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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)

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ClinicalTrials.gov Identifier: NCT03037385
Recruitment Status : Active, not recruiting
First Posted : January 31, 2017
Last Update Posted : May 16, 2022
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
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 Drug: pralsetinib (BLU-667) Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 589 participants
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
Official Title: A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors
Actual Study Start Date : March 17, 2017
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : February 29, 2024


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 Name: 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 Name: BLU-667




Primary Outcome Measures :
  1. (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 participant terminates from the study ]
  2. (Phase 1) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Every cycle (28 days) for approximately 12 months or earlier if participant terminates from the study, and 30 days after the last dose ]
  3. (Phase 2) Overall Response Rate (ORR) [ Time Frame: 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

  4. (Phase 2) Number of Participants with AEs and SAEs [ Time Frame: 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 :
  1. (Phase 1) 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 12 months) in participants without progressive disease ]
    As assessed by RECIST v1.1 or RANO, as appropriate per tumor type

  2. (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 (Up to approximately 12 months) ]
    Clinical Benefit Rate (CBR), Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS)

  3. (Phase 2) CBR [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  4. (Phase 2) DOR [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  5. (Phase 2) DCR [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
  6. (Phase 2) PFS [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months) ]
  7. (Phase 2) Overall Survival (OS) [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle (Up to approximately 84 months) ]
  8. (Phase 2) RET Gene Status and Correlation Between RET Gene Status and ORR, CBR, DOR, DCR and Other Antineoplastic Measures [ Time Frame: 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)

  9. (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 ]
  10. (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 ]
  11. (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 ]
  12. (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

  13. (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 participants only

  14. (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 participants only

  15. (Phase 2) Assess Intracranial Response Rate and Time to Intracranial Progression in Participants With NSCLC [ Time Frame: Approximately every 8 weeks or 16 weeks based on the treatment cycle ]
    Target by RECIST v1.1 or RANO



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor.

    • All participants treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
  • Diagnosis during dose expansion (Phase 2) - All participants (with the exception of participants with MTC enrolled in Groups 3, 4, and 9) must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below.

    • Group 1 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy.
    • Group 2 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy, including those who have not had any systemic therapy. Prior platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if the last dose of platinum was 4 months or more before the first dose of study drug.
    • Group 3 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.
    • Group 4 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib and/or vandetanib.
    • Group 5 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received standard of care (SOC) appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate), and must not have been eligible for any of the other groups.
    • Group 6 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective tyrosine kinase inhibitor (TKI) that inhibits RET
    • Group 7 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups
    • Group 8 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum based chemotherapy (China only).
    • Group 9 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit, and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only).
  • Participants must have non-resectable disease.
  • Dose expansion (Phase 2): Participants in all groups (except Group 7) must have measurable disease per RECIST v1.1 (or RANO, criteria if appropriate for tumor type).
  • Participants agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Phase 2, Group 6, participants are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.
  • Participants has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.

Key Exclusion Criteria:

  • Participant's cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1 or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation.
  • Participants had any of the following within 14 days prior to the first dose of study drug:

    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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03037385


Locations
Show Show 79 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Layout table for investigator information
Study Director: Clinical Trials Hoffmann-La Roche
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03037385    
Other Study ID Numbers: BO42863
2016-004390-41 ( EudraCT Number )
BLU-667-1101 ( Registry Identifier: CT.Gov )
First Posted: January 31, 2017    Key Record Dates
Last Update Posted: May 16, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hoffmann-La Roche:
RET Lung
RET Thyroid
RET fusion
RET alteration
RET mutation
RET positive
RET inhibitor
RET altered
RET rearrangement
RET NSCLC
RET medullary thyroid cancer
RET-rearranged NSCLC
RET-rearranged thyroid
M918T
TRIM33-RET
RET fusion lung cancer
RET fusion thyroid cancer
lung cancer mutation
BLU 667
RET tyrosine kinase
RET gene mutation
RET kinase
RET MTC
advanced lung cancer
advanced non small cell lung cancer
metastatic lung cancer
KIF5B-RET
CCDC6-RET
NCOA4-RET
advance solid tumor
Additional relevant MeSH terms:
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Carcinoma
Neoplasms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Colonic Neoplasms
Thyroid Neoplasms
Neuroendocrine Tumors
Colorectal Neoplasms
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Head and Neck Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Thyroid Cancer, Papillary
Carcinoma, Neuroendocrine
Neoplasms by Histologic Type
Thoracic Neoplasms
Intestinal Neoplasms
Neoplasms, Glandular and Epithelial
Respiratory Tract Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Endocrine Gland Neoplasms
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Adenocarcinoma, Papillary
Gastrointestinal Diseases
Digestive System Diseases