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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 : August 14, 2019
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

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.

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 : Blueprint Medicines Corporation has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 527 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 previously treated with SOC
  • 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
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 : March 2020
Estimated Study Completion Date : March 2023


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 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 ]
  2. (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 ]
  3. (Phase 2) 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

  4. (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 ]

Secondary Outcome Measures :
  1. (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

  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 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 ]
  3. (Phase 2 ) 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 ]
  4. (Phase 2 ) 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 ]
  5. (Phase 2 ) Disease Control Rate (DCR) [ 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 ]
  6. (Phase 2 ) Progression Free Survival (PFS) [ 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 ]
  7. (Phase 2 ) Overall Survival (OS) [ 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 ]
  8. (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 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 ]
  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 patients 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 patients only



Information from the National Library of Medicine

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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 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 Groups 3 and 4) 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, definitely 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 previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups.
    • Group 6 - patients must have a pathologically documented, definitely 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
  • Patients must have non-resectable disease. Phase 1 only patients must have progressed following standard therapy or have not adequately responded to standard therapy, or the patient 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.
  • 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

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


Contacts
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Contact: Blueprint Medicines 617-714-6707 studydirector@blueprintmedicines.com

  Show 45 Study Locations
Sponsors and Collaborators
Blueprint Medicines Corporation

Additional Information:
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Responsible Party: Blueprint Medicines Corporation
ClinicalTrials.gov Identifier: NCT03037385     History of Changes
Other Study ID Numbers: BLU-667-1101
2016-004390-41 ( EudraCT Number )
First Posted: January 31, 2017    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
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 Blueprint Medicines Corporation:
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
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
Thyroid Cancer, Papillary
Carcinoma, Neuroendocrine
Neoplasms by Site
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
Colonic Diseases
Intestinal Diseases