A Phase I/II, Multi-Center, Open-Label, Dose-Escalation, Safety and Efficacy Study of PHY906 Plus Capecitabine in Patients With Advanced Pancreatic Carcinoma

Inclusion criteria

• Men or women ≥18 years of age with either a histologic or cytologic diagnosis of locally advanced or metastatic pancreatic adenocarcinoma. However, patients with other solid malignancies will be allowed to participate during the dose escalating Phase I part of the study, who had failed to respond to standard therapy or for which no standard therapy exists.
• In the phase I portion, patients may either have had no prior chemotherapy (chemotherapy naive), or have been refractory to or relapsed from standard chemotherapy, including capecitabine-based regimens. However, in the phase II portion of the study, only pancreatic cancer patients with prior gemcitabine therapy will be eligible. No prior 5-FU/capecitabine chemotherapy will be allowed EXCEPT previous adjuvant treatment with 5-FU or capecitabine (radiosensitizing dose) with radiation completed at least 6 weeks prior to study entry.
• All patients in both the phase I and phase II portions of this study must have at least one previously unirradiated, unidimensionally measurable lesion by computerized tomography (CT) or magnetic resonance imaging (MRI) scan of ≥ 20 mm (if conventional CT scan) or ≥ 10 mm (if spiral CT scan).
• Patients with biliary or gastro-duodenal obstruction must have drainage or by pass prior to starting chemotherapy.
• Patients with adequate hepatic function defined as

• AST/ALT ≤ 2.5 X ULN;
• Total Bilirubin ≤ 2.0 XULN;
• Alkaline Phosphatase ≤ 5 X ULN (in presence of liver metastasis); or
• Alkaline Phosphatase ≤ 2.5 X ULN (in absence of liver metastasis).
• Patients should have an adequate renal function as indicated by a serum creatinine <1.6 mg/dL or calculated creatinine clearance ≥ 50 mL/min. (Calculated by Cockcroft-Gault equation).
• Baseline performance status must be Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2.
• Women patients who are known to be capable of conception should have a negative serum pregnancy test (beta-human chorionic gonadotropin [beta-hCG]) within 2 weeks of starting the study; all patients should agree to use adequate non-estrogenic birth control methods, consistent with the institute's standard form of contraception if conception is possible during the study.
• Provide written informed consent prior to screening.
• Patients with adequate hematologic tests:

• Hemoglobin ≥ 9.0 g/dL;
• Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L;
• Platelet count ≥ 100.0 x 10 9/L;

Exclusion criteria

• Patients who are pregnant or breastfeeding.
• Any prior palliative radiation therapy (other than used in the adjuvant therapy of pancreatic cancer > 6 weeks) must have been completed more than 21 days before entry into the study and evaluable lesions must not have been included in the radiation portal.
• Patients with prior capecitabine therapy for pancreatic cancer (Phase II).
• Patients with active CNS metastases.
• Patients with known hypersensitivity or a history of marked intolerance to 5-FU are ineligible.
• Because cimetidine can decrease the clearance of 5-FU, patients should not enter on this study until cimetidine is discontinued.
• Patients should not receive concurrent therapy with either sorivudine or brivudine, while receiving capecitabine. If a patient has received prior sorivudine or brivudine, then at least four weeks must elapse before the patient receives capecitabine therapy.
• Exclude sexually active males unwilling to practice contraception during the study.
• Lack of physical integrity of the upper gastrointestinal tract, inability to swallow tablets or those who have malabsorption syndrome.
• Clinically significant cardiac disease not well controlled with medication (e.g., congestive heart failure, symptomatic coronary artery disease, and cardiac arrhythmias) or myocardial infarction within the last 12 months.
• No concurrent radiotherapy is allowed.
• Known DPD (dihydropyrimidine dehydrogenase) deficiency.
• Patients who have received any previous treatment consisting of standard chemotherapy (gemcitabine in Phase II study; others in Phase I) within 21 days or an investigational agent (Phase I) within 30 days on study. Toxicity related to the previous therapy must have resolved prior to study entry.
• Patients with previous or concurrent malignancy except for inactive non-melanoma skin cancer and/or in situ carcinoma of the cervix, or other solid tumor treated curatively and without evidence of recurrence within the last 3 years prior to study entry.
• Patients taking herbal medicine(s), including supplement(s), are eligible if they discontinue the herbal medicine(s)/supplement(s) at least 7 days prior to study entry.
• Known allergy or hypersensitivity to PHY906 or any of the components used in the PHY906 formulations, or to capecitabine.
• Serious concurrent medical illness, which would jeopardize the ability of the patient to receive the chemotherapy program outlined in this protocol with reasonable safety.
• Patients with active infections requiring intravenous antibiotic therapy are not eligible until the infection has resolved.