Clinical trial NCT00604721: Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer
Official title: A Phase 2 Study of AZD6244 in Advanced or Metastatic Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Primary Hepatocellular Carcinoma
Advanced Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-01-30
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Radiographic Objective Response (OR)
timeFrame: 33 weeks
Secondary outcomes:
measure: Median Progression Free Survival (PFS)
timeFrame: 33 weeks
measure: Median Overall Survival (OS)
timeFrame: 33 weeks
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: H. Lee Moffitt Cancer Center and Research Institute
name: Bert O'Neil
role: PRINCIPAL_INVESTIGATOR
References: