Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: selumetinib
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy)<br>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<br>* Given orally<br>* Other names: AZD6244;Other: pharmacological study<br> <br> * Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Radiographic Objective Response (OR) | 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. | 33 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | Progression free survival has been defined as time from the start of treatment to disease progression or death as a result of any cause. | 33 weeks | 
| Median Overall Survival (OS) | Overall survival has been defined as time from the start of treatment to death as a result of any cause. | 33 weeks |