Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Participants With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in participants with medullary thyroid cancer (MTC), RET-altered NSCLC and other RET-altered solid tumors.

Detailed Description
-----------------
The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part (Phase 2). Both parts will enroll participants with advanced non-resectable NSCLC, advanced non-resectable thyroid cancer and other advanced solid tumors that have progressed following standard systemic therapy, have not adequately responded to standard systemic therapy, or the participants must be intolerant to or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.

Official Title
-----------------
A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors

Conditions
-----------------
RET-altered Non Small Cell Lung Cancer, Medullary Thyroid Cancer, RET-altered Papillary Thyroid Cancer, RET-altered Colon Cancer, RET-altered Solid Tumors, Lung Neoplasm, Carcinoma, Non-Small-Cell Lung, Thyroid Diseases, Thyroid Neoplasm, Thyroid Cancer, Papillary, Carcinoma, Neuroendocrine, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms by Site, Neoplasms, Lung Diseases, Respiratory Tract Disease, Carcinoma, Bronchogenic, Bronchial Neoplasms, Endocrine System Diseases, Endocrine Gland Neoplasm, Head and Neck Neoplasms, Adenocarcinoma, Papillary, Adenocarcinoma, Carcinoma, Neoplasms, Glandular and Epithelial, Neoplasms by Histologic Type, Neuroendocrine Tumors, Neuroectodermal Tumors, Neoplasms, Germ Cell and Embryonal, Neoplasms, Nerve Tissue, Colonic Neoplasms, Colorectal Neoplasms, Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasm, Digestive System Disease, Gastrointestinal Disease, Colonic Diseases, Intestinal Disease

Intervention / Treatment
-----------------
* Drug: pralsetinib (BLU-667)


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor. All participants treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood. Diagnosis during dose expansion (Phase 2) - All participants (with the exception of participants with MTC enrolled in Groups 3, 4, and 9) must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below. Group 1 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy. Group 2 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy, including those who have not had any systemic therapy. Prior platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if the last dose of platinum was 4 months or more before the first dose of study drug. Group 3 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib. Group 4 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib and/or vandetanib. Group 5 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received standard of care (SOC) appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate), and must not have been eligible for any of the other groups. Group 6 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective tyrosine kinase inhibitor (TKI) that inhibits RET Group 7 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups Group 8 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum based chemotherapy (China only). Group 9 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit, and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only). Participants must have non-resectable disease. Dose expansion (Phase 2): Participants in all groups (except Group 7) must have measurable disease per RECIST v1.1 (or RANO, criteria if appropriate for tumor type). Participants agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Phase 2, Group 6, participants are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue. Participants has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. Key Exclusion Criteria: Participant's cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1 or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation. Participants had any of the following within 14 days prior to the first dose of study drug: Platelet count < 75 × 10^9/L. Absolute neutrophil count < 1.0 × 10^9/L. Hemoglobin < 9.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present. Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease. Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min. Total serum phosphorus > 5.5 mg/dL QT interval corrected using Fridericia's formula (QTcF) > 470 msec or history of prolonged QT syndrome or Torsades de pointes, or familial history of prolonged QT syndrome. Clinically significant, uncontrolled, cardiovascular disease. Central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms. Clinically symptomatic interstitial lung disease or interstitial pneumonitis including radiation pneumonitis Participants in Groups 1-5 and 7 (Phase 2) previously treated with a selective RET inhibitor Participant had a major surgical procedure within 14 days of the first dose of study drug Participant had a history of another primary malignancy that had been diagnosed or required therapy within the a year prior to the study Pregnant or breastfeeding female participants

