Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors

Primary Objectives • To determine the MTD and recommended Phase 2 dose (RP2D) of BLU-667. • To determine the safety and tolerability of BLU-667 Secondary Objectives • To characterize the pharmacokinetic (PK) profile of BLU-667 and correlate drug exposure with safety assessments. • To assess RET gene status in plasma and tumor tissue. • To characterize the pharmacodynamics of BLU-667, including, but not limited to, changes in blood calcitonin and carcinoembryonic antigen (CEA; in medullary thyroid cancer patients), and changes in tumor pSHC, DUSP6 and SPRY4 messenger ribonucleic acid (mRNA) levels. • To describe preliminary evidence of BLU-667 antineoplastic activity according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Pralsetinib(BLU-667)

Pralsetinib(BLU-667)

Capsule

100

Primary Endpoints:
• MTD and RP2D of BLU-667.
• Overall safety profile of BLU-667, as assessed by the type, frequency,
severity, timing, and relationship to study drug of any adverse event
(AEs), serious adverse events (SAEs), changes in vital signs, ECGs, and
safety laboratory tests.

Secondary Endpoints:
• PK parameters of BLU-667: maximum plasma concentration (Cmax),
time to maximum plasma concentration (tmax), area under the plasma
concentration versus time curve from 0 to 24 hours (AUC0-24), area
under the plasma concentration versus time curve from 0 to infinity
(AUCinf), terminal half-life (t½ ), apparent clearance (CL/F), and
accumulation ratio (R).
• RET gene status in plasma circulating tumor deoxyribonucleic acid
(ctDNA) and tumor tissue.
• Pharmacodynamic parameters of BLU-667: changes in tumor/blood
including, but not limited to, changes in blood calcitonin and CEA
(MTC patients); and changes in tumor biomarker levels (p-SHC,
DUSP6 and SPRY4) levels.
• Overall response rate (ORR), defined as the rate of complete response
(CR) and partial response (PR), duration of response (DOR), and
clinical benefit rate (CBR), defined as the rate of CR, PR, and stable
disease (SD), as per RECIST, version 1.1.

Inclusion Criteria
Patients meeting the following criteria will be eligible for participation in the study:
1. Patient is ≥ 18 years of age.
2. 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 MTC, or a RET-altered
solid tumor per local assessment of tumor tissue and/or blood.
• Part 1 enrichment patients must have MTC or a RET-altered solid tumor per local
assessment of tumor tissue and/or blood.
3. 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 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.
4. 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.
5. Dose expansion (Part 2) patients must have measurable disease per RECIST.
6. 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.
7. Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of
0-2.
8. Patient or legal guardian provides informed consent to participate in the study.

Exclusion Criteria
Patients meeting any of the following criteria will not be eligible for participation in the
study:
1. Patient has NSCLC with a targetable mutation in EGFR, ALK, or ROS1.
2. Patient has any of the following within 14 days prior to the first dose of study drug:
a. Platelet count < 75 × 109
/L.
b. Absolute neutrophil count (ANC) < 1.0 × 109
/L.
c. Hemoglobin < 9.0 g/dL (red blood cell [RBC] transfusion and erythropoietin
(EPO) 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.
d. 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.
e. Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in
presence of Gilbert’s disease.
f. Estimated (Cockroft-Gault formula) or measured creatinine clearance
< 40 mL/min.
3. Patient has a QT interval corrected using Fridericia’s formula (QTcF) > 470 msec.
Patient has a history of prolonged QT syndrome or Torsades de pointes. Patient has a
familial history of prolonged QT syndrome.
4. Patient has clinically significant, uncontrolled, cardiovascular disease including
congestive heart failure Grade III or IV according to the New York Heart Association
(NYHA) classification; myocardial infarction or unstable angina within the previous
6 months, uncontrolled hypertension, or clinically significant, uncontrolled
arrhythmias, including bradyarrhythmias that may cause QT prolongation (e.g.,
Type II second degree heart block or third degree heart block).
5. Patient has central nervous system (CNS) metastases or a primary CNS tumor that is
associated with progressive neurological symptoms or requires increasing doses of
corticosteroids to control the CNS disease. If a patient requires corticosteroids for
management of CNS disease, the dose must have been stable for the two weeks
preceding C1D1.
6. Patient received any anti-cancer therapy (including both systemic therapy and
radiotherapy) within 14 days or 5 half-lives (whichever is shorter) prior to the first
dose of study drug.
7. Dose expansion patients (Part 2): Patient has previously received treatment with a
selective RET inhibitor, such as LOXO-292, unless the patient’s tumor has acquired a
resistant mutation known to be sensitive to BLU-667.
8. Patient received neutrophil growth factor support within 14 days of the first dose of
study drug.
9. Patient requires treatment with a prohibited medication or herbal remedy (as specified
in Appendix 2) that cannot be discontinued at least 2 weeks before the start of study
drug administration.
10. Patient has had a major surgical procedure within 14 days of the first dose of study
drug (procedures such as central venous catheter placement, tumor needle biopsy, and
feeding tube placement are not considered major surgical procedures).
11. Patient has a history of another primary malignancy that has been diagnosed or
required therapy within the past year. The following prior malignancies are not
exclusionary: completely resected basal cell and squamous cell skin cancer,
curatively treated localized prostate cancer, curatively treated localized thyroid
cancer, and completely resected carcinoma in situ of any site.
12. Patient is unwilling or unable to comply with scheduled visits, drug administration
plan, laboratory tests, or other study procedures and study restrictions.
13. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain
from sexual intercourse or employ highly effective contraception during the study
drug administration period and for at least 30 days after the last dose of study drug.
Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or
employ highly effective contraception during the study drug administration period
and for at least 90 days after the last dose of study drug. Refer to Section 9.6.1 for
acceptable methods of contraception.
14. Pregnant females, as documented by a serum beta human chorionic gonadotropin
(β-hCG) pregnancy test consistent with pregnancy, obtained within 7 days prior to the
first dose of study drug. Females with β-hCG values that are within the range for
pregnancy but are not pregnant (false-positives) may be enrolled with written consent
of the Sponsor, after pregnancy has been ruled out. Females of non-childbearing
potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral
oophorectomy; hysterectomy) do not require a serum β-hCG test.
15. If female, patient is breastfeeding.
16. Patient has prior or ongoing clinically significant illness, medical condition, surgical
history, physical finding, or laboratory abnormality that, in the Investigator’s opinion,
could affect the safety of the patient; alter the absorption, distribution, metabolism, or
excretion of the study drug; or impair the assessment of study results.