Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Phase 2

Completed

Conditions: Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer

Interventions: Drug: selumetinib
Other: pharmacological study

Registration Number: NCT00604721

Lead Sponsor: National Cancer Institute (NCI)

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:

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 19

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy)	pharmacological study	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.
Treatment (enzyme inhibitor therapy)	selumetinib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.

Trial Locations

Locations (6): Emory University
🇺🇸
Atlanta, Georgia, United States
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
H. Lee Moffitt Cancer Center and Research Institute
🇺🇸
Tampa, Florida, United States
Vanderbilt University
🇺🇸
Nashville, Tennessee, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States