Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00604721
First received: January 17, 2008
Last updated: May 12, 2014
Last verified: May 2013
  Purpose

This phase II trial is studying selumetinib to see how well it works in treating patients with locally advanced or metastatic liver cancer. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for their growth.


Condition Intervention Phase
Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Drug: selumetinib
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Number of Participants With Radiographic Objective Response (OR) [ Time Frame: 33 weeks ] [ Designated as safety issue: No ]

    To ascertain the objective response rate (Complete Response + Partial Response [CR+PR]) of patients with the single-agent AZD6244. Our study utilized Response Evaluation Criteria in Solid Tumors (RECIST) to evaluate response.

    Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

    Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.



Secondary Outcome Measures:
  • Median Progression Free Survival (PFS) [ Time Frame: 33 weeks ] [ Designated as safety issue: No ]
    Progression free survival has been defined as time from the start of treatment to disease progression or death as a result of any cause.

  • Median Overall Survival (OS) [ Time Frame: 33 weeks ] [ Designated as safety issue: No ]
    Overall survival has been defined as time from the start of treatment to death as a result of any cause.


Enrollment: 19
Study Start Date: November 2007
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (enzyme inhibitor therapy)
Patients receive a single dose of selumetinib on day 1 and undergo blood collection for PK sampling pre-dose (within 30 min of dosing), 15 and 30 minutes and 1, 2, 4, 8, 12, 24 and 48 hours post-dose. Beginning 48 hours after the initial dose and continuing until day 21, patients receive oral selumetinib twice daily. Patients also undergo blood collection for PK sampling on day 15 of course 1. In all subsequent courses, patients receive selumetinib on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: selumetinib
Given orally
Other Names:
  • ARRY-142886
  • AZD6244
Other: pharmacological study
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To ascertain the objective response rate (complete response and partial response) in patients with locally advanced or metastatic hepatocellular carcinoma treated with AZD6244 (selumetinib).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of AZD6244 when administered to patients with hepatocellular carcinoma and mild (Child's A to compensated Child's B) liver dysfunction.

II. To describe the pharmacokinetics (PK) of AZD6244 in this patient population and compare in exploratory fashion to the established PK profile in patients with normal hepatic function.

III. To estimate the time to event functions of progression, progression-free survival (PFS), (and PFS associated with treatment), and overall survival.

IV. To explore, preliminarily, the possible correlations between baseline mitogen-activated protein kinase (MEK) activation (i.e., presence of phospho-MEK) and radiographic response or time to progression.

V. To investigate the effects of AZD6244 on MEK kinase activity in peripheral blood mononuclear cells from patients treated with this drug.

OUTLINE:

Patients receive a single dose of selumetinib on day 1 and undergo blood collection for pharmacokinetic (PK) sampling pre-dose (within 30 min of dosing), 15 and 30 minutes and 1, 2, 4, 8, 12, 24 and 48 hours post-dose. Beginning 48 hours after the initial dose and continuing until day 21, patients receive oral selumetinib twice daily. Patients also undergo blood collection for PK sampling on day 15 of course 1. In all subsequent courses, patients receive selumetinib on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Selumetinib blood concentrations are quantified by high performance liquid chromatography. Patients also undergo tumor biopsy by CT or ultrasound guidance at baseline and on day 8. Peripheral blood mononuclear cells and tumor tissue are evaluated for mitogen-activated protein kinase baseline activity and post-treatment activity.

After completion of study treatment, patients are followed periodically for up to 2 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meets 1 of the following criteria:

    • Histologically or cytologically confirmed hepatocellular carcinoma
    • Serum alpha fetoprotein > 1000ng/dL with characteristic imaging findings coupled with the appropriate clinical scenario (i.e., chronic hepatitis and/or cirrhosis)

      • Child's A or B cirrhosis allowed

        • If Child's B cirrhosis is present, the patient may not have significant encephalopathy or ascites that requires paracentesis and must meet laboratory criteria (i.e., well-compensated Child's B)
  • Metastatic disease (including any proven lymph node metastases) or localized disease not amenable to potentially curative transplant/locoregional/surgical therapy as determined by a qualified surgeon or tumor board
  • Measurable disease, defined as at least one unidimensionally measurable ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan
  • No known brain metastases
  • ECOG performance status ≤ 2
  • Life expectancy > 3 months
  • Leukocytes ≥ 3,000/mm³
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelets ≥ 75,000/mm³
  • Total bilirubin < 2 times upper limit of normal (ULN)
  • AST/ALT < 5 times ULN
  • Creatinine < 1.5 mg/dL or creatinine clearance ≥ 60 mL/min
  • INR < 1.4
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception before, during, and for 4 weeks after completion of study treatment
  • Willing to undergo protocol-required tumor biopsies (patients must also be able to have any anticoagulation held for an appropriate period of time)
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to AZD6244 or its excipient Captisol®
  • No refractory nausea and vomiting or chronic gastrointestinal diseases (e.g., inflammatory bowel disease) that would preclude adequate absorption
  • No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
  • No active illicit substance or alcohol abuse
  • Able to understand and willing to sign a written informed consent document
  • Recovered from prior therapy
  • At least 4 weeks since prior chemo embolization, radio embolization (90Y microspheres), resection, or radio frequency/cryoablation

    • Must have measurable disease outside the treated area or unequivocal evidence of disease progression within the treated area
  • More than 4 weeks since prior radio therapy or major surgery
  • No prior organ transplantation
  • No prior systemic chemotherapy
  • No prior sorafenib
  • No prior therapeutic antibody or experimental systemic therapy (oral or intravenous)
  • No prior hepatic artery infusion of chemotherapy
  • No prior mitogen-activated protein kinase inhibitor
  • No prior significant bowel resection that would preclude adequate absorption
  • No concurrent fruit or juice of the grapefruit during AZD6244 therapy
  • No concurrent anti retroviral therapy for HIV-positive patients
  • No other concurrent investigational or commercial agents or therapies for this cancer
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00604721

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Investigators
Principal Investigator: Bert O'Neil H. Lee Moffitt Cancer Center and Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00604721     History of Changes
Obsolete Identifiers: NCT00550719, NCT01656291
Other Study ID Numbers: NCI-2009-00247, 07-0973, 77782, MCC-07-0973, VU-VICC-GI-0726, GCRC-2625-ORC, MCC-15260, CDR0000571751, N01CM62207, N01CM62208
Study First Received: January 17, 2008
Results First Received: June 22, 2012
Last Updated: May 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Liver Neoplasms
Adenocarcinoma
Digestive System Diseases
Digestive System Neoplasms
Liver Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on October 22, 2014