A Phase I Trial of PTK787/ZK222584 in Combination With Bevacizumab (Avastin) in Patients With Refractory and/or Advanced Malignancies

Inclusion Criteria:

- Histologically proven advanced solid tumors that are resistant to standard treatment
and/or for which there is no known effective therapy

- Age ≥ 18 years old

- ECOG Performance Status of 0 or 1

- Laboratory values ≤ 7 days prior to treatment:

- Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (≥ 1500/mm3)

- Platelets (PLT) ≥ 100 x 109/L (≥ 100,000/mm3)

- Hemoglobin (Hgb) ≥ 9 g/dL

- Serum creatinine ≤ 1.5 ULN

- Serum bilirubin ≤ 1.5 ULN

- International Normalized Ratio (INR) <2.0

- Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤
3.0 x ULN

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

- Life expectancy ≥ 12 weeks

- Written informed consent obtained according to local guidelines

Exclusion Criteria:

- History or presence of central nervous system (CNS) disease (i.e., primary brain
tumor, malignant seizures, CNS metastases or carcinomatous meningitis)

- Patients with a history of another primary malignancy ≤ 5 years, with the exception
of inactive basal or squamous cell carcinoma of the skin

- Prior chemotherapy ≤ 3 weeks prior to registration and/or randomization. Patients
must have recovered from all therapy-related toxicities

- Prior biologic or immunotherapy ≤ 2 weeks prior to registration and/or randomization.
Patients must have recovered from all therapy-related toxicities

- Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior
to randomization. Patients must have recovered from all therapy-related toxicities.
The site of previous radiotherapy should have evidence of progressive disease if this
is the only site of disease

- Major surgery (i.e., laparotomy) ≤ 4 weeks prior to randomization. Minor surgery ≤ 2
weeks prior to randomization. Insertion of a vascular access device is not
considered major or minor surgery in this regard. Patients must have recovered from
all surgery-related toxicities

- Patients who have received investigational drugs ≤ 4 weeks prior to registration
and/or randomization

- Prior therapy with anti-VEGF agents (including PTK787/ZK222584 and bevacizumab)

- Pleural effusion or ascites that causes respiratory compromise (≥ CTC grade 2
dyspnea)

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential not employing an effective method of birth control. Barrier contraceptives
must be used throughout the trial in both sexes. Oral, implantable, or injectable
contraceptives may be affected by cytochrome P450 interactions, and are therefore not
considered effective for this study. Women of childbearing potential must have a
negative serum pregnancy test 48 hours prior to administration of study treatment.
Please refer to appendix 3 for a list of examples of substrates of human liver
microsomal P450 enzymes

- Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study:

- Uncontrolled high blood pressure (>160/100 on medication), history of labile
hypertension, or history of poor compliance with an antihypertensive regimen

- Unstable angina pectoris

- Symptomatic congestive heart failure

- Myocardial infarction ≤ 6 months prior to registration

- Serious uncontrolled cardiac arrhythmia

- Uncontrolled diabetes

- Active or uncontrolled infection

- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung

- Chronic renal disease

- Acute or chronic liver disease (e.g., hepatitis, cirrhosis)

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of PTK787/ZK 222584 (i.e., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability
to swallow the tablets)

- Patients with confirmed diagnosis of human immunodeficiency virus (HIV) infection are
excluded at the investigator's discretion if he/she feels that 1) a potential drug
interaction between PTK787/ZK 222584 and any of the patient's anti-HIV medications
could influence the efficacy of the anti-HIV medication, or 2) it may place the
patient at risk due to the pharmacologic activity of PTK787/ZK 222584. Please refer
to appendix 3 for a list of examples of substrates of human liver microsomal P450
enzymes

- Patients who are taking therapeutic warfarin sodium (Coumadin) or similar oral
anticoagulants that are metabolized by the cytochrome P450 system. Heparin is
allowed. Please refer to appendix 3 for a list of examples of substrates of human
liver microsomal P450 enzymes

- Patients receiving chronic daily treatment with aspirin (> 325 mg/day) or with daily
doses of platelet inhibitory non-steroidal anti-inflammatory agents (e.g. Ibuprofen
800 mg qid, naproxen 500 mg bid)

- Patients receiving chronic steroid therapy

- Any nonhealing wound, ulcer, or long bone fracture

- Clinical history of hemoptysis or hematemesis within the past 3 months

- Clinical evidence or history of a bleeding diathesis or coagulopathy

- History of stroke within 6 months

- Patients unwilling to or unable to comply with the protocol