A Phase I Study to Determine the Safety of Imatinib in Combination With PTK787/ZK222584 in Patients With Refractory and/or Advanced Solid Tumors
1. Patients must have biopsy-proven, advanced, incurable solid tumors refractory to
standard treatment or for which there is no known standard treatment.
2. ECOG performance status 0 or 1.
3. Life expectancy of at least three months.
4. At least three weeks from any previous chemotherapy or 4 weeks from all
5. Completed any previous radiotherapy at least two weeks prior to study entry.
6. Adequate end organ function, defined as the following: total bilirubin < 1.5 x ULN,
creatinine < 1.5 x ULN, ANC > 1500/µL, platelets > 100,000/µL.
7. Serum bilirubin <= 1.5 x the institutional upper-limit of normal and alkaline
phosphatase, AST (SGOT), and ALT (SGPT) <= 2.5 x the institutional upper-limit of
normal (within 7 days prior to initial treatment).
8. Hemoglobin >= 9 gm/dL (may be transfused or receive erythropoietin to maintain or
exceed this level).
9. Patients with a history of brain metastases are eligible, but only if they have had
previous treatment for the metastases and these are inactive and asymptomatic at the
time of enrollment in this study.
10. Patients must be able to understand the nature of this study and give written
11. Female patients of childbearing potential must have negative pregnancy test within 7
days before initiation of study drug dosing. Postmenopausal women must be
amenorrheic for at least 12 months to be considered of non-childbearing potential.
Male and female patients of reproductive potential must agree to employ an effective
barrier method of birth control throughout the study and for up to 3 months following
discontinuation of study drug. Oral, injectable, and injection contraceptives should
not be considered effective as they may be affected by cytochrome P450 interactions.
12. Must have evaluable-disease
13. Must be > 18 years of age.
14. Patients may have received prior systemic chemotherapy, i.e. there is no limit on the
number of prior regimens the patient may have received.
1. Female patients who are pregnant or are lactating.
2. History of acute myocardial infarction within 6 months. In addition, patients are
ineligible if they have clinically significant cardiovascular disease (e.g.
uncontrolled hypertension, unstable angina), New York Heart Association grade II or
greater congestive heart failure, serious cardiac arrhythmia requiring medication, or
> grade II peripheral vascular disease.
3. Patients with a prior malignancy (except for adequately treated basal-cell or
squamous-cell skin cancers, in situ carcinomas, or low grade [Gleason score 3+3 or
less] localized prostate cancer) in the past 5 years will be excluded.
4. Patients with active concurrent infections or patients with serious underlying
medical conditions will be excluded from the study.
5. Women who are pregnant or lactating are ineligible. All men and women of
reproductive potential must agree to use effective contraception while receiving
treatment in this study. (See 3.1.11)
6. Patients who are concurrently using phenytoin, carbamazepine, barbiturates,
rifampicin, phenobarbital, systemic retinoids, or St. John's Wort are ineligible.
7. Patients who have had a prior grade 4 thromboembolic event are ineligible. Patients
who have had a grade 3 thromboembolic event are ineligible unless they have an
in-range INR (usually between 2 and 3) on a stable dose of low molecular weight
heparin or unfractionated heparin. In addition, patients who have clinical or
radiologic evidence of clots in the renal veins, inferior vena cava, hepatic veins,
or portal vein are ineligible. Since warfarin is metabolized through the CYP450
system, no therapeutic anticoagulation with warfarin (e.g. Coumadin or Coumadine)
will be permitted in patients participating in this study. As an alternative,
therapeutic anticoagulation may be accomplished using low-molecular weight heparin
(e.g. Lovenox) or heparin. Mini-Dose Coumadin (e.g. 1 mg qd) is permitted for
prophylaxis of central venous catheter thrombosis, at the discretion of the treating
physician. In general, the use of Coumadin is discouraged on this protocol.
8. Major surgical procedure, open biopsy; or significant traumatic injury within 28 days
or anticipation of need for major surgical procedure during the course of the study.
9. Patients with PEG or G-tubes are ineligible.
10. Proteinuria; if > 1+ on dipstick at baseline patients must have 24-hour urine
collection. Patients with > 500mg protein/24 hrs are ineligible. (See Appendix A -
Evaluation and Management of Proteinuria).
11. Any nonhealing wound, ulcer, or bone fracture.
12. Any clinical evidence or history of a bleeding diathesis or coagulopathy.
13. Participation in another experimental drug study within 28 days of starting
14. History of any other disease, physical examination finding, or clinical laboratory
finding giving reasonable suspicion of a disease or condition that contraindicates
use of an investigational drug or that might affect interpretation of the results of
the study or render the subject at high risk from treatment complications.
15. Presence of poorly controlled hypertension (as defined by the treating clinician) If
a patient's condition is deteriorating, laboratory evaluations should be repeated <
48 hours prior to initiation of therapy.
16. Prior VEGF therapy.
17. 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).