Patient case: 45-year-old female with medullary thyroid carcinoma; genetic feature: RET

Clinical trial: Phase 1 Study of BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors

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.

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.

Eligibility: 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.

Relevance to patient case: possibly relevant