Liver and Intrahepatic Biliary Tract Cancer, Recurrent Extrahepatic Bile Duct Cancer, Unresectable Extrahepatic Bile Duct Cancer
Conditions
Brief summary
This phase II trial is studying how well selumetinib works in treating patients with biliary cancer that cannot be removed by surgery. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the objective response rate (complete response \[CR\] and partial response \[PR\]) in patients with unresectable biliary carcinoma treated with AZD6244 (selumetinib). SECONDARY OBJECTIVES: I. To evaluate the toxicity profile of this drug in these patients. II. To evaluate the 6- and 12-month survival, 6-month progression-free survival, and overall survival rates of patients treated with this drug. III. To correlate genetic mutations, epigenetic silencing, and/or protein levels of RAS/RAF/MEK/ERK signaling pathway activation with therapeutic efficacy of AZD6244 in these patients. IV. To genotype tumors for the presence of RAS mutations (i.e., NRAS, KRAS, HRAS) and BRAF mutations (e.g., V600E) in biliary tumor samples from these patients. V. To assess the presence of activation of the MEK1, MEK2, ERK, and/or Akt pathways in tumor samples from these patients. VI. To assess the epigenetic alterations (i.e., methylation) affecting the level of gene/protein expression of RASSF1A, NORE1A, and NORE1B in tumor samples from these patients. OUTLINE: Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Formalin fixed paraffin-embedded tissue blocks or fresh tissue samples are obtained from all patients prior to treatment. Tissue samples are analyzed by immunohistochemistry for the expression level of target proteins (MEK, p-MEK, ERK, p-ERK, Akt, p-AKT, RASSF1A, NORE1A and NORE1B); PCR for mutational status of target genes RAS, BRAF and EGFR); and in methylation-specific PCR for methylation of target gene promoters (promoters for RASSF1A, NORE1A and NORE1B). Samples are also analyzed by quantitative real-time PCR to compare methylation status. Fresh frozen tissue, when available, is evaluated by Western analysis to measure expression levels of target proteins. After completion of study treatment, patients are followed up for 4 weeks.
Interventions
DRUGselumetinib
Given orally
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
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
* Histologically confirmed biliary tract carcinoma * Surgically unresectable disease * Meets any of the following criteria for biliary cancers only: * Received ≤ 1 prior systemic anticancer therapy, including chemoembolization * Received prior cryotherapy, radiofrequency ablation, ethanol injection, transarterial chemoembolization, or photodynamic therapy AND meets the following criteria: * More than 6 weeks have elapsed since any of the prior therapy described above * Indicator lesion(s) must be outside the area of prior treatment OR must demonstrate clear evidence of disease progression if the only indicator lesion is inside the prior treatment area * Indicator lesion must have clearly distinct edges on CT scan * Prior radiotherapy with or without the use of a fluoropyrimidine as a radiosensitizer is allowed, provided more than 12 weeks have elapsed since treatment * Fresh or paraffin-embedded tissue from tumor blocks must be available for review * Measurable disease, defined as ≥ 1 unidimensionally measurable lesion \> 20 mm by conventional techniques or \> 10 mm by spiral CT scan * No known brain metastases * Life expectancy \> 12 weeks * ECOG performance status (PS) 0-1 or Karnofsky PS 70-100% * ANC ≥ 1,500/μL * Platelet count ≥ 75,000/μL * Total bilirubin ≤ 2 times upper limit of normal(ULN) * AST or ALT ≤ 3 times ULN * Serum albumin ≥ 2.5 mg/dL * INR ≤ 1.5 (not receiving anticoagulation therapy) * Creatinine normal or creatinine clearance ≥ 60 mL/min * Not pregnant or nursing * Negative pregnancy test * Fertile women must use effective contraception during and for four weeks after the last dose of AZD6244 * Fertile men must use effective contraception during and for 16 weeks after the last dose of AZD6244 * No significant traumatic injury within the past 3 weeks * No uncontrolled symptoms consistent with encephalopathy * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or its excipient, Captisol® * No QTc interval \> 500 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., hypokalemia or family history of long QT interval syndrome), including NYHA class III-IV heart failure * No other malignancy within the past 3 years, except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix * No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption * No uncontrolled concurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situation that would limit compliance with study requirements * No malignant hypertension within the past year * No prior sorafenib or MEK inhibitors * More than 4 weeks since prior chemotherapy, biologic therapy, or immunotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered to ≤ grade 1 adverse events * No major surgery within the past 3 weeks * No other concurrent investigational agents * No concurrent requirement for medication that can prolong the QT interval * No concurrent combination antiretroviral therapy for HIV-positive patients * No concurrent consumption of grapefruit or grapefruit juice
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (CR and PR) | Every 8 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Profile of AZD6244 | From the time of first treatment with AZD6244, assessed up to 4 weeks | Toxicitity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 |
| Median Progression Free Survival for Patients | Up to 6 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Overall Survival | Up to 12 months | — |
| RAS/RAF/MEK/ERK Signaling Pathway Activation | At baseline | — |
| Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation | At baseline | Measure the proteins levels of RAS/RAF/MEK/ERK signaling pathway activation to AZD6244 |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled to the trial between December 2007 and January 2009
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Enzyme Inhibitor Therapy) Patients receive oral selumetinib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
selumetinib: Given orally
laboratory biomarker analysis: Correlative studies | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | ineligible, incorrect diagnosis | 1 |
Baseline characteristics
| Characteristic | Treatment (Enzyme Inhibitor Therapy) |
|---|---|
| Age, Continuous | 55.6 years |
| Disease site Extrahepatic | 4 patients |
| Disease site Gallbladder | 7 patients |
| Disease site Intrahepatic | 17 patients |
| Eastern Cooperative Oncology Group (ECOG) 0 (Fully active) | 11 patients |
| Eastern Cooperative Oncology Group (ECOG) 1 (Restricted activity) | 17 patients |
| Metastasis site Liver and other sites | 16 patients |
| Metastasis site Liver only | 7 patients |
| Metastasis site Other (soft tissue, lymph nodes and lung) | 5 patients |
| Number of target lesions | 4 lesions |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment United States | 28 patients |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 28 |
| serious Total, serious adverse events | 0 / 28 |
Outcome results
Primary
Objective Response Rate (CR and PR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: Every 8 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Objective Response Rate (CR and PR) | Complete Response | 0 patients |
| Treatment (Enzyme Inhibitor Therapy) | Objective Response Rate (CR and PR) | Partial Response | 3 patients |
Secondary
Median Progression Free Survival for Patients
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Median Progression Free Survival for Patients | 3.7 months |
Secondary
Overall Survival
Time frame: Up to 12 months
Population: Kaplan-Meier
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Overall Survival | 9.8 months |
Secondary
Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation
Measure the proteins levels of RAS/RAF/MEK/ERK signaling pathway activation to AZD6244
Time frame: At baseline
Population: Only 27 patients had pAKT and pERK performed due to 2 samples not available for analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation | pAKT | 1.23 mg/ml | Standard Deviation 0.98 |
| Treatment (Enzyme Inhibitor Therapy) | Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation | pERK | 1.36 mg/ml | Standard Deviation 1.09 |
Secondary
RAS/RAF/MEK/ERK Signaling Pathway Activation
Time frame: At baseline
Population: Data was not collected and analyzed
Secondary
Toxicity Profile of AZD6244
Toxicitity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0
Time frame: From the time of first treatment with AZD6244, assessed up to 4 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Toxicity Profile of AZD6244 | Rash | 90 percent of patients |
| Treatment (Enzyme Inhibitor Therapy) | Toxicity Profile of AZD6244 | Xerostomia | 54 percent of patients |
| Treatment (Enzyme Inhibitor Therapy) | Toxicity Profile of AZD6244 | Nausea | 50 percent of patients |