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

Study Overview
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Brief Summary
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RATIONALE: AZD0530 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving AZD0530 together with gemcitabine may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of AZD0530 when given together with gemcitabine and to see how well they work in treating patients with locally advanced or metastatic pancreatic cancer that cannot be removed by surgery.

Detailed Description
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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.

Official Title
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A Phase I/II Study of AZD0530 in Combination With Gemcitabine in Patients With Advanced Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: AZD0530
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD0530 + Gemcitabine<br> | Drug: AZD0530<br>* Taken daily every 4 weeks<br>Drug: gemcitabine hydrochloride<br>* 1000mg/m2 IV weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (complete [CR] and partial response [PR] or stable disease [SD]) at 8 weeks | Response is assessed every other cycle and will be reported on at final analysis | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Toxicity is assessed from the time of first treatment and final results will be reported at final analysis | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the pancreas, stage III pancreatic cancer, recurrent pancreatic cancer, stage IV pancreatic cancer