Selumetinib in Treating Patients With Biliary Cancer That Cannot Be Removed By Surgery

Unresectable Extrahepatic Bile Duct Cancer Clinical Trial

Official title:

A Phase 2 Study of AZD6244 in Biliary Cancers

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00553332
• Other study ID #: NCI-2009-00251
• Secondary ID: OSU 07056OSU-070
• Status: Active, not recruiting
• Phase: Phase 2
• First received: November 2, 2007
• Last updated: April 1, 2013
• Start date: November 2007

Study information

• Verified date: April 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT01645644

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 35
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bile Duct Neoplasms
• Biliary Tract Neoplasms
• Cholangiocarcinoma
• Liver and Intrahepatic Biliary Tract Cancer
• Recurrent Extrahepatic Bile Duct Cancer
• Unresectable Extrahepatic Bile Duct Cancer

Intervention

Drug:
• selumetinib
Given orally

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	University of Michigan Cancer Center (UMCC) Research Base	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Wayne State University	Detroit	Michigan
United States	Vanderbilt University	Nashville	Tennessee
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate (CR and PR)	Response will be evaluated in this study using the new international criteria proposed by Response Evaluation Criteria in Solid Tumors (RECIST) committee. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. A Simon 2-stage minimax design, which minimizes the maximum sample size given specified alpha and beta error rates will be utilize.	Every 8 weeks	No
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	From the time of first treatment with AZD6244, assessed up to 4 weeks	Yes
Secondary	Percentage of patients who are progression-free and alive	Progression will be evaluated in this study using the new international criteria proposed by RECIST committee	Up to 6 months	No
Secondary	Overall survival		Up to 12 months	No
Secondary	RAS/RAF/MEK/ERK signaling pathway activation		At baseline	No
Secondary	Genetic mutations		At baseline	No
Secondary	Epigenetic silencing		At baseline	No
Secondary	Protein levels of RAS/RAF/MEK/ERK signaling pathway activation		At baseline	No