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

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

Sponsors

Lead Sponsor: Hoffmann-La Roche

Source 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 patients with medullary thyroid cancer, 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 patients 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 patients 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.

Overall Status Recruiting
Start Date 2017-03-17
Completion Date 2024-02-29
Primary Completion Date 2021-12-31
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure 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 patient terminates from the study
(Phase 1) Number of patients with adverse events and serious adverse events Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose
(Phase 2) Overall response rate Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2) Number of patients with adverse events and serious adverse events Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose
Secondary Outcome
Measure Time Frame
(Phase 1) Overall response rate Approximately every 8 weeks during treatment, 14 days after the last dose, and every 3 months after the last dose (up to 2 years) in patients without progressive disease
(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
(Phase 2 ) Clinical Benefit Rate (CBR) Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2 ) Duration of Response (DOR) Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2 ) Disease Control Rate (DCR) Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2 ) Progression Free Survival (PFS) Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2 ) Overall Survival (OS) Approximately every 8 weeks or 16 weeks based on the treatment cycle
(Phase 2) RET gene status and correlation between RET gene status and ORR, CBR, DOR, DCR and other antineoplastic measures 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 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 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 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) 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 patients with NSCLC Approximately every 8 weeks or 16 weeks based on the treatment cycle
Enrollment 647
Condition
Intervention

Intervention Type: Drug

Intervention Name: pralsetinib (BLU-667)

Description: pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants

Other Name: BLU-667

Eligibility

Criteria:

Key Inclusion Criteria: - Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor. - All patients treated at doses > 120 mg per day must have medullary thyroid cancer (MTC), or a RET-altered solid tumor per local assessment of tumor tissue and/or blood. - Diagnosis during dose expansion (Phase 2) - All patients (with the exception of patients 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 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy. - Group 2 - patients 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 - patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib. - Group 4 - patient must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treat with cabozantinib and/or vandetanib. - Group 5 -patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received 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 be eligible for any of the other groups. - Group 6 - patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective TKI that inhibits RET - Group 7 - patients 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 - patients 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 - patients must have pathologically documented, definitively diagnosed advanced MTC that has 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). - Patients must have non-resectable disease. - Patient 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, patients are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue. - Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. Key Exclusion Criteria: - Patient'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. - Patient has 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 - Patients in Groups 1-5 and 7 (Phase 2) previously treated with a selective RET inhibitor

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Clinical Trials Study Director Hoffmann-La Roche
Overall Contact

Last Name: Reference Study ID Number: BO42863 http://www.roche.com/about_roche/roche_worldwide.htm

Phone: 888-662-6728 (U.S. and Canada)

Email: [email protected]

Location
Facility: Status:
Mayo Clinic | Phoenix, Arizona, 85054, United States Recruiting
UC Irvine Medical Center | Orange, California, 92868, United States Recruiting
University of Colorado Cancer Center | Aurora, Colorado, 80045, United States Recruiting
Georgetown University Medical Center | Washington, District of Columbia, 20007, United States Recruiting
Mayo Clinic | Jacksonville, Florida, 32224, United States Recruiting
University of Miami Hospitals and Clinics, Sylvester Comprehensive Cancer Center | Miami, Florida, 33136, United States Recruiting
Maryland Oncology Hematology, PA - Columbia | Columbia, Maryland, 21044-3257, United States Recruiting
Massachusetts General Hospital | Boston, Massachusetts, 02114, United States Recruiting
University of Michigan | Ann Arbor, Michigan, 48109, United States Recruiting
Mayo Clinic | Rochester, Minnesota, 55905, United States Recruiting
Washington University School of Medicine, Siteman Cancer Center | Saint Louis, Missouri, 63110, United States Recruiting
Albany Medical Center | Albany, New York, 12208-3412, United States Recruiting
Jack D. Weiler Hospital | Bronx, New York, 10461-2301, United States Recruiting
Cornell University | New York, New York, 10021, United States Recruiting
Oregon Health and Science University | Portland, Oregon, 97239, United States Recruiting
University of Pennsylvania Hospital | Philadelphia, Pennsylvania, 19104, United States Recruiting
UPMC CancerCenter | Pittsburgh, Pennsylvania, 15213-1862, United States Recruiting
Texas Oncology - Austin | Austin, Texas, 78705-1165, United States Recruiting
Texas Oncology - Baylor Charles A. Sammons Cancer Center | Dallas, Texas, 75246, United States Recruiting
University of Texas MD Anderson Cancer Center | Houston, Texas, 77030, United States Recruiting
University of Washington, Seattle Cancer Care Alliance | Seattle, Washington, 98109, United States Recruiting
Antwerp University Hospital | Edegem, 2650, Belgium Recruiting
Beijing Cancer Hospital | Beijing, 100036, China Recruiting
West China Hospital, Sichuan University | Chengdu, 610041, China Recruiting
Sichuan Cancer Hospital & Institute | Chongqing, 400030, China Recruiting
Chongqing Cancer Hospital | Chongqing, 404100, China Recruiting
Fujian Provincial Cancer Hospital | Fuzhou, 350014, China Recruiting
First Affiliated Hospital of Gannan Medical University | Ganzhou, 341000, China Recruiting
Sun Yat-sen University Cancer Center | Guangzhou, 510060, China Recruiting
Guangdong Provincial People's Hospital | Guangzhou, 510080, China Recruiting
Nanfang Hospital of Southern Medical University | Guangzhou, 510515, China Recruiting
Zhejiang Provincial People's Hospital | Hangzhou, 310000, China Recruiting
Zhejiang Cancer Hospital | Hangzhou, 310022, China Recruiting
Anhui Provincial Cancer Hospital | Hefei, 230031, China Recruiting
Jinan Central Hospital | Jinan, 250013, China Recruiting
Gansu Provincial Cancer Hospital | Lanzhou, 730050, China Recruiting
Fudan University Shanghai Cancer Center | Shanghai, 200032, China Recruiting
Liaoning Cancer Hospital & Institute | Shenyang, 110042, China Recruiting
Tianjin Medical University Cancer Institute and Hospital | Tianjin, 300041, China Recruiting
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology | Wuhan, 430022, China Recruiting
Henan Cancer Hospital | Zhengzhou, 450008, China Recruiting
Institut Bergonié | Bordeaux, 33076, France Recruiting
CHRU de Lille - Hôpital Claude Hurier Servide d'Endocrinologie et Diabétologie | Lille, 59037, France Recruiting
Centre Leon Berard | Lyon, 69373, France Recruiting
Centre Antoine Lacassagne | Nice, 6100, France Recruiting
Hospital Tenon | Paris, 75020, France Recruiting
Institut Curie | Paris, 75248, France Recruiting
CHU de Rennes - Hôpital Pontchaillou | Rennes, 35033, France Recruiting
Insitut Claudius Regaud | Toulouse, 31059, France Recruiting
Gustave Roussy | Villejuif, 94805, France Recruiting
HELIOS Klinikum Emil von Behring | Berlin, 14165, Germany Recruiting
Universitätsklinikum Essen | Essen, 45147, Germany Recruiting
Thoraxklinik Heidelberg | Heidelberg, 69126, Germany Recruiting
Klinikum der Universitat Munchen | Munich, 81377, Germany Recruiting
Pius-Hospital Oldenberg | Oldenburg, 26121, Germany Recruiting
The Chinese University of Hong Kong | Hong Kong, Hong Kong Recruiting
Istituto Europeo di Oncologia Sviluppo Nuovi Farmaci per Terapie Innovative | Milano, 20141, Italy Recruiting
Grande Ospedale Metropolitano Niguarda | Milan, 20162, Italy Recruiting
Ospedale Santa Maria delle Croci | Ravenna, 48124, Italy Recruiting
Istituto Nazionale Tumori Regina Elena | Rome, 144, Italy Recruiting
Seoul National University Hospital | Seoul, 03080, Korea, Republic of Recruiting
Severance Hospital | Seoul, 03722, Korea, Republic of Recruiting
Asan Medical Center | Seoul, 05505, Korea, Republic of Recruiting
Samsung Medical Center | Seoul, 6351, Korea, Republic of Recruiting
Nederlands Kanker Instituut - Antoni van Leeuwenhoek Ziekenhuis | Amsterdam, 1066 CX, Netherlands Recruiting
University Medical Center Groningen | Groningen, 9713, Netherlands Recruiting
National Cancer Centre Singapore | Singapore, 169160, Singapore Recruiting
Hospital Universitari Vall d'Hebron | Barcelona, 08035, Spain Recruiting
Hospital Clinic Barcelona | Barcelona, 08036, Spain Recruiting
Hospital Duran I Reynals | Barcelona, 08908, Spain Recruiting
Hospital Universitario Ramon y Cajal | Madrid, 28034, Spain Recruiting
Hospital Universitario 12 de Octubre Servicio de Oncologia Medica | Madrid, 28041, Spain Recruiting
National Taiwan University Hospital | Taipei City, 10002, Taiwan Recruiting
Taipei Veterans General Hospital | Taipei, 11217, Taiwan Recruiting
NHS Grampian - Aberdeen Royal Infirmary | Aberdeen, AB25 2ZN, United Kingdom Recruiting
Sarah Cannon Research Institute | London, W1G 6AD, United Kingdom Recruiting
Guy's Hospital St. Thomas NHS Foundation Trust | London, United Kingdom Recruiting
NIHR UCLH Clinical Research Facility, University College of London NHS Foundation Trust | London, United Kingdom Recruiting
The Christie NHS Foundation Trust | Manchester, United Kingdom Recruiting
Location Countries

Belgium

China

France

Germany

Hong Kong

Italy

Korea, Republic of

Netherlands

Singapore

Spain

Taiwan

United Kingdom

United States

Verification Date

2021-05-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access Yes
Condition Browse
Number Of Arms 2
Arm Group

Label: Phase 1 Dose Escalation

Type: Experimental

Description: Multiple doses of pralsetinib (BLU-667) for oral administration.

Label: Phase 2 Dose Expansion

Type: Experimental

Description: Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.

Acronym ARROW
Patient Data No
Study Design Info

Allocation: Non-Randomized

Intervention Model: Parallel Assignment

Intervention 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)

Primary Purpose: Treatment

Masking: None (Open Label)

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