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

January 17, 2008
May 12, 2014
November 2007
June 2012   (final data collection date for primary outcome measure)
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.

objective response rate [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00604721 on ClinicalTrials.gov Archive Site
  • 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.
  • safety and tolerability of dosing AZD6244 [ Time Frame: continuous ] [ Designated as safety issue: Yes ]
  • time to progression, progression-free survival,and overall survival [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]
  • correlations between baseline MEK activation (i.e presence of phospho-MEK) and radiographic response or time to progression [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]
  • effects of AZD6244 on MEK kinase activity in tumor biopsies from patients [ Time Frame: baseline ] [ Designated as safety issue: No ]
  • effects of AZD6244 on MEK kinase activity in PBMCs in the study population [ Time Frame: Two weeks ] [ Designated as safety issue: No ]
  • describe the pharmacokinetics of AZD6244 in this patient population and compare in exploratory fashion to the established PK profile in patients with normal hepatic function [ Time Frame: three weeks ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer
A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma

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.

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.

Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Drug: selumetinib
    Given orally
    Other Names:
    • ARRY-142886
    • AZD6244
  • Other: pharmacological study
    Other Name: pharmacological studies
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.
Interventions:
  • Drug: selumetinib
  • Other: pharmacological study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
19
June 2012
June 2012   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00604721
NCI-2009-00247, 07-0973, 77782, MCC-07-0973, VU-VICC-GI-0726, GCRC-2625-ORC, MCC-15260, CDR0000571751, N01CM62207, N01CM62208
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Bert O'Neil H. Lee Moffitt Cancer Center and Research Institute
National Cancer Institute (NCI)
May 2013

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