Clinical Trial - NCT03037385

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

Recruiting

Sponsor: Blueprint Medicines Corporation

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03037385

Protocol Info

Short Description: Phase 1 BLU-667 in Thyroid Cancer, NSCLC, And Other Solid Tumors
Long Description: 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
MGH Status: Open
Sponsor: Blueprint Medicines
Disease Program: Thoracic

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




Purpose

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 Title Intervention 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 pralsetinib (BLU-667) Phase 1/Phase 2
Study Type Interventional
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

Primary Outcome Measures

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]


Secondary Outcome Measures

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

(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] [Designated as safety issue: ]

Estimated Enrollment: 527
Study Start Date: March 2017
Estimated Study Completion Date: March 2023
Estimated Primary Completion Date: March 2020
Arms Assigned Interventions

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

Experimental:Phase 2 Dose Expansion

Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03037385

Locations

  • United States, Arizona
    • Mayo Clinic Phoenix, Arizona, United States, 85054
  • United States, California
    • UC Irvine Medical Center Orange, California, United States, 92868
  • United States, Colorado
    • University of Colorado Cancer Center Aurora, Colorado, United States, 80045
  • United States, District of Columbia
    • Georgetown University Medical Center Washington, District of Columbia, United States, 20007
  • United States, Florida
    • Mayo Clinic Jacksonville, Florida, United States, 32224
    • University of Miami Hospitals and Clinics, Sylvester Comprehensive Cancer Center Miami, Florida, United States, 33136
  • United States, Massachusetts
    • Massachusetts General Hospital Boston, Massachusetts, United States, 02114
  • United States, Michigan
    • University of Michigan Ann Arbor, Michigan, United States, 48109
  • United States, Minnesota
    • Mayo Clinic Rochester, Minnesota, United States, 55905
  • United States, Missouri
    • Washington University School of Medicine, Siteman Cancer Center Saint Louis, Missouri, United States, 63110
  • United States, New York
    • Cornell University New York, New York, United States, 10021
  • United States, Oregon
    • Oregon Health and Science University Portland, Oregon, United States, 97239
  • United States, Pennsylvania
    • University of Pennsylvania Hospital Philadelphia, Pennsylvania, United States, 19104
  • United States, Texas
    • Texas Oncology - Baylor Charles A. Sammons Cancer Center Dallas, Texas, United States, 75246
    • University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030
  • United States, Washington
    • University of Washington, Seattle Cancer Care Alliance Seattle, Washington, United States, 98109
  • China,
    • Tianjin Cancer Institute Tianjin, , China, 300060
  • France,
    • Institut Bergonié Bordeaux, , France, 33076
    • CHRU de Lille - Hôpital Claude Hurier Servide d'Endocrinologie et Diabétologie Lille, , France, 59037
    • Centre Leon Berard Lyon, , France, 69373
    • Institut Curie Paris, , France, 75248
    • CHU de Rennes - Hôpital Pontchaillou Rennes, , France, 35033
    • Insitut Claudius Regaud Toulouse, , France, 31059
    • Gustave Roussy Villejuif, , France, 94805
  • Germany,
    • Universitätsklinikum Essen Essen, , Germany, 45147
    • Thoraxklinik Heidelberg Heidelberg, , Germany, 69126
    • Klinikum der Universitat Munchen Munich, , Germany, 81377
    • Pius-Hospital Oldenberg Oldenburg, , Germany, 26121
  • Italy,
    • Istituto Europeo di Oncologia Sviluppo Nuovi Farmaci per Terapie Innovative Milano, , Italy, 20141
    • Grande Ospedale Metropolitano Niguarda Milan, , Italy, 20162
    • Ospedale Santa Maria delle Croci Ravenna, , Italy, 48124
  • Korea, Republic of,
    • Seoul National University Hospital Seoul, , Korea, Republic of, 03080
    • Severance Hospital Seoul, , Korea, Republic of, 03722
    • Asan Medical Center Seoul, , Korea, Republic of, 05505
  • Netherlands,
    • University Medical Center Groningen Groningen, , Netherlands, 9713
  • Singapore,
    • National Cancer Centre Singapore Singapore, , Singapore, 169160
  • Spain,
    • Hospital Universitari Vall d'Hebron Barcelona, , Spain, 08035
    • Hospital Clinic Barcelona Barcelona, , Spain, 08036
    • Hospital Duran I Reynals Barcelona, , Spain, 08908
    • Hospital Universitario Ramon y Cajal Madrid, , Spain, 28034
    • Hospital Universitario 12 de Octubre Servicio de Oncologia Medica Madrid, , Spain, 28041
  • Taiwan,
    • National Taiwan University Hospital Taipei City, , Taiwan, 10002
  • United Kingdom,
    • Guy's Hospital St. Thomas NHS Foundation Trust London, , United Kingdom,
    • NIHR UCLH Clinical Research Facility, University College of London NHS Foundation Trust London, , United Kingdom,
    • The Christie NHS Foundation Trust Manchester, , United Kingdom,

Sponsors and Collaborators

Blueprint Medicines Corporation

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03037385
Other Study ID Numbers: 2016-004390-41
Study First Received:
Last Updated:
Health Authority:

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

V804L

V804M

thyroid cancer RET inhibitor

lung cancer RET inhibitor

RET PTC

rearranged during transfection

RET-PTC1

RET-PTC

RET-PTC3

RET-PTC4

PRKAR1A-RET

RET-PTC2

GOLGA5-RET

RET-PTC5

ERC1-RET

KTN1-RET

RET-PTC8

HOOK3-RET

PCM1-RET

TRIM24-RET

RET-PTC6

TRIM27-RET

RET-PTC7

AKAP13-RET

FKBP15-RET

SPECC1L-RET

TBL1XR1-RET

BCR-RET

FGRF1OP-RET

RFG8-RET

Additional relevant MeSH terms:

Carcinoma

Neoplasms

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Adenocarcinoma

Thyroid Diseases

Lung Diseases

Thyroid Neoplasms

Neuroendocrine Tumors

Colorectal Neoplasms

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Head and Neck Neoplasms

Gastrointestinal Diseases

Digestive System Diseases

Respiratory Tract Diseases

Colonic Neoplasms

Thyroid Cancer, Papillary

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine System Diseases

Carcinoma, Neuroendocrine

Colonic Diseases

Neoplasms by Site

Intestinal Diseases

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

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019