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

Phase 1

Completed

• Conditions: RET-altered Non Small Cell Lung Cancer; Thyroid Diseases; Thyroid Neoplasm; Thoracic Neoplasms; Carcinoma, Bronchogenic; Head and Neck Neoplasms; Carcinoma; Neoplasms, Germ Cell and Embryonal; Digestive System Neoplasm; Carcinoma, Neuroendocrine
• Interventions: Drug: pralsetinib (BLU-667)

• Registration Number: NCT03037385
• Lead Sponsor: Hoffmann-La Roche

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2017-01-20
• Study First Submitted QC: 2017-01-27
• Study First Posted: 2017-01-31
• Study Start: 2017-03-17
• Primary Completion: 2024-03-21
• Study Completion: 2024-03-21
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-10
• Last Update Posted: 2024-04-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 589

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

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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:

  1. Platelet count < 75 × 10^9/L.
  2. Absolute neutrophil count < 1.0 × 10^9/L.
  3. 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.
  4. 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.
  5. Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease.
  6. Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min.
  7. 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 2 Dose Expansion	pralsetinib (BLU-667)	Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.
Phase 1 Dose Escalation	pralsetinib (BLU-667)	Multiple doses of pralsetinib (BLU-667) for oral administration.

Primary Outcome Measures

Name	Time	Method
(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)	Approximately every 8 weeks or 16 weeks based on the treatment cycle	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
(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

Name	Time	Method
(Phase 1) ORR	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	As assessed by RECIST v1.1 or RANO, as appropriate per tumor type
(Phase 1) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR, PFS and Other Antineoplastic Measures	Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 12 months)	Clinical Benefit Rate (CBR), Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS)
(Phase 2) DCR	Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2) Electrocardiogram (ECG) Assessment Using QT Analysis	Effects of BLU-667 on ECG parameters on Cycle 1 Day 1 and Cycle 1 Day 15	Will be measured from lead II and will be corrected for heart rate (QTc)n using Fridericia's correction factors
(Phase 2) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR and Other Antineoplastic Measures	On Day 1 of Cycle 1 (each cycle is of 28 days), 2 and 3 and every other cycle thereafter up to Cycle 13	RET gene status (i.e. gene fusion partner or primary mutation and, for MTC, whether hereditary or sporadic)
(Phase 2) Assess Intracranial Response Rate and Time to Intracranial Progression in Participants With NSCLC	Approximately every 8 weeks or 16 weeks based on the treatment cycle	Target by RECIST v1.1 or RANO
(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) DOR	Approximately every 8 weeks or 16 weeks based on the treatment cycle
(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) Pharmacodynamic Parameters Including Changes in Blood Calcitonin	Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13	MTC participants only
(Phase 2) CBR	Approximately every 8 weeks or 16 weeks based on the treatment cycle
(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 Terminal Elimination Half-life (t1/2)	Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4
(Phases 1 and 2) Pharmacodynamic Parameters Including Tumor Marker, Carcinoembryonic Antigen (CEA)	Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13	MTC participants only

Trial Locations

Locations (72)

Thoraxklinik Heidelberg gGmbH; 🇩🇪 Heidelberg, Germany

Universitair Medisch Centrum Groningen; 🇳🇱 Groningen, Netherlands

Maryland Oncology Hematology, P.A.; 🇺🇸 Columbia, Maryland, United States

Massachusetts General Hospital.; 🇺🇸 Boston, Massachusetts, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Texas Oncology - Baylor Charles A. Sammons Cancer Center; 🇺🇸 Dallas, Texas, United States

Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

The affiliated Cancer Hospital, School of Medicine, UESTC; 🇨🇳 Chengdu, China

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Seattle Cancer Care Alliance; 🇺🇸 Seattle, Washington, United States

Zhejiang Provincial People?s Hospital; 🇨🇳 Hangzhou, China

Gansu Cancer Hospital; 🇨🇳 Lanzhou, China

Jinan Central Hospital; 🇨🇳 Jinan City, China

Sylvester Comprehensive Cancer Center; University of Miami School of Medicine; 🇺🇸 Miami, Florida, United States

University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Mayo Clinic Hospital; 🇺🇸 Phoenix, Arizona, United States

UC Irvine Medical Center; 🇺🇸 Orange, California, United States

Mayo Clinic-Jacksonville; 🇺🇸 Jacksonville, Florida, United States

Weill Cornell Medical College-New York Presbyterian Hospital; 🇺🇸 New York, New York, United States

Mayo Clinic Rochester; 🇺🇸 Rochester, Minnesota, United States

Washington University School of Medicine in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

Stellar - Chance Laboratories; 🇺🇸 Philadelphia, Pennsylvania, United States

Texas Oncology-Austin Midtown; 🇺🇸 Austin, Texas, United States

Beijing Cancer Hospital; 🇨🇳 Beijing, China

Antwerp University Hospital; 🇧🇪 Edegem, Belgium

West China Hospital, Sichuan University; 🇨🇳 Chengdu, China

Chongqing Cancer Hospital; 🇨🇳 Chongqing, China

Sun Yet-sen University Cancer Center; 🇨🇳 Guangzhou City, China

First Affiliated Hospital of Gannan Medical University; 🇨🇳 Ganzhou, China

Fujian Provincial Cancer Hospital; 🇨🇳 Fuzhou City, China

Guangdong General Hospital; 🇨🇳 Guangzhou, China

Fudan University Shanghai Cancer Center; 🇨🇳 Shanghai City, China

Tianjin Medical University Cancer Institute & Hospital; 🇨🇳 Tianjin, China

Union Hospital Tongji Medical College Huazhong University of Science and Technology; 🇨🇳 Wuhan City, China

Zhejiang Cancer Hospital; 🇨🇳 Zhejiang, China

Henan Cancer Hospital; 🇨🇳 Zhengzhou, China

Institut Bergonie; 🇫🇷 Bordeaux, France

Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez; 🇫🇷 Lille, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Institut Curie; 🇫🇷 Paris, France

CHU de Rennes - Hopital de Pontchaillo; 🇫🇷 Rennes, France

Centre Léon Bérard; 🇫🇷 Lyon, France

Hôpital Larrey;Université Paul Sabatier; 🇫🇷 Toulouse, France

Helios Klinikum Emil von Behring GmbH; 🇩🇪 Berlin, Germany

Gustave Roussy; 🇫🇷 Villejuif, France

Universitätsklinikum Essen; Innere Klinik und Poliklinik für Tumorforschung; 🇩🇪 Essen, Germany

Pius-Hospital; Klinik fuer Haematologie und Onkologie; 🇩🇪 Oldenburg, Germany

Klinikum der Universität München; 🇩🇪 Muenchen, Germany

Istituto Nazionale Tumori Regina Elena; 🇮🇹 Roma, Lazio, Italy

Ospedale Santa Maria Delle Croci; 🇮🇹 Ravenna, Emilia-Romagna, Italy

IEO; Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative; 🇮🇹 Milano, Lombardia, Italy

Asst Grande Ospedale Metropolitano Niguarda; 🇮🇹 Milano, Lombardia, Italy

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital, Yonsei University Health System; Oncology; 🇰🇷 Seoul, Korea, Republic of

Antoni van Leeuwenhoek Ziekenhuis; 🇳🇱 Amsterdam, Netherlands

National Cancer Centre; 🇸🇬 Singapore, Singapore

Institut Catala d Oncologia Hospitalet; 🇪🇸 Hospitalet de Llobregat, Barcelona, Spain

Hospital Ramon y Cajal; Servicio de Oncologia; 🇪🇸 Madrid, Spain

Vall d?Hebron Institute of Oncology (VHIO), Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario 12 de Octubre; Servicio de Oncologia; 🇪🇸 Madrid, Spain

Taipei Veterans General Hospital; 🇨🇳 Taipei City, Taiwan

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

Guys and St Thomas NHS Foundation Trust, Guys Hospital; 🇬🇧 London, United Kingdom

Sarah Cannon Research Institute; 🇬🇧 London, United Kingdom

University College London Hospitals NHS Foundation Trust; NIHR UCLH Clinical Research Facility; 🇬🇧 London, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

The Chinese University of Hong Kong; 🇭🇰 Shatin, Hong Kong