Phase I Study of PTK/ZK in Combination With Pemetrexed Disodium (ALIMTA®)

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed advanced solid tumor

- Standard curative therapies do not exist or are no longer effective

- Pleural, peritoneal, or pericardial effusions allowed

- Clinically significant effusions must be drained prior to treatment (e.g.,
symptomatic pleural or peritoneal effusion)

- If patient is asymptomatic but the effusion volume is approximately > 500
mL or produces measurable objective changes related to the effusion (e.g.,
echocardiographic ventricular compression or hypoxia on pulse oximetry),
effusion should be drained

- No symptomatic (≥ grade 2 dyspnea [CTCAE v3.0]) serosal effusion that is not
amenable to drainage

- No symptomatic, untreated, or uncontrolled CNS metastases

- Patients with CNS metastases treated with whole-brain radiotherapy (WBRT) are
eligible for study treatment ≥ 1 day after completion of WBRT

PATIENT CHARACTERISTICS:

- Life expectancy ≥ 12 weeks

- ECOG performance status 0-2

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception

- No concurrent oral, implantable, or injectable contraceptives as the only means
of contraception

- Absolute neutrophil count ≥ 1,500/mm³

- Hemoglobin ≥ 9 g/dL

- Platelet count ≥ 100,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST ≤ 3 times ULN (5 times ULN if liver involvement)

- Creatinine clearance ≥ 45 mL/min

- Random urine protein:osmolality ratio ≤ 0.40 OR total urinary protein ≤ 500 mg on
24-hour urine collection

- No active, bleeding diathesis

- No greater than normal risk of bleeding

- No contraindications to folic acid, cyanocobalamin, or dexamethasone

- No clinically significant infection

- No symptomatic, untreated, or uncontrolled seizure disorder

- No significant traumatic injury within the past 4 weeks

- No concurrent severe and/or uncontrolled medical conditions, including any of the
following:

- Labile hypertension or history of poor compliance with antihypertensive
medication

- Angina pectoris

- Congestive heart failure within the past 3 months, unless ejection fraction >
45%

- Myocardial infarction within the past 6 months

- Cardiac arrhythmia

- Diabetes

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

- Deep venous thrombosis or pulmonary embolism within the past 2 years

- No prolonged QTc (> 450 msec for males and > 470 msec for females)

- No known history of congenital or acquired prolonged QTc syndrome

- No chronic renal disease

- No acute or chronic liver disease (e.g., hepatitis or cirrhosis)

- No impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of vatalanib, including any of the following:

- Ulcerative disease

- Uncontrolled nausea

- Vomiting

- Diarrhea

- Malabsorption syndrome

- Bowel obstruction

- Able to swallow tablets

- No serious condition that, in the opinion of the investigator, would preclude study
compliance

PRIOR CONCURRENT THERAPY:

- More than 3 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)

- More than 6 weeks since prior bevacizumab

- More than 4 weeks since prior major surgery (e.g., laparotomy) or open biopsy (2
weeks for minor surgery)

- Insertion of a vascular access device is not considered major or minor surgery

- More than 2 weeks since prior immunotherapy or biologic therapy

- More than 4 weeks since prior full-field radiotherapy (2 weeks for limited-field
radiotherapy)

- The site of prior radiotherapy should have evidence of progressive disease, if
this is the only site of disease

- No prior radiotherapy to ≥ 30% of bone marrow

- More than 4 weeks since prior hormonal therapy or any ancillary therapy considered
investigational

- More than 12 months since prior pemetrexed disodium-containing regimens

- Prior therapy with monoclonal antibody to vascular endothelial growth factor (VEGF),
VEGF Trap, small molecules with receptor tyrosine kinase activity against VEGF
receptor, and antisense oligonucleotide therapy against VEGF messenger RNA allowed

- Able to permanently discontinue aspirin dose of ≥ 1.3 grams/day for ≥ 10 days before
and after pemetrexed disodium treatment

- Concurrent radiotherapy for symptom palliation to nontarget sites (e.g., painful
pre-existing bony metastasis) allowed

- Study treatment is withheld until radiotherapy is completed

- Concurrent bisphosphonates for lytic metastatic bone disease allowed

- Concurrent ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) with
short elimination half-lives (e.g., fenoprofen, indomethacin, ketoprofen, tolmetin,
meclofenamate) are allowed provided 1 of the following criteria are met:

- Creatinine clearance ≥ 80 mL/min

- Creatinine clearance 45-79 mL/min (mild to moderate renal insufficiency) AND
NSAID dosing interrupted for a period of 2 days before, the day of, and 2 days
after administration of pemetrexed disodium

- Concurrent NSAIDs with longer half-lives (e.g., nabumetone, piroxicam, oxaprozin,
naproxen, diflunisal, and other NSAIDs not mentioned previously