Bortezomib and Carboplatin in Treating Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving bortezomib together with carboplatin works in treating patients with metastatic pancreatic cancer. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with carboplatin may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate overall survival (OS) at 6 months with the combination of bortezomib and carboplatin in patients who previously received 1 prior regimen for metastatic pancreatic cancer. SECONDARY OBJECTIVES: I. To evaluate the objective tumor response rate, the duration of response, time to tumor progression, and overall survival. II. To evaluate biological effects on peripheral blood mononuclear cells. III. To evaluate the safety profile of this combination. IV. To evaluate archival tissue for epithelial-to-mesenchymal transition (EMT) and E-cadherin and Zeb-1. OUTLINE: Patients receive bortezomib intravenously (IV) on days 1, 4, 8, and 11 and carboplatin intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months.

Official Title
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A Phase II Study of Bortezomib in Combination With Carboplatin in Patients With Metastatic Pancreatic Cancer

Conditions
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Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Stage IV Pancreatic Cancer

Intervention / Treatment
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* Drug: bortezomib
* Drug: carboplatin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed adenocarcinoma or carcinoma of the pancreas that is metastatic and not amenable to resection with curative intent Patients must have measurable disease defined by RECIST criteria; for the purpose of this study, primary mass in the pancreas is not considered as measurable disease Patients must have received one (1), and only one, prior systemic regimen for metastatic disease; patients who have received prior cisplatin or oxaliplatin are eligible; a systemic regimen administered for unresectable locally advanced disease that subsequently progressed to metastatic will be counted as 1 prior regimen; chemotherapy administered as adjuvant therapy or as a radiation sensitizer is not counted as a prior regimen Prior radiation is permitted; however, at least 3 weeks must have elapsed since the completion of prior radiation therapy and patients must have recovered from all associated toxicities to NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 ≤ Grade 1 at the time of registration; measurable disease must be outside the previous radiation field or a new lesion inside the port must be present At least two weeks must have elapsed since any major surgery and patients must have recovered from all associated toxicities to ≤ CTCAE Grade 1 at the time of registration At least 4 weeks must have elapsed since previous chemotherapy except for regimens that are administered on a daily, weekly, or every other week schedule, in which case at least 2 weeks must have elapsed since previous chemotherapy; patients must have recovered from all associated toxicities to CTCAE ≤ Grade 1 at the time of registration ECOG performance status =< 1 (Karnofsky >= 70%) Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Hemoglobin ≥ 9 g/dl Total bilirubin =<1.5 X institutional upper limit of normal AST (SGOT) & ALT (SGPT) =< 2.5 X institutional upper limit of normal or =< 5 X institutional upper limit of normal if patient has liver metastasis Creatinine ≤ 1.5 mg/dL OR creatinine clearance >= 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Other prior malignancy is allowed as long as the patient does not require active treatment for their second malignancy and there is no radiographic evidence of second malignancy; patients who are receiving hormonal therapy for breast or prostate cancer as adjuvant treatment are eligible The effects of bortezomib on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because carboplatin, the other therapeutic agent used in this trial, is known to be teratogenic, women of child-bearing potential and men of reproductive potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document; written informed consent must be obtained prior to any evaluations being performed solely for the purposes of screening for eligibility for this study Exclusion Criteria: Patients who have only locally advanced disease (not metastatic) are excluded Patients who have received prior treatment with carboplatin, bortezomib, or another proteasome inhibitor are excluded Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; however, brain imaging studies are not required to assess eligibility if the patient has no neurological signs or symptoms Patients with current neurotoxicity, defined as greater than CTCAE Grade 1 neurotoxicity Patients must not be planning to receive any other concomitant anticancer treatment including chemotherapy, radiation therapy, biologic agents, or any other investigational drugs Patients must not have significant history of cardiac disease, i.e., unstable angina, congestive heart failure with New York Heart Association class 3 or 4, and myocardial infarction within the last 6 months Pregnant women are excluded from this study because bortezomib is a proteasome inhibitor agent with the potential for teratogenic or abortifacient effects; carboplatin has been shown to be embryotoxic and teratogenic in rats; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with bortezomib and carboplatin, breastfeeding should be discontinued if the mother is treated with these drugs HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with bortezomib and carboplatin; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

Ages Eligible for Study
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Minimum Age: 18 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: Treatment<br>Patients receive bortezomib IV on days 1, 4, 8, and 11 and carboplatin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: bortezomib<br>* Given IV<br>Drug: carboplatin<br>* Given IV<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate at 6 Months | Overall survival (OS) at 6 months with the combination of bortezomib and carboplatin in participants who previously received 1 prior regimen for metastatic pancreatic cancer from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months. Rate equals number of participants living at 6 months following treatment divided by the total number of participants. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response Rate measured by number of patients per the total treatment population who partially or completely responded to treatment. Participants reevaluated for response every 6 weeks. In addition to a baseline scan, confirmatory scans at 4 weeks following initial documentation of objective response. | from assignment of treatment until the date of first documented progression, assessed up to 17 months |