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
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.
- 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
- Lung Diseases
- Respiratory Tract Disease
- Carcinoma, Bronchogenic
- Bronchial Neoplasms
- Endocrine System Diseases
- Endocrine Gland Neoplasm
- Head and Neck Neoplasms
- Adenocarcinoma, Papillary
- 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
- Eligible Ages
- Over 18 Years
- Eligible Genders
- Accepts Healthy Volunteers
- 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, definitively 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, definitively 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.
- 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:
- Platelet count < 75 × 10^9/L.
- Absolute neutrophil count <1.0 × 10^9/L.
- 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.
- 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.
- Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease.
- Estimated (Cockcroft-Gault formula) or measured creatinine clearance <40 mL/min.
- 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
- Phase 1/Phase 2
- Study Type
- 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
- Primary Purpose
- None (Open Label)
Phase 1 Dose Escalation
|Multiple doses of pralsetinib (BLU-667) for oral administration.||
Phase 2 Dose Expansion
|Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.||
- Blueprint Medicines Corporation
Study ContactBlueprint Medicines
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.