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

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ClinicalTrials.gov Identifier: NCT02191878
Recruitment Status : Completed
First Posted : July 16, 2014
Last Update Posted : January 16, 2019
Sponsor:
Information provided by (Responsible Party):
Arbutus Biopharma Corporation

Tracking Information
First Submitted Date  ICMJE July 9, 2014
First Posted Date  ICMJE July 16, 2014
Last Update Posted Date January 16, 2019
Study Start Date  ICMJE June 2014
Actual Primary Completion Date May 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 14, 2014)
Maximum tolerated dose (MTD) [ Time Frame: Up to 6 months after initial dose. ]
Laboratory assessments
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2014)
  • Preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: Upon every 2 cycles of treatment for up to 6 months ]
    Obtain preliminary assessment of anti-tumor activity by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1)
  • Clinical Benefit Rate at maximum tolerated dose (MTD) in Expansion Cohort [ Time Frame: Upon completion of treatment of expansion cohort; up to 6 months after last participant is dosed. ]
    Assessed after completion of Phase 2.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 14, 2014)
Assessment of Pharmacodynamic Effect [ Time Frame: Upon completion of cycle 1 and cycle 2 treatment; 1 and 2 months after last participant is dosed in expansion cohort. ]
Assessment of target mRNA reduction in participants consenting to pre- and post-treatment tumor biopsies.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Intravenous TKM-080301 in Subjects With Advanced Hepatocellular Carcinoma
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatocellular Carcinoma
  • Hepatoma
  • Liver Cancer, Adult
  • Liver Cell Carcinoma, Adult
Intervention  ICMJE Drug: TKM-080301
TKM-080301 intravenous infusion
Other Name: PLK1-HCC
Study Arms  ICMJE Experimental: Phase 1 Escalation / Phase 2 Expansion

Phase 1 - dose escalation with intravenous infusion of TKM-080301 to determine MTD.

Phase 2 - dose expansion at the MTD.

Intervention: Drug: TKM-080301
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 20, 2016)
43
Original Estimated Enrollment  ICMJE
 (submitted: July 14, 2014)
38
Actual Study Completion Date  ICMJE July 2016
Actual Primary Completion Date May 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   China,   Korea, Republic of,   Singapore,   Taiwan,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02191878
Other Study ID Numbers  ICMJE TKM-HCC-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Arbutus Biopharma Corporation
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Arbutus Biopharma Corporation
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mark Kowalski, M.D., Ph.D. Tekmira Pharmaceuticals
PRS Account Arbutus Biopharma Corporation
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP