Sorafenib With or Without Gemcitabine in Treating Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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This randomized phase II is studying how well giving sorafenib with or without gemcitabine works in treating patients with metastatic pancreatic cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. 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 sorafenib together with gemcitabine may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective response rate in patients with metastatic pancreatic cancer treated with concurrent gemcitabine and BAY43-9006 and sequential BAY 43-9006 followed by gemcitabine/BAY 43-9006 at progression. SECONDARY OBJECTIVES: I. To determine the six month overall survival rate, 3 month progression free survival rate, time to tumor progression and overall survival of patients with metastatic pancreatic cancer treated with concurrent gemcitabine and BAY43-9006 and sequential BAY 43-9006 followed by gemcitabine/BAY 43-9006 at progression. II. To determine the safety profile of gemcitabine and BAY43-9006 in patients with metastatic pancreatic cancer and compared to those treated with single agent BAY 43-9006. III. To determine whether mRNA expression levels of genes involved in the gemcitabine pathway (RR, dck, dcd) and genes involved in the Raf pathway (cyclin D, VEGFR2, p21) will predict for time to progression, overall survival, and response, in patients with metastatic pancreatic cancer treated with concurrent gemcitabine and BAY43-9006 and sequential BAY 43-9006 followed by gemcitabine/BAY 43-9006 at progression. IV. To determine whether genomic polymorphisms of genes (measured in peripheral blood mononuclear cells) involved in the gemcitabine pathway (RR) and genes involved in the ras pathway (VEGFR2, cyclin D, p21) will predict for time to progression, overall survival, tumor response, and toxicity in patients with advanced cancer of the pancreas treated with concurrent gemcitabine and BAY43-9006 and sequential BAY 43-9006 followed by gemcitabine/BAY 43-9006 at progression. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral sorafenib twice daily on days 1-28. Patients experiencing disease progression cross over to Arm II. ARM II: Patients receive oral sorafenib as in Arm I and gemcitabine IV over 100 minutes on days 1, 8, and 15. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Official Title
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A Randomized Phase II Study of BAY 43-9006 in Combination With Gemcitabine in Metastatic Pancreatic Carcinoma

Conditions
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Stage IV Pancreatic Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: gemcitabine hydrochloride
* 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 metastatic pancreatic carcinoma Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan No prior chemotherapy for metastatic disease is allowed; prior adjuvant chemotherapy is allowed provided that patients did not receive gemcitabine and the chemotherapy completed > 6 months prior to initiation of study therapy Available tumor biopsy specimen (paraffin embedded or fresh frozen) that was obtained at the time of diagnosis and/or prior to study entry is required Life expectancy of greater than 3 months ECOG performance status =< 1 Leukocytes >= 3,000/μL Absolute neutrophil count >= 1,500/μL Platelets >= 100,000/μL Hemoglobin >= 9 mg/dL Total bilirubin =< 1.5 X institutional upper limit of normal AST(SGOT)/ALT(SGPT) =< 3 X institutional upper limit of normal, unless the liver is involved with tumor, in which the AST (SGOT)/ALT (SGPT) must be =< 5 X institutional upper limit of normal Creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 The effects of BAY 43-9006 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because raf kinase inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men 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 Exclusion Criteria: Because BAY 43-9006 is at least partially metabolized by the CYP 3A enzyme in the liver, the possible effect that inhibitors of CYP 3A may have on BAY 43-9006 is unknown; therefore, patients taking inhibitors of CYP 3A (such as ketoconazole, itraconazole, and ritonavir) may not be enrolled in this study Patients may not be receiving any other investigational agents 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 History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 or gemcitabine Secondary primary malignancy (except in situ carcinoma of the cervix, in situ cancer of the prostate, in situ cancer of the breast or adequately treated nonmelanomatous carcinoma of the skin or other malignancy treated at least 5 years previously with no evidence of recurrence); concurrent or history of another malignancy =< 5 years Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because BAY 43-9006 is a kinase inhibitor agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 43-9006, breastfeeding should be discontinued if the mother is treated with BAY 43-9006 Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy; therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated Patients with evidence of bleeding diathesis Patients receiving therapeutic doses of anticoagulation; prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed

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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (sorafenib tosylate)<br>Patients receive 400 mg oral sorafenib twice daily on days 1-28. Patients experiencing disease progression cross over to Arm II. | Drug: sorafenib tosylate<br>* Given PO<br>* Other names: SFN;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II (sorafenib tosylate, gemcitabine hydrochloride)<br>Patients receive 400 mg oral sorafenib as in Arm I and 1000 mg/m2 gemcitabine IV over 100 minutes on days 1, 8, and 15. | Drug: sorafenib tosylate<br>* Given PO<br>* Other names: SFN;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;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 |
| --- | --- | --- |
| Objective Response (OR = CR or PR) as Determined by the RECIST Criteria | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT scan, MRI, X-ray: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Every 6 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier by arm. | From first day of treatment to time of death due to any cause, assessed up to 6 months | 
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier by arm. The probability of progression-free survival at 3 months and overall survival at 6 months, and their Greenwood's standard errors will be summarized by arm. | From first day of treatment to the first observation of disease progression or death due to any cause, assessed up to 3 months |