Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT00604721
Collaborator
(none)
19
6
1
55
3.2
0.1

Study Details

Study Description

Brief Summary

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.

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:
  1. 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.

  2. 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.

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

  4. 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.

  5. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
19 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma
Study Start Date :
Nov 1, 2007
Actual Primary Completion Date :
Jun 1, 2012
Actual Study Completion Date :
Jun 1, 2012

Arms and Interventions

Arm Intervention/Treatment
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 Names:
  • pharmacological studies
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Radiographic Objective Response (OR) [33 weeks]

      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

    1. Median Progression Free Survival (PFS) [33 weeks]

      Progression free survival has been defined as time from the start of treatment to disease progression or death as a result of any cause.

    2. Median Overall Survival (OS) [33 weeks]

      Overall survival has been defined as time from the start of treatment to death as a result of any cause.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 H. Lee Moffitt Cancer Center and Research Institute Tampa Florida United States 33612
    2 Emory University Atlanta Georgia United States 30322
    3 University of North Carolina Chapel Hill North Carolina United States 27599
    4 Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center Columbus Ohio United States 43210
    5 Vanderbilt University Nashville Tennessee United States 37232
    6 Virginia Commonwealth University Richmond Virginia United States 23298

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Bert O'Neil, H. Lee Moffitt Cancer Center and Research Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00604721
    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
    • NCT00550719
    • NCT01656291
    First Posted:
    Jan 30, 2008
    Last Update Posted:
    May 28, 2014
    Last Verified:
    May 1, 2013
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title AZD6244 Treatment
    Arm/Group Description The first 6 patients with moderate liver dysfunction (Child's B or total bilirubin 1.5-2x ULN) were to comprise a "moderate liver dysfunction" safety cohort. AZD6244 was administered at a dose of 100 mg twice daily (48 hours after initial single dose for PK), approximately 12 hours apart, in a mix and drink formulation. For the purposes of evaluation, a cycle was defined as 21 days. Dosing for the remainder of patients (efficacy cohort) was to be determined by the algorithm presented in the safety cohort.
    Period Title: Overall Study
    STARTED 19
    COMPLETED 17
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title AZD6244 Treatment
    Arm/Group Description The first 6 patients with moderate liver dysfunction (Child's B or total bilirubin 1.5-2x ULN) were to comprise a "moderate liver dysfunction" safety cohort. AZD6244 was administered at a dose of 100 mg twice daily (48 hours after initial single dose for PK), approximately 12 hours apart, in a mix and drink formulation. For the purposes of evaluation, a cycle was defined as 21 days. Dosing for the remainder of patients (efficacy cohort) was to be determined by the algorithm presented in the safety cohort.
    Overall Participants 19
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    15
    78.9%
    >=65 years
    4
    21.1%
    Age, Customized (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    57
    Sex: Female, Male (Count of Participants)
    Female
    6
    31.6%
    Male
    13
    68.4%
    Region of Enrollment (participants) [Number]
    United States
    19
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Radiographic Objective Response (OR)
    Description 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.
    Time Frame 33 weeks

    Outcome Measure Data

    Analysis Population Description
    Participants who completed a full 21 day cycle of therapy
    Arm/Group Title Safety Cohort: AZD6244 Treatment
    Arm/Group Description The first 6 patients with moderate liver dysfunction (Child's B or total bilirubin 1.5-2x ULN) were to comprise a "moderate liver dysfunction" safety cohort. AZD6244 was administered at a dose of 100 mg twice daily (48 hours after initial single dose for PK), approximately 12 hours apart, in a mix and drink formulation. For the purposes of evaluation, a cycle was defined as 21 days. Dosing for the remainder of patients (efficacy cohort) was determined by the algorithm presented in the safety cohort.
    Measure Participants 17
    Number [participants]
    0
    0%
    2. Secondary Outcome
    Title Median Progression Free Survival (PFS)
    Description Progression free survival has been defined as time from the start of treatment to disease progression or death as a result of any cause.
    Time Frame 33 weeks

