Phase 1-2 Vatalanib and Gemcitabine in Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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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.

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

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Vatalanib
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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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

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 Dose Exploration 0 - Gemcitabine 700 + vatalanib 1250<br>Gemcitabine 700 mg/m2 + vatalanib 1250 mg daily | Drug: Vatalanib<br>* Vatalanib 250 mg PO Q12 hours x 7 days, 8th day forward 500 mg PO Q12 hours<br>* Other names: PTK787/ZK 222584;Drug: Gemcitabine<br>* 850 mg/m2<br>* Other names: Gemzar;|
| Experimental: Stage 1 Dose Exploration 1 - Gemcitabine 850 + vatalanib 1250<br>Gemcitabine 850 mg/m2 + vatalanib 1250 mg | Drug: Vatalanib<br>* Vatalanib 250 mg PO Q12 hours x 7 days, 8th day forward 500 mg PO Q12 hours<br>* Other names: PTK787/ZK 222584;Drug: Gemcitabine<br>* 850 mg/m2<br>* Other names: Gemzar;|
| Experimental: Stage 1 Dose Explrtion2 - Gemcitabine850+vatalanib 2x250/2x500<br>Gemcitabine 850 mg/m2 + vatalanib 250 mg Q12 hours x 1 week then 500 mg Q12 hours thereafter | Drug: Vatalanib<br>* Vatalanib 250 mg PO Q12 hours x 7 days, 8th day forward 500 mg PO Q12 hours<br>* Other names: PTK787/ZK 222584;Drug: Gemcitabine<br>* 850 mg/m2<br>* Other names: Gemzar;|
| Experimental: Stage 2 Dose Expansion - Gemcitabine850+vatalanib 2x250/2x500<br>Gemcitabine 850 mg/m2 + vatalanib 250 mg Q12 hours x 1 week then 500 mg Q12 hours thereafter | Drug: Vatalanib<br>* Vatalanib 250 mg PO Q12 hours x 7 days, 8th day forward 500 mg PO Q12 hours<br>* Other names: PTK787/ZK 222584;Drug: Gemcitabine<br>* 850 mg/m2<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-Treatment Failure (Intent-To-Treat Analysis) | For the purposes of an Intent-to-Treat (ITT) analysis, Time-to-Treatment Failure (TTF) was defined as the time from treatment initiation to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, lost-to-follow-up, or death. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-Progression, Evaluable Patients | Represents the evaluable subset of subjects that terminated from the study due to disease progression (endpoint). Does not include any other form of treatment failure, nor lost-to-follow-up. | 12 months |