Study of Gemcitabine and Erlotinib Plus Sorafenib (GES) in Metastatic Pancreatic Cancer

Until very recently, additional therapies in pancreatic cancer have targeted either the vascular endothelial growth factor (VEGF) or epidermal growth factor (EGF) pathways, a strategy which has shown variable clinical efficacy. This inconsistency is not surprising, given the knowledge that tumors have a certain level of signal redundancy which may limit the effectiveness of any one single-targeted therapy. The dual blockade of the EGF and VEGF pathways takes aim at two of the most active cascades in tumorigenesis. Preliminarily, a phase II study done in pancreatic cancer with gemcitabine, bevacizumab and erlotinib or cetuximab has shown promising results and will most likely proceed to phase III study for definitive efficacy assessment (Kindler et al, 2006).

In this study, targeted blockade is carried one step further with the inhibition of the signaling cascade downstream of receptor tyrosine kinases at the level of raf. Given the fact that the majority of pancreatic tumors display constitutive activation of the Ras/Raf/MEK/ERK pathway, it is hoped that the addition of sorafenib to gemcitabine and erlotinib will obtain a more complete blockade of the signal transduction cascade responsible for pancreatic tumor growth and progression.

Inclusion criteria

• Histologically or cytologically confirmed pancreatic adenocarcinoma not amenable to curative treatment with surgery. Patients with locally advanced disease must have disease that extends outside the boundaries of a standard radiation port.
• Measurable disease, as defined by Response Evaluation Criteria In Solid Tumors (RECIST). This requires 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. Pleural effusions and ascites are not considered measurable lesions.
• No prior cytotoxic chemotherapy for metastatic disease. Prior adjuvant chemotherapy is allowed, however at least 6 months must have elapsed from administration of the last dose of chemotherapy or radiotherapy.
• No prior therapy with a VEGF, EGFR, or multi-targeted kinase inhibitor.
• Age >18 years.
• Life expectancy of greater than 3 months.
• Eastern Cooperative Oncology Group performance status 0-1.
• Normal organ and marrow function as defined below:

• White blood cells (WBC) >3,000/µl
• Absolute neutrophil count >1,500/µl
• Platelets >100,000/µl
• Total bilirubin ≤ 2.5 x institutional upper limit of normal (ULN)
• Transaminases(SGOT/ SGPT)

• without liver mets ≤ 2.5 x institutional ULN
• with liver mets ≤ 5 x institutional ULN
• International Normalized Ratio (INR)

• patients not on warfarin ≤ 1.5
• patients on warfarin ≤ 3
• Renal Function: Serum creatinine ≤ 1.5 xULN
• Proteinuria: Urine protein <1+, or 24hr urine protein <500 mg
• At least 30 days since receiving any investigational drug.
• Patients who received prior radiation therapy must have a site of measurable disease that is not located within the prior radiation port.
• Patients who are on warfarin anticoagulation are allowed to participate as long as they fit the following 3 criteria:

• They are therapeutic on a stable warfarin dose
• Their INR target range is no greater than 3
• They are monitored with regular INR testing
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.
• Women of childbearing potential and men must agree to use adequate contraception (barrier method birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of study drugs.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• No prior treatment with bevacizumab, cetuximab, or erlotinib. Prior gemcitabine in the adjuvant setting completed more than six months previously will be allowed.
• No other investigational agents.
• No central nervous system (CNS) disease, including primary brain tumors, brain metastasis, or history of a cerebro-vascular accident (CVA) or transient ischemic attack (TIA) within 6 months of starting therapy.
• No allergic reactions to compounds similar to erlotinib or sorafenib.
• Because an increased risk of bleeding may occur following sorafenib administration, no patients will be allowed with a history of bleeding diathesis or coagulopathy. No grade > 2 pulmonary hemorrhage or > grade 3 other hemorrhage within 28 days of beginning therapy.
• No recent invasive procedures defined as follows: Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 of therapy
• No Patients with clinically significant cardiovascular disease, defined as:

• Uncontrolled hypertension
• Myocardial infarction < 6 months prior to registration and new onset angina within 3 months (controlled stable angina acceptable)
• New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris
• Grade II or greater peripheral vascular disease
• No serious or non-healing wound, ulcer, or bone fracture.
• No active infection requiring parental antibiotics.
• No currently active second malignancy other than non-melanoma skin cancer or carcinoma in-situ of the cervix.
• If a patient is on full-dose anticoagulants (warfarin or low molecular weight heparins are allowed), the following criteria should be met for enrollment: they must have a therapeutic INR, no greater than 3, on a stable dose of warfarin.
• No use of thrombolytic agents within 1 month of study initiation.
• No gastrointestinal tract disease resulting in an inability to take oral medication or prior surgical procedures affecting absorption. This may include patients with or without requirements for IV alimentation.
• No women who are pregnant (positive pregnancy test) or nursing. Fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 3 months after the completion of antibody therapy.
• Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, no HIV-positive patients, including those receiving combination anti-retroviral therapy, are allowed on the study.
• Any condition that impairs patient's ability to swallow whole pills
• Any malabsorption problem