AZD0530 and Gemcitabine in Locally Advanced/Metastatic Pancreatic Cancer That Cannot Be Removed By Surgery

OBJECTIVES:

Phase I

• Determine the maximum tolerated dose of AZD0530 when given in combination with gemcitabine in patients with unresectable, locally advanced or metastatic pancreatic cancer.
• Determine the safety and tolerability of this regimen in these patients.
• Determine toxicity profile and dose-limiting toxicity of this regimen in these patients.
• Determine pharmacokinetic profile of this regimen in these patients.
• Correlate the toxicity profile with the pharmacokinetics of this regimen in these patients.

Phase II

• Determine the objective response rate (partial and complete response) and prolonged stable disease rate in patients treated with this regimen.
• Determine the median survival, 1-year survival, response or stable disease duration, time to disease progression, clinical benefit response, and progression-free survival of patients treated with this regimen.
• Determine the toxicity of this regimen in these patients.
• Correlate changes in serum CTX levels (post-treatment vs baseline) with response and other clinical outcomes in patients treated with this regimen.

OUTLINE: This is a phase I, open-label, multicenter, dose-escalation study of AZD0530 followed by a phase II study.

• Phase I: Patients receive oral AZD0530 once daily on days 1-28 and gemcitabine IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients receive 2 additional courses after achieving complete response or stable partial response. Patients with ongoing stable disease receive up to 6 courses. Patients who discontinue gemcitabine due to unacceptable toxicity or who complete 6 courses of therapy may continue to receive AZD0530 alone in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of AZD0530 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

• Phase II: Patients receive AZD0530 at the MTD determined in phase I and gemcitabine as in phase I.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed pancreatic adenocarcinoma

• Unresectable disease
• Locally advanced or metastatic disease
• Clinically or radiologically documented disease

• Measurable or evaluable disease (phase I)
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan (phase II)

• Measurable lesion must be outside of previously irradiated field if it is the sole site of disease unless there is documented disease progression
• No known brain metastases

PATIENT CHARACTERISTICS:

Performance status

• ECOG 0-2

Life expectancy

• More than 12 weeks

Hematopoietic

• Platelet count ≥ 100,000/mm^3
• Absolute granulocyte count ≥ 1,500/mm^3

Hepatic

• Bilirubin normal
• AST and ALT ≤ 2 times upper limit of normal (ULN) (5 times ULN if clearly attributable to liver metastasis)

Renal

• Creatinine normal

Cardiovascular

• No active cardiomyopathy
• No congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No uncontrolled hypertension
• No myocardial infarction within the past 12 months

Pulmonary

• No pulmonary disease requiring oxygen supplementation

Gastrointestinal

• Must not require IV hyperalimentation
• No uncontrolled inflammatory gastrointestinal (GI) disease (e.g., Crohn's disease or ulcerative colitis)
• No active peptic ulcer disease
• No postsurgical malabsorption characterized by uncontrolled diarrhea that results in weight loss and vitamin deficiency
• No other GI tract disease resulting in an inability to take oral medications
• Must be able to take oral medication without crushing, dissolving, or chewing tablets
• Pancreatic enzyme supplementation allowed provided the above conditions are met

Immunologic

• No immune deficiency
• No active, uncontrolled, or serious infection
• No know hypersensitivity to study drugs or their components
• No known HIV positivity

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of psychiatric illness (e.g., uncontrolled psychotic disorders) or neurologic disorder that would preclude study compliance
• No other serious medical condition or illness that would preclude study participation
• No other malignancy within the past 5 years except curatively treated nonmelanomatous skin cancer or carcinoma in situ of the cervix or bladder

PRIOR CONCURRENT THERAPY:

Chemotherapy

• No prior chemotherapy except fluorouracil (with or without leucovorin calcium) or gemcitabine given concurrently with radiotherapy as a radiosensitizer

• At least 4 weeks since prior fluorouracil or gemcitabine

Endocrine therapy

• Concurrent systemic hormonal therapy for symptom control (e.g., appetite stimulation, pain, or nausea) allowed

Radiotherapy

• See Disease Characteristics
• See Chemotherapy
• At least 4 weeks since prior radiotherapy for local disease and recovered

Surgery

• At least 3 weeks since prior major surgery

Other

• At least 2 weeks since prior anticancer therapy or investigational agents
• The following drugs must not be used for 1-2 weeks before, during, and for 1-2 weeks after completion of study treatment:

• Ketoconazole
• Itraconazole
• Ritonavir
• Mibefradil
• Clarithromycin
• Saquinavir mesylate
• Indinavir sulfate
• Erythromycin
• Nefazodone hydrochloride
• Fluconazole
• Diltiazem hydrochloride
• Alfentanil hydrochloride
• Carbamazepine
• Cyclosporine
• Tacrolimus
• Lovastatin
• Simvastatin
• Any other drug known to be a potent inhibitor of cytochrome 3A4
• No other concurrent anticancer therapy or investigational agents