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1 (Complete): Advanced MTC, NSCLC or other solid tumor 30-600mg (PO QD or BID) Phase 2 (400mg QD): Group 1: RET fusion NSCLC previously treated with a platinum chemotherapy Group 2: RET fusion NSCLC not previously treated for metastatic disease Group 3: MTC previously treated with cabozantinib and/or vandetanib Group 4: MTC not previously treated with cabozantinib or vandetanib Group 5: Other solid tumors with a RET fusion not eligible for any of the other groups and previously treated with SOC or have no acceptable SOC for their tumor type as determined by the investigator Group 6: Any solid tumor with a RET alteration (fusion or mutation) previously treated with a selective RET Inhibitor Group 7: Other solid tumors with a RET mutation previously treated with SOC Group 8: RET fusion NSCLC previously treated with a platinum chemotherapy (China only) Group 9: MTC not previously treated with systemic therapy for advanced or metastatic disease (China only)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>Multiple doses of pralsetinib (BLU-667) for oral administration. | Drug: pralsetinib (BLU-667)<br>* pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants<br>* Other names: BLU-667;|
| Experimental: Phase 2 Dose Expansion<br>Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation. | Drug: pralsetinib (BLU-667)<br>* pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants<br>* Other names: BLU-667;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase 1) Determination of Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib |  | Cycle 1 (28 days) of treatment for MTD and at the end of every cycle (28 days) for RP2D for approximately 12 months or earlier if participant terminates from the study | 
| (Phase 1) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Every cycle (28 days) for approximately 12 months or earlier if participant terminates from the study, and 30 days after the last dose | 
| (Phase 2) Overall Response Rate (ORR) | As assessed by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) or Response Assessment in Neuro-Oncology (RANO), as appropriate per tumor type | Approximately every 8 weeks or 16 weeks based on the treatment cycle | 
| (Phase 2) Number of Participants with AEs and SAEs |  | Every cycle (28 days) for approximately 24 months or earlier if participant terminates from the study, and 30 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase 1) ORR | As assessed by RECIST v1.1 or RANO, as appropriate per tumor type | Approximately every 8 weeks during treatment, 14 days after the last dose, and every 3 months after the last dose (Up to 12 months) in participants without progressive disease | 
| (Phase 1) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR, PFS and Other Antineoplastic Measures | Clinical Benefit Rate (CBR), Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS) | Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 12 months) | 
| (Phase 2) CBR |  | Approximately every 8 weeks or 16 weeks based on the treatment cycle | 
| (Phase 2) DOR |  | Approximately every 8 weeks or 16 weeks based on the treatment cycle | 
| (Phase 2) DCR |  | Approximately every 8 weeks or 16 weeks based on the treatment cycle | 
| (Phase 2) PFS |  | Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months) | 
| (Phase 2) Overall Survival (OS) |  | Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months) | 
| (Phase 2) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR and Other Antineoplastic Measures | RET gene status (i.e. gene fusion partner or primary mutation and, for MTC, whether hereditary or sporadic) | On Day 1 of Cycle 1 (each cycle is of 28 days), 2 and 3 and every other cycle thereafter up to Cycle 13 | 
| (Phases 1 and 2) Pharmacokinetic Parameters Including Maximum Plasma Drug Concentration (Cmax) |  | Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4 | 
| (Phases 1 and 2) Pharmacokinetic Parameters Including Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) |  | Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4 | 
| (Phases 1 and 2) Pharmacokinetic Parameters Including Terminal Elimination Half-life (t1/2) |  | Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4 | 
| (Phase 2) Electrocardiogram (ECG) Assessment Using QT Analysis | Will be measured from lead II and will be corrected for heart rate (QTc)n using Fridericia's correction factors | Effects of BLU-667 on ECG parameters on Cycle 1 Day 1 and Cycle 1 Day 15 | 
| (Phases 1 and 2) Pharmacodynamic Parameters Including Changes in Blood Calcitonin | MTC participants only | Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13 | 
| (Phases 1 and 2) Pharmacodynamic Parameters Including Tumor Marker, Carcinoembryonic Antigen (CEA) | MTC participants only | Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13 | 
| (Phase 2) Assess Intracranial Response Rate and Time to Intracranial Progression in Participants With NSCLC | Target by RECIST v1.1 or RANO | Approximately every 8 weeks or 16 weeks based on the treatment cycle | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RET Lung, RET Thyroid, RET fusion, RET alteration, RET mutation, RET positive, RET inhibitor, RET altered, RET rearrangement, RET NSCLC, RET medullary thyroid cancer, RET-rearranged NSCLC, RET-rearranged thyroid, M918T, TRIM33-RET, RET fusion lung cancer, RET fusion thyroid cancer, lung cancer mutation, BLU 667, RET tyrosine kinase, RET gene mutation, RET kinase, RET MTC, advanced lung cancer, advanced non small cell lung cancer, metastatic lung cancer, KIF5B-RET, CCDC6-RET, NCOA4-RET, advance solid tumor, V804L, V804M, thyroid cancer RET inhibitor, lung cancer RET inhibitor, RET PTC, rearranged during transfection, RET-PTC1, 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, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET