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.
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.
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
patients with MTC enrolled in Groups 3, 4, and 9) 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, have previously received SOC
appropriate for their tumor type (unless there is no accepted standard therapy
for the tumor type or the Investigator has determined that treatment with
standard therapy is not appropriate), and must not be 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
- Group 8 - patients must have pathologically documented, definitively diagnosed
locally advanced or metastatic NSCLC with a RET fusion that was previously
treated with a platinum based chemotherapy (China only).
- Group 9 - patients must have pathologically documented, definitively diagnosed
advanced MTC that has progressed within 14 months prior to the Screening Visit,
and was not previously treated with systemic therapy (except prior cytotoxic
chemotherapy is allowed) for advanced or metastatic disease (China only).
- Patients must have non-resectable disease.
- Patient agrees to provide tumor tissue (archived, if available or a fresh biopsy) for
RET status confirmation and is willing to consider an on-treatment tumor biopsy, if
considered safe and medically feasible by the treating Investigator. For Phase 2,
Group 6, patients are required to undergo a pretreatment biopsy to define baseline RET
status in tumor tissue.
- 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
