Clinical trial NCT02191878: Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Hepatoma
Liver Cancer, Adult
Liver Cell Carcinoma, Adult
Keywords: Liver Cancer
Liver Neoplasms
Liver Epithelial Neoplasms
Liver Cancer, malignant
Lead sponsor: Arbutus Biopharma Corporation
Sponsor class: INDUSTRY
First posted: 2014-07-16
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: Up to 6 months after initial dose.
Secondary outcomes:
measure: Preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
timeFrame: Upon every 2 cycles of treatment for up to 6 months
measure: Clinical Benefit Rate at maximum tolerated dose (MTD) in Expansion Cohort
timeFrame: Upon completion of treatment of expansion cohort; up to 6 months after last participant is dosed.
Other outcomes:
measure: Assessment of Pharmacodynamic Effect
timeFrame: Upon completion of cycle 1 and cycle 2 treatment; 1 and 2 months after last participant is dosed in expansion cohort.
Locations:
city: Tucson
country: United States
facility: Arizona Clinical Research Center
state: Arizona
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Hong Kong
country: China
facility: Queen Mary Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: ASAN Medical Center
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Severence Hospital, Yonsei, University Health System
city: Singapore
country: Singapore
facility: National University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital, Shuang-Ho Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
Study officials:
affiliation: Tekmira Pharmaceuticals
name: Mark Kowalski, M.D., Ph.D.
role: STUDY_DIRECTOR
References:
citation: El Dika I, Lim HY, Yong WP, Lin CC, Yoon JH, Modiano M, Freilich B, Choi HJ, Chao TY, Kelley RK, Brown J, Knox J, Ryoo BY, Yau T, Abou-Alfa GK. An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma. Oncologist. 2019 Jun;24(6):747-e218. doi: 10.1634/theoncologist.2018-0838. Epub 2018 Dec 31.