Phase 1-2 Vatalanib and Gemcitabine in Advanced Pancreatic Cancer

A Phase 1-2 Study of the VEGF Receptor Tyrosine Kinase Inhibitor PTK787/ZK 222584 and Gemcitabine in Patients With Advanced Pancreatic Cancer

The purpose of the study is to determine the optimal safe and tolerable dose of gemcitabine in combination with once daily or twice daily dose of PTK/ZK in patients with unresectable pancreatic cancer. The Phase II part of this study planned to determine the antitumor activity of this regimen and its effectiveness of preventing tumor growth and spread.

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of the pancreas

• Unresectable (due to involvement of critical vasculature, adjacent organ invasion, or presence of metastasis)

• If > 5 years between the primary surgery and the development of metastatic disease, then separate histological or cytological confirmation of metastatic disease

• Primary or metastatic lesion within 4 weeks prior to entry of study

• WHO performance status of 0 to 2

• ≤ 18 years of age

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 10e9/L (>= 1500/mm3)

• Platelets (PLT) ≥ 100 x 10^9/L (≥ 100,000/mm3)

• Hemoglobin (Hgb) ≥ 9 g/dL

• Serum creatinine ≤ 1.5 upper limit of normal (ULN)

• Serum bilirubin ≤ 1.5 ULN

• Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase

  • (ALT/SGPT) ≤ 3.0 x ULN OR
  • ≤ 5 x ULN if liver metastases present

• Proteinuria:

  • Negative for proteinuria based on dip stick reading OR
  • If dip stick reading is +1 result, then total urinary protein ≤ 500 mg and measured creatinine clearance (CrCl) ≥ 50 mL/min from a 24-hour urine collection

• Life expectancy ≥ 12 weeks

• Ability to give written informed consent

Exclusion Criteria

• For the "phase 1" portion of the study: prior gemcitabine will be therapy.

• For the "phase 2" portion of the study: any prior chemotherapy {except for low-dose 5-fluorouracil (5-FU)as a radiosensitizer]

• Radiotherapy (RT). The site of previous RT must have progressive disease if the only site of disease).

  • Prior full field radiotherapy ≤ 4 weeks prior to enrollment OR
  • Limited field radiotherapy ≤ 2 weeks prior to enrollment. Patients must have recovered from all therapy-related toxicities.

• Prior biologic or immunotherapy ≤ 2 weeks prior to registration.

• Prior therapy with anti-VEGF agents

• History or presence of central nervous system (CNS) disease

• Patients with a history of another primary malignancy ≤ 5 years (Exception: inactive basal or squamous cell carcinoma of the skin)

• Major surgery ≤ 4 weeks prior to enrollment. (Exception: insertion of a vascular access device)

• Minor surgery ≤ 2 weeks prior to enrollment. (Exception: insertion of a vascular access device)

• Concurrent use of other investigational agents and patients who have received investigational drugs ≤ 4 weeks prior to enrollment.

• Pregnant, or breast-feeding, not employing an effective method of birth control.

• Pre-existing peripheral sensory neuropathy with functional impairment (≥ CTCAE grade 2 neuropathy)

• Respiratory compromise due to pleural effusion or ascites (≥ CTCAE grade 2 dyspnea)

• QTc > 450 ms (male) or > 470 ms (female)

• Uncontrolled high blood pressure

• History of labile hypertension

• History of poor compliance with an antihypertensive regimen

• Unstable angina pectoris

• Symptomatic congestive heart failure

• Myocardial infarction ≤ 6 months prior to registration / randomization

• Serious uncontrolled cardiac arrhythmia

• Uncontrolled diabetes

• Active or uncontrolled infection

• Interstitial pneumonia

• Extensive and symptomatic interstitial fibrosis of the lung

• Chronic renal disease

• Acute or chronic liver disease

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of vatalanib

• Human immunodeficiency virus (HIV) infection (confirmed), if there is potential for interaction between vatalanib and any anti-HIV medication

• HIV infection (confirmed) judged to increase subject risk due to the pharmacologic activity of vatalanib

• Receiving warfarin sodium (Coumadin) or similar. Heparin is allowed.

• Unwilling to or unable to comply with