Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma

Open-Label, Multi-Center, Phase 1, Dose Escalation Study With Phase 2 Expansion Cohort to Determine the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma

This study is an open-label, multi-center, phase 1, dose escalation study with a phase 2 expansion cohort to determine the safety, pharmacokinetics and preliminary anti-tumor activity of intravenous TKM-080301 in subjects with advanced hepatocellular carcinoma (HCC).

This study is being done to:

• Test the safety and tolerability of TKM-080301 in subjects with advanced hepatocellular carcinoma
• Find the highest dose of TKM-080301 that can be given without causing side effects, called the maximum tolerated dose (MTD).
• Provide a preliminary assessment of anti-tumor activity of TKM-080301

Study design: Open label, multi-center, 3 + 3 dose-escalation study with an expansion cohort at the maximum tolerated dose (MTD) to investigate safety, tolerability, PK, and preliminary anti-tumor activity of TKM 080301 in subjects with HCC.

Sequential cohorts of 3 to 6 subjects will receive escalating doses of TKM 080301 according to a pre-specified dose escalation scheme. Assessment of dose-limiting toxicities (DLTs) will be made during Cycle 1 to determine the maximum tolerated dose (MTD). Once the MTD level is established, approximately 20 subjects will be enrolled in an expansion cohort to further confirm the safety and tolerability of TKM-080301 at the MTD.

Study Population: A minimum of 9 and up to approximately 18 adult male or female subjects with histologically or cytologically confirmed metastatic or locally advanced inoperable HCC and a life expectancy of 3 months or more are planned in the dose escalation phase. Approximately 20 subjects are planned in the expansion cohort.

Study Treatment: TKM-080301 will be administered by intravenous (IV) infusion, once weekly for 3 consecutive weeks followed by a 1 week rest period. This 28-day treatment period constitutes 1 cycle.

Subjects who demonstrate clinical benefit without progression per RECIST 1.1 guidelines may receive treatment beyond 6 cycles if the Investigator considers it is in the best interest of the subject, and only with the approval of the Medical Monitor. Subjects would then continue TKM 080301 therapy until withdrawal of consent, disease progression or unacceptable toxicity occurs.

Pharmacokinetics (PK) Subjects will undergo blood sample collection for PK analysis during cycles 1 and 2.

Study Duration: Each treatment cycle will have duration of 28 days and each subject will typically receive up to 6 cycles of treatment. The total duration of the study is expected to be approximately 28 months.

Key Inclusion Criteria:

• Child-Pugh class of A
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5.0 × ULN
• Total bilirubin ≤3.0 mg/dL
• Platelets ≥75,000 /mL
• International Normalized Ratio (INR) ≤1.7
• Subjects must meet the protocol-defined criteria for both hepatitis B virus (HBV) and hepatitis C virus (HCV) status

Key Exclusion Criteria:

• History of significant cardiovascular disease will be excluded
• History of liver transplant.
• Diagnosis of fibrolamellar HCC or tumors of mixed histology.
• Subjects known to be positive for Human immunodeficiency virus (HIV) infection.
• Known central nervous system (CNS) or brain metastases.
• Poorly controlled ascites and/or requirement for therapeutic paracentesis more frequently than once every 3 months.
• Symptomatic encephalopathy within 3 months prior to the first dose of TKM-080301 and/or requirement for medication for encephalopathy.
• Esophageal variceal bleeding within 2 weeks prior to the first dose of TKM-080301.
• Asthma or chronic obstructive pulmonary disease (COPD) requiring daily medication.
• Prior therapy with nitrosoureas or mitomycin within 6 weeks prior to the first dose of TKM-080301.
• Prior therapy with any biologic chemotherapeutic or investigational drug within 5 half-lives or 3 weeks, whichever is longer prior to the first dose of TKM 080301.