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Selumetinib in Treating Patients With Locally Advanced or Metastatic Liver Cancer

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

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00604721
Enrollment
19
Registered
2008-01-30
Start date
2007-11-30
Completion date
2012-06-30
Last updated
2014-05-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

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.

Interventions

DRUGselumetinib

Given orally

OTHERpharmacological study

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
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

Design outcomes

Primary

MeasureTime frameDescription
Number of Participants With Radiographic Objective Response (OR)33 weeksTo 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

MeasureTime frameDescription
Median Progression Free Survival (PFS)33 weeksProgression 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 weeksOverall survival has been defined as time from the start of treatment to death as a result of any cause.

Countries

United States

Participant flow

Participants by arm

ArmCount
AZD6244 Treatment
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.
19
Total19

Withdrawals & dropouts

PeriodReasonFG000
Overall StudyPhysician Decision1
Overall StudyWithdrawal by Subject1

Baseline characteristics

CharacteristicAZD6244 Treatment
Age, Categorical
<=18 years
0 Participants
Age, Categorical
>=65 years
4 Participants
Age, Categorical
Between 18 and 65 years
15 Participants
Age, Customized57 years
Region of Enrollment
United States
19 participants
Sex: Female, Male
Female
6 Participants
Sex: Female, Male
Male
13 Participants

Adverse events

Event typeEG000
affected / at risk
deaths
Total, all-cause mortality
— / —
other
Total, other adverse events
0 / 19
serious
Total, serious adverse events
8 / 19

Outcome results

Primary

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.

Time frame: 33 weeks

Population: Participants who completed a full 21 day cycle of therapy

ArmMeasureValue (NUMBER)
Safety Cohort: AZD6244 TreatmentNumber of Participants With Radiographic Objective Response (OR)0 participants
Secondary

Median Overall Survival (OS)

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

Time frame: 33 weeks

Population: Participants who completed a full 21 day cycle of therapy

ArmMeasureValue (MEDIAN)
Safety Cohort: AZD6244 TreatmentMedian Overall Survival (OS)4.2 months
Secondary

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.

Time frame: 33 weeks

Population: Participants who completed a full 21 day cycle of therapy

ArmMeasureValue (MEDIAN)
Safety Cohort: AZD6244 TreatmentMedian Progression Free Survival (PFS)1.4 months

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026