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 (ARROW)

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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms; Neoplasms by Histologic Type; Lung Diseases; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Gastrointestinal Neoplasms; Neoplasms, Germ Cell and Embryonal; Head and Neck Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Thyroid Diseases; Neuroectodermal Tumors; Neoplasms, Nerve Tissue; Colonic Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Neuroendocrine Tumors; Colonic Neoplasms; Medullary Thyroid Cancer; Carcinoma, Neuroendocrine; Thyroid Cancer, Papillary; Adenocarcinoma, Papillary; Digestive System Neoplasm; Digestive System Disease; Gastrointestinal Disease; Endocrine Gland Neoplasm; Respiratory Tract Disease; Intestinal Disease; Lung Neoplasm; Thyroid Neoplasm; RET-altered Solid Tumors; RET-altered Non Small Cell Lung Cancer; RET-altered Papillary Thyroid Cancer; RET-altered Colon Cancer
• Intervention / Treatment: Drug: pralsetinib (BLU-667)

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.

• Study Type: Interventional
• Enrollment (Actual): 590
• Phase: Phase 2; Phase 1

Expanded Access

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Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • Antwerp University Hospital
• China
  • Beijing, China, 100142
    • Beijing Cancer Hospital
  • Beijing, China, 100036
    • Beijing Cancer Hospital
  • Chengdu, China, 610041
    • West China Hospital, Sichuan University
  • Chengdu, China, 610041
    • The affiliated Cancer Hospital, School of Medicine, UESTC
  • Chongqing, China, 400030
    • Chongqing Cancer Hospital
  • Fuzhou City, China, 350014
    • Fujian provincial Cancer Hospital
  • Ganzhou, China, 341000
    • First Affiliated Hospital of Gannan Medical University
  • Guangzhou, China, 510060
    • Sun Yet-sen University Cancer Center
  • Guangzhou, China, 510080
    • Guangdong General Hospital
  • Hangzhou, China, 310022
    • Zhejiang Cancer Hospital
  • Jinan City, China, 250013
    • Jinan Central Hospital
  • Lanzhou, China, 730050
    • Gansu Cancer Hospital
  • Shanghai, China, 200032
    • Fudan University Shanghai Cancer Center
  • Shanghai City, China, 200120
    • Fudan University Shanghai Cancer Center
  • Tianjing, China, 300060
    • Tianjin Medical University Cancer Institute & Hospital
  • Wuhan City, China, 430023
    • Union Hospital Tongji Medical College Huazhong University of Science and Technology
  • Zhengzhou, China, 450008
    • Henan Cancer Hospital
• France
  • Bordeaux, France, 33000
    • Institut Bergonie
  • Lille, France, 59037
    • Centre Hospitalier Régional Universitaire de Lille (CHRU) - Hôpital Claude Huriez
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Nice, France, 6100
    • Centre Antoine Lacassagne
  • Paris, France, 75248
    • Institut Curie
  • Rennes cedex 09, France, 35033
    • CHU de Rennes - Hopital de Pontchaillo
  • Toulouse, France, 31059
    • Hopital Larrey
  • Villejuif CEDEX, France, 94800
    • Gustave Roussy
• Germany
  • Berlin, Germany, 14165
    • Helios Klinikum Emil von Behring GmbH
  • Essen, Germany, 45122
    • Universitatsklinikum Essen
  • Heidelberg, Germany, 69126
    • Thoraxklinik Heidelberg gGmbH
  • München, Germany, 81377
    • Klinikum der Universität München
  • Oldenburg, Germany, 26121
    • Pius-Hospital
• Hong Kong
  • Shatin, Hong Kong, 123456
    • The Chinese University of Hong Kong
• Italy
  • Emilia-Romagna
    • Ravenna, Emilia-Romagna, Italy, 48100
      • Ospedale Santa Maria delle Croci
  • Lazio
    • Roma, Lazio, Italy, 00144
      • Istituto Nazionale Tumori Regina Elena
  • Lombardia
    • Milano, Lombardia, Italy, 20162
      • ASST Grande Ospedale Metropolitano Niguarda
    • Milano, Lombardia, Italy, 20141
      • IEO
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital, Yonsei University Health System
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Antoni Van Leeuwenhoek Ziekenhuis
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Vall d?Hebron Institute of Oncology (VHIO), Barcelona
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Institut Catala d Oncologia Hospitalet
• Taiwan
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei City, Taiwan, 11217
    • Taipei Veterans General Hospital
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guys and St Thomas NHS Foundation Trust, Guys Hospital
  • London, United Kingdom, W1T 7HA
    • University College London Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • California
    • Orange, California, United States, 92868
      • UC Irvine Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic-Jacksonville
    • Miami, Florida, United States, 33136-1002
      • Sylvester Comprehensive Cancer Center
  • Maryland
    • Columbia, Maryland, United States, 21044-3257
      • Maryland Oncology Hematology, P.A.
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2696
      • Massachusetts General Hospital.
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0934
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55902-3003
      • Mayo Clinic Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1010
      • Washington University School of Medicine in St. Louis
  • New York
    • Albany, New York, United States, 12208-3412
      • Albany Medical Center
    • New York, New York, United States, 10021
      • Weill Cornell Medical College-New York Presbyterian Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Texas
    • Austin, Texas, United States, 78705-1165
      • Texas Oncology-Austin Midtown
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Charles A. Sammons Cancer Center
    • Houston, Texas, United States, 77030-4000
      • The University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib	MTD was defined as the highest tolerated dose of pralsetinib without causing dose limiting toxicities (DLTs). DLT was defined as any Grade ≥3 adverse event (AE) occurring during Cycle 1 during Phase 1 (dose escalation) that is not clearly caused by something other than pralsetinib. RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase.	Up to approximately 30.8 months
Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs)	An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.	From Cycle 1 Day 1 up to 30 days after the final dose of study drug (up to approximately 6.7 years)
Phase 2: Overall Response Rate (ORR)	ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) for at least two assessments with at least 28 days apart and no disease progression (PD) in between. Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), were presented.	Up to approximately 79.8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: ORR	ORR was defined as the percentage of participants with a confirmed CR or PR for at least two assessments with at least 28 days apart and no PD in between. Per RECIST v1.1, CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), was presented.	Up to approximately 28 months
Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status	Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., Kinesin family member 5B (KIF5B), coiled-coil domain containing 6 (CCDC6), nuclear receptor coactivator 4 (NCOA4)). RET genotypes were determined by local testing and/or central analysis of circulating tumor deoxyribonucleic acid (ctDNA). ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3.	Up to approximately 79.8 months
Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3.	Up to approximately 79.8 months
Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in both MTC and differentiated TC (DTC). These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for OM 3.	Up to approximately 79.8 months
Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status	Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR, or stable disease (SD) which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).	Up to approximately 79.8 months
Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).	Up to approximately 79.8 months
Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in both MTC and DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. CBR was assessed in participants having specific RET rearrangements. CBR was defined as the percentage of participants with a confirmed CR or PR or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).	Up to approximately 79.8 months
Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status	Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).	Up to approximately 79.8 months
Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).	Up to approximately 79.8 months
Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in both MTC and DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR was defined as the percentage of participants with a confirmed CR/PR, or SD. CR and PR were defined per RECIST as outlined in the description for OM 3. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline).	Up to approximately 79.8 months
Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status	Oncogenic RET rearrangements have been identified in 1%-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5), CCDC6, NCOA4). RET genotypes were determined by local testing &/or central analysis of circulating tumor deoxyribonucleic acid (ctDNA). DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR=disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to <10 mm. PR=at least a 30% decrease in SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study. DOR was analyzed using the Kaplan-Meier (KM) method.	Up to approximately 79.8 months
Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR= disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to <10 mm. PR=at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the Kaplan-Meier (KM) method.	Up to approximately 79.8 months
Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status	Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR was assessed in participants having specific RET rearrangements. DOR=time from first documented CR/PR to date of first documented PD or death due to any cause, whichever occurs first. Per RECIST, CR= disappearance of all target lesions or any pathological lymph nodes (target or non-target) having a reduction in the short axis to <10 mm. PR=at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in absence of CR. PD=as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the KM method.	Up to approximately 79.8 months
Phase 2: DOR	DOR was defined as the time from first documented response (CR/PR) to the date of first documented PD or death due to any cause, whichever occurs first. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DOR was analyzed using the KM methods.	Up to approximately 79.8 months
Phase 2: CBR	CBR was defined as the percentage of participants with CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). CBR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented.	Up to approximately 79.8 months
Phase 2: DCR	DCR was defined as the percentage of participants with a confirmed CR/PR, or SD, per RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DCR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented.	Up to approximately 79.8 months
Phase 2: Progression-free Survival (PFS)	PFS was defined as the time from the first dose of pralsetinib to the date of first documented PD or death due to any cause, whichever occurred first. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). PFS was analyzed using KM methods.	Up to approximately 7 years
Phase 2: Overall Survival (OS)	OS was defined as the time from the first dose of pralsetinib to the date of death due to any causes.	Up to approximately 7 years
Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants	ORR=percentage of participants with CR or PR for at least 2 assessments with at least 28 days apart & no PD in between. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/or cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR =at least a 30% decrease in the SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in the absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or the identification of new CNS/brain lesion. PD=either at least 20% increase in the SOD of target CNS/brain lesion, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of any CNS/brain lesion identified as RECIST 1.1 nontarget lesions at baseline, or the identification of new CNS/brain lesion.	Up to approximately 79.8 months
Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants	CBR=percentage of participants with CR/PR/SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in 1 cycle) from first dose date. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/ cerebellum identified at baseline&disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR=at least a 30% decrease in SOD of any CNS/brain lesion, identified as target lesions at baseline & if in absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or identification of new CNS/brain lesion. SD=neither sufficient shrinkage for PR nor sufficient increase for PD for target/non-target CNS/brain lesion, taking as reference smallest SOD while on study. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion.	Up to approximately 79.8 months
Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants	DCR=percentage of participants with a confirmed CR/PR, or SD. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/or cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR =at least a 30% decrease in the SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in the absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or the identification of new CNS/brain lesion. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target/non-target CNS/brain lesion, taking as reference the smallest SOD while on study. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion.	Up to approximately 79.8 months
Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants	DOR=time from first documented CR/PR to the date of first documented PD/death due to any cause, whichever occurs first. CR=disappearance of all target CNS/brain lesion, including lesions in brain stem &/ cerebellum identified at baseline & disappearance of all non-target CNS/brain lesion at baseline & no identification of new CNS/brain lesion. PR=at least a 30% decrease in SOD of any CNS/brain lesion, identified as RECIST 1.1 target lesions at baseline & if in absence of unequivocal progression of any non-target CNS/brain lesion at baseline, or identification of new CNS/brain lesion. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion. DOR was analyzed using the KM methods.	Up to approximately 79.8 months
Phase 1: Maximum Plasma Concentration (Cmax)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Time to Maximum Plasma Concentration (Tmax)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast)	The maximum values for Tlast slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	24 hours postdose on Day 1 of Cycle 1 (1 cycle = 28 days)
Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Apparent Volume of Distribution (Vz/F)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Terminal Elimination Half-Life (t½)	The maximum values for t1/2 slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol. Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Apparent Oral Clearance (CL/F)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Accumulation Ratio for Cmax (RCmax)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Accumulation Ratio for AUC (RAUC)	Number of participants in each arm of this OM is based on the actual treatment received. 1 participant originally assigned to the 200/100 mg arm received the 100/100 mg treatment and hence, was counted under the 100/100 mg arm for this OM.	24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: Cmax		Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: Tmax		Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: Tlast	The maximum values for Tlast slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: AUC0-24		24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: C24hr		24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: t½	The maximum values for t1/2 slightly exceed 24 hours because the analysis used the actual time, i.e., the duration between dosing and actual sample collection, rather than the nominal sampling time of 24 hours specified in the protocol. The timeframe has been given as per nominal sampling timepoints pre-specified in the protocol.	Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 2: CL/F		Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)
Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6)	The dose dependent change in a mitogen-activated protein kinases (MAPK) pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker DUSP6 levels was explored.	Baseline, Week 4
Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4)	The dose dependent change in a MAPK pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker SPRY4 levels was explored.	Baseline, Week 4

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Publications and helpful links

General Publications

• Subbiah V, Cassier PA, Siena S, Garralda E, Paz-Ares L, Garrido P, Nadal E, Vuky J, Lopes G, Kalemkerian GP, Bowles DW, Seetharam M, Chang J, Zhang H, Green J, Zalutskaya A, Schuler M, Fan Y, Curigliano G. Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med. 2022 Aug;28(8):1640-1645. doi: 10.1038/s41591-022-01931-y. Epub 2022 Aug 12.
• Popat S, Liu SV, Scheuer N, Hsu GG, Lockhart A, Ramagopalan SV, Griesinger F, Subbiah V. Addressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer. Nat Commun. 2022 Jun 17;13(1):3500. doi: 10.1038/s41467-022-30908-1.
• Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, Brose MS, Zhu VW, Leboulleux S, Bowles DW, Baik CS, Adkins D, Keam B, Matos I, Garralda E, Gainor JF, Lopes G, Lin CC, Godbert Y, Sarker D, Miller SG, Clifford C, Zhang H, Turner CD, Taylor MH. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021 Aug;9(8):491-501. doi: 10.1016/S2213-8587(21)00120-0. Epub 2021 Jun 9.
• Gainor JF, Curigliano G, Kim DW, Lee DH, Besse B, Baik CS, Doebele RC, Cassier PA, Lopes G, Tan DSW, Garralda E, Paz-Ares LG, Cho BC, Gadgeel SM, Thomas M, Liu SV, Taylor MH, Mansfield AS, Zhu VW, Clifford C, Zhang H, Palmer M, Green J, Turner CD, Subbiah V. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021 Jul;22(7):959-969. doi: 10.1016/S1470-2045(21)00247-3. Epub 2021 Jun 9.

Helpful Links

• More information about the study

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2017
• Primary Completion (Actual): March 21, 2024
• Study Completion (Actual): March 21, 2024

Study Registration Dates

• First Submitted: January 20, 2017
• First Submitted That Met QC Criteria: January 27, 2017
• First Posted (Estimated): January 31, 2017

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 30, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: RET gene mutation; RET inhibitor; advanced lung cancer; metastatic lung cancer; RET Lung; RET NSCLC; M918T; TRIM33-RET; BLU 667; KIF5B-RET; CCDC6-RET; RET rearrangement; 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; RET-PTC7; AKAP13-RET; FKBP15-RET; SPECC1L-RET; TBL1XR1-RET; BCR-RET; FGRF1OP-RET; RFG8-RET; V804L; V804M; RET fusion; RET alteration; RET mutation; RET Thyroid; RET positive; RET altered; RET medullary thyroid cancer; RET-rearranged NSCLC; RET-rearranged thyroid; RET fusion lung cancer; RET fusion thyroid cancer; lung cancer mutation; RET tyrosine kinase; RET kinase; RET MTC; advanced non small cell lung cancer; advance solid tumor; thyroid cancer RET inhibitor; lung cancer RET inhibitor; RET PTC; rearranged during transfection
• Additional Relevant MeSH Terms: Rectal Diseases; Bronchial Diseases; Neoplasms, Neuroepithelial; Thyroid Cancer, Papillary; Thyroid Diseases; Neoplasms; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Lung Diseases; Carcinoma; Lung Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Gastrointestinal Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma; Head and Neck Neoplasms; Neuroendocrine Tumors; Intestinal Neoplasms; Carcinoma, Neuroendocrine; Neoplasms, Germ Cell and Embryonal; Intestinal Diseases; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Respiratory Tract Diseases; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Thyroid Neoplasms; Thoracic Neoplasms; Respiratory Tract Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Adenocarcinoma, Papillary; Neoplasms, Nerve Tissue; Bronchial Neoplasms; Carcinoma, Bronchogenic; Antineoplastic Agents; Pralsetinib
• Other Study ID Numbers: BO42863; 2016-004390-41 (EudraCT Number); BLU-667-1101 (Registry Identifier: CT.Gov)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No