    Outcome Measure Data

    Analysis Population Description
    Participants who completed a full 21 day cycle of therapy
    Arm/Group Title AZD6244 Treatment
    Arm/Group Description The first 6 patients with moderate liver dysfunction (Child's B or total bilirubin 1.5-2x ULN) were to comprise a "moderate liver dysfunction" safety cohort. AZD6244 was administered at a dose of 100 mg twice daily (48 hours after initial single dose for PK), approximately 12 hours apart, in a mix and drink formulation. For the purposes of evaluation, a cycle was defined as 21 days. Dosing for the remainder of patients (efficacy cohort) was to be determined by the algorithm presented in the safety cohort.
    Measure Participants 17
    Median (95% Confidence Interval) [months]
    1.4
    3. Secondary Outcome
    Title Median Overall Survival (OS)
    Description Overall survival has been defined as time from the start of treatment to death as a result of any cause.
    Time Frame 33 weeks

    Outcome Measure Data

    Analysis Population Description
    Participants who completed a full 21 day cycle of therapy
    Arm/Group Title AZD6244 Treatment
    Arm/Group Description The first 6 patients with moderate liver dysfunction (Child's B or total bilirubin 1.5-2x ULN) were to comprise a "moderate liver dysfunction" safety cohort. AZD6244 was administered at a dose of 100 mg twice daily (48 hours after initial single dose for PK), approximately 12 hours apart, in a mix and drink formulation. For the purposes of evaluation, a cycle was defined as 21 days. Dosing for the remainder of patients (efficacy cohort) was to be determined by the algorithm presented in the safety cohort.
    Measure Participants 17
    Median (95% Confidence Interval) [months]
    4.2

    Adverse Events

    Time Frame 1 year, 5 months
    Adverse Event Reporting Description All 19 participants were evaluated for toxicity.
    Arm/Group Title AZD6244 Treatment
    Arm/Group Description The first 6 patients with moderate liver dysfunction (Child's B or total bilirubin 1.5-2x ULN) were to comprise a "moderate liver dysfunction" safety cohort. AZD6244 was administered at a dose of 100 mg twice daily (48 hours after initial single dose for PK), approximately 12 hours apart, in a mix and drink formulation. For the purposes of evaluation, a cycle was defined as 21 days. Dosing for the remainder of patients (efficacy cohort) was to be determined by the algorithm presented in the safety cohort.
    All Cause Mortality
    AZD6244 Treatment
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    AZD6244 Treatment
    Affected / at Risk (%) # Events
    Total 8/19 (42.1%)
    Blood and lymphatic system disorders
    Hemoglobin - Possbily related 1/19 (5.3%) 1
    Hemoglobin - Unlikely to be related 1/19 (5.3%) 1
    Gastrointestinal disorders
    Gastrointestinal - Other - Unlikely to be related 1/19 (5.3%) 1
    Nausea - Possibly related 1/19 (5.3%) 1
    General disorders
    Death - Death not associated with CTCAE term - Disease progression - 1 Event definitely related 5/19 (26.3%) 5
    Hemorrhage/Bleeding - GI - Liver - Unrelated 1/19 (5.3%) 1
    Hemorrhage/Bleeding - GU/Urinary - Possibly related 1/19 (5.3%) 1
    Fatigue - Possibly related 1/19 (5.3%) 1
    Hepatobiliary disorders
    Hepatobiliary/Pancreas - Liver dysfunction/failure - Unrelated 1/19 (5.3%) 1
    Metabolism and nutrition disorders
    AST, SGOT - Probably related 1/19 (5.3%) 1
    AST, SGOT - Possibly related 1/19 (5.3%) 1
    Bilirubin - Possibly related 1/19 (5.3%) 1
    Albumin, serum-low (hypoalbuminemia) - Possibly related 1/19 (5.3%) 1
    Other (Not Including Serious) Adverse Events
    AZD6244 Treatment
    Affected / at Risk (%) # Events
    Total 0/19 (0%)

    Limitations/Caveats

    The study was stopped at the interim analysis due to lack of radiographic response.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Bert. H. O'Neil, Associate Professor, Clinical Research
    Organization UNC Lineberger Comprehensive Cancer Center
    Phone 919-966-4431
    Email bert_oneil@med.unc.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00604721
    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
    • NCT00550719
    • NCT01656291
    First Posted:
    Jan 30, 2008
    Last Update Posted:
    May 28, 2014
    Last Verified:
    May 1, 2013