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A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma

Phase 2
18 Years
Not Enrolling
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

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Trial Information

A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma


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


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

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.


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.

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With Radiographic Objective Response (OR)

Outcome 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.

Outcome Time Frame:

33 weeks

Safety Issue:


Principal Investigator

Bert O'Neil

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

November 2007

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Advanced Adult Primary Liver Cancer
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center Columbus, Ohio  43210-1240
Vanderbilt University Nashville, Tennessee  37232-6305
University of North Carolina Chapel Hill, North Carolina  27599
Emory University Atlanta, Georgia  30322
Virginia Commonwealth University Richmond, Virginia