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

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ClinicalTrials.gov Identifier: NCT03037385
Recruitment Status : Recruiting
First Posted : January 31, 2017
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Blueprint Medicines Corporation

Brief Summary:
This is a Phase 1, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of 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 Drug: BLU-667 Phase 1

Detailed Description:
The study consists of 2 parts, a dose-escalation part (Part 1) and an expansion part (Part 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 in patients who are intolerant to or have declined standard therapy.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 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 2021
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: BLU-667

Dose Escalation: Multiple doses of BLU-667 for oral administration.

Dose Expansion: Oral dose of BLU-667 as determined during Dose Escalation.

Drug: BLU-667
BLU-667 is a potent and selective inhibitor of the RET mutations, fusions, and predicted resistant mutants




Primary Outcome Measures :
  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. 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. 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


Secondary Outcome Measures :
  1. DOR, DCR, PFS and 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 ]
  2. RET gene status and correlation between RET gene status and ORR, 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 ]
  3. Pharmacokinetic parameters [ Time Frame: Approximately every 2 weeks in Cycle 1 and monthly through Cycle 4 ]
  4. Pharmacodynamic parameters [ Time Frame: Approximately every 2 weeks in Cycle 1 and monthly through Cycle 3 and every other month through Cycle 12 ]

Other Outcome Measures:
  1. Changes in patient-reported outcomes as assessed by the European Organization for Research and Treatment of Cancer Core QoL Questionnaire [ Time Frame: Day 1 of every cycle ]


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.


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 (Part 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 (Part 2) - All patients in Groups 1, 2, 5 and 6 must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous and nonsense mutations) solid tumor, as determined by local 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 rearrangement that was previously treated with a multi-kinase inhibitor (MKI) that inhibits RET, such as cabozantinib, lenvatanib, vandetanib, ponatinib, sorafenib and alectinib.
    • Group 2 - patients must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET rearrangement that was not previously treated with a MKI.
    • 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 a MKI.
    • Group 4 - patient must have pathologically documented, definitely diagnosted advanced MTC that has progressed within 14 months prior to the Screening Visit and was not previously treat with a MKI.
    • Group 5 -patients must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET rearrangement/fusion or mutation, other than NSCLC and MTC.
    • Group 6 - patient must have a pathologically documented, definitely diagnosed advanced solid tumor with an oncogenic RET rearrangement/fusion or mutation that was previously treated with a previous selective TKI that inhibits RET
  • Patient must have non-resectable disease that has progressed following standard therapy or has not adequately responded to standard therapy, or the patient must be intolerant to or have declined available standard therapies, 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.
  • 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.
  • Patients in Groups 1-5 (Part 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
Contact: Blueprint Medicines 617-714-6707 studydirector@blueprintmedicines.com

  Show 30 Study Locations
Sponsors and Collaborators
Blueprint Medicines Corporation

Additional Information:
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: November 14, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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
BLUE 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:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Thyroid Diseases
Thyroid Neoplasms
Carcinoma
Carcinoma, Neuroendocrine
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Endocrine System Diseases
Endocrine Gland Neoplasms
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue