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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 : April 10, 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 NSCLC, thyroid cancer and other solid tumors.

Condition or disease Intervention/treatment Phase
Lung Cancer, Nonsmall Cell Thyroid Cancer Solid Tumor Medullary Thyroid Cancer Papillary Thyroid Cancer Non Small Cell Lung Cancer Colon Cancer 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 NSCLC, advanced 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 : 115 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. 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 ]
  4. Changes in ECG findings [ Time Frame: Every cycle (28 days) up to Cycle 4 ]

Secondary Outcome Measures :
  1. Maximum plasma concentration (Cmax) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  2. Time to maximum plasma concentration (Tmax) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  3. 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 ]
  4. Terminal half-life (t1/2) of BLU-667 [ Time Frame: Every cycle (28 days) up to Cycle 4 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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).

  9. 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 ]
  10. 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).



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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 and 4 must have a RET-altered (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 tyrosine kinase inhibitor (TKI) that inhibits RET, such as cabozantinib, 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 TKI that inhibits RET.
    • Group 3 - patients must have pathologically documented, definitively diagnosed advanced MTC that has progressed within 14 months prior to the Screening Visit.
    • Group 4 - patients must have a pathologically documented, definitively diagnosed advanced solid tumor with a RET alteration, other than NSCLC and MTC.
  • 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 0-2.

Key Exclusion Criteria:

  • Patient has NSCLC with a targetable mutation in EGFR, ALK, or ROS1.
  • 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.

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

Locations
United States, California
UC Irvine Medical Center Recruiting
Orange, California, United States, 92868
United States, Florida
University of Miami Hospitals and Clinics, Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
United States, Missouri
Washington University School of Medicine, Siteman Cancer Center Recruiting
Saint Louis, Missouri, United States, 63110
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Singapore
National Cancer Centre Singapore Recruiting
Singapore, Singapore, 169160
Spain
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain, 08035
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: April 10, 2018
Last Verified: April 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