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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 (ARROW)

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ClinicalTrials.gov Identifier: NCT03037385
Recruitment Status : Recruiting
First Posted : January 31, 2017
Last Update Posted : November 9, 2021
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE January 20, 2017
First Posted Date  ICMJE January 31, 2017
Last Update Posted Date November 9, 2021
Actual Study Start Date  ICMJE March 17, 2017
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2020)
  • (Phase 1) Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of pralsetinib [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
    As assessed by RECIST v1.1 or RANO, as appropriate per tumor type
  • (Phase 2) Number of patients with adverse events and serious adverse events [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 27, 2017)
  • Determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BLU-667 [ Time Frame: 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 ]
  • Number of patients with adverse events and serious adverse events [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 30 days after the last dose ]
  • Changes in clinical laboratory results [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study, and 14 days after the last dose ]
  • Changes in ECG findings [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2020)
  • (Phase 1) Overall response rate [ Time Frame: 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 ]
    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 [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  • (Phase 2 ) Clinical Benefit Rate (CBR) [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  • (Phase 2 ) Duration of Response (DOR) [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  • (Phase 2 ) Disease Control Rate (DCR) [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  • (Phase 2 ) Progression Free Survival (PFS) [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  • (Phase 2 ) Overall Survival (OS) [ Time Frame: 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 [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
    RET gene status (i.e. gene fusion partner or primary mutation and, for MTC, whether hereditary or sporadic)
  • (Phases 1 and 2) Pharmacokinetic parameters including maximum plasma drug concentration (Cmax) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4 ]
  • (Phase 2) Electrocardiogram (ECG) Assessment using QT analysis [ Time Frame: 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
  • (Phases 1 and 2) Pharmacodynamic parameters including changes in blood calcitonin [ Time Frame: Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13 ]
    MTC patients only
  • (Phases 1 and 2) Pharmacodynamic parameters including tumor marker, carcinoembryonic antigen (CEA) [ Time Frame: Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 13 ]
    MTC patients only
  • (Phase 2) Assess intracranial response rate and time to intracranial progression in patients with NSCLC [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
    Target by RECIST v1.1 or RANO
Original Secondary Outcome Measures  ICMJE
 (submitted: January 27, 2017)
  • Maximum plasma concentration (Cmax) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  • Time to maximum plasma concentration (Tmax) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  • Area under the plasma concentration time curve from 0 to 24 hours (AUC0-24) and from 0 to infinity (AUCinf) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  • Terminal half-life (t1/2) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  • RET gene status in plasma circulating tumor deoxyribonucleic acid (ctDNA) and tumor tissue [ Time Frame: 28-day treatment Cycles 1, 2, and 3, every other cycle thereafter through the first 12 months of treatment, and 14 days after the last dose ]
  • Change in blood calcitonin (medullary thyroid cancer patients) [ Time Frame: 28-day treatment Cycles 1, 2, and 3, every other cycle thereafter through the first 12 months of treatment, and 14 days after the last dose ]
  • Change in tumor biomarker levels (phosphorylated SHC adaptor protein [p-SHC] and dual specificity phosphatase 6 [DUSP6] [ Time Frame: 28-day treatment Cycles 1, 2, and 3, every other cycle thereafter through the first 12 months of treatment, and 14 days after the last dose ]
  • Overall response rate (ORR) [ Time Frame: 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 ]
    ORR is defined as the rate of complete response (CR) and partial response (PR).
  • Duration of response (DOR) [ Time Frame: 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 ]
  • Clinical benefit rate (CBR) [ Time Frame: 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 ]
    CBR is defined as the rate of CR, PR, and stable disease (SD).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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)
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE Drug: pralsetinib (BLU-667)
pralsetinib (BLU-667) is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants
Other Name: BLU-667
Study Arms  ICMJE
  • Experimental: Phase 1 Dose Escalation
    Multiple doses of pralsetinib (BLU-667) for oral administration.
    Intervention: Drug: pralsetinib (BLU-667)
  • Experimental: Phase 2 Dose Expansion
    Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.
    Intervention: Drug: pralsetinib (BLU-667)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 21, 2020)
647
Original Estimated Enrollment  ICMJE
 (submitted: January 27, 2017)
115
Estimated Study Completion Date  ICMJE February 29, 2024
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: BO42863 https://forpatients.roche.com/ 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Belgium,   China,   France,   Germany,   Hong Kong,   Italy,   Korea, Republic of,   Netherlands,   Singapore,   Spain,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03037385
Other Study ID Numbers  ICMJE BO42863
2016-004390-41 ( EudraCT Number )
BLU-667-1101 ( Registry Identifier: CT.Gov )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP