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

A Phase 2 Study of AZD6244 in Biliary Cancers

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.

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.

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