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

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 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 (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 (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.

- 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

- 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 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 (Part 2) previously treated with a selective RET
inhibitor