Called by a Local Lab (Positive Percent Agreement) | The Concordance of the Local Lab and the Central Lab RET Results: Percentage of Participants with RET-Positive Specimens as Called by the Central Lab, which is also RET-Positive as Called by a Local Lab (Positive Percent Agreement) | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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medullary thyroid carcinoma, targeted therapy