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

January 14, 2019 updated by: Arbutus Biopharma Corporation

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

43

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada
        • Princess Margaret Hospital
  • China
      • Hong Kong, China
        • Queen Mary Hospital
  • Korea, Republic of
      • Seoul, Korea, Republic of
        • Severence Hospital, Yonsei, University Health System
    • Gyeonggi-do
      • Seoul, Gyeonggi-do, Korea, Republic of, 110744
        • Seoul National University Hospital
      • Seoul, Gyeonggi-do, Korea, Republic of, 135-710
        • Samsung Medical Center
      • Seoul, Gyeonggi-do, Korea, Republic of, 138-736
        • Asan Medical Center
  • Singapore
      • Singapore, Singapore
        • National University Hospital
  • Taiwan
      • Taipei, Taiwan
        • National Taiwan University Hospital
      • Taipei, Taiwan
        • Taipei Veterans General Hospital
      • Taipei, Taiwan
        • Taipei Medical University Hospital, Shuang-Ho Hospital
  • United States
    • Arizona
      • Tucson, Arizona, United States, 85715
        • Arizona Clinical Research Center
    • California
      • San Francisco, California, United States, 94115
        • University of California San Francisco
    • Missouri
      • Kansas City, Missouri, United States, 64131
        • Kansas City Research Institute
    • New York
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
    • Texas
      • Dallas, Texas, United States, 75230
        • Mary Crowley Cancer Research Centers

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Drug: TKM-080301
TKM-080301 intravenous infusion
Other Names:
  • PLK1-HCC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose (MTD)
Time Frame: Up to 6 months after initial dose.
Laboratory assessments
Up to 6 months after initial dose.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
Upon every 2 cycles of treatment for up to 6 months
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.
Upon completion of treatment of expansion cohort; up to 6 months after last participant is dosed.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Upon completion of cycle 1 and cycle 2 treatment; 1 and 2 months after last participant is dosed in expansion cohort.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Arbutus Biopharma Corporation

Investigators

  • Study Director: Mark Kowalski, M.D., Ph.D., Tekmira Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2014

Primary Completion (Actual)

May 1, 2016

Study Completion (Actual)

July 1, 2016

Study Registration Dates

First Submitted

July 9, 2014

First Submitted That Met QC Criteria

July 14, 2014

First Posted (Estimate)

July 16, 2014

Study Record Updates

Last Update Posted (Actual)

January 16, 2019

Last Update Submitted That Met QC Criteria

January 14, 2019

Last Verified

January 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TKM-HCC-001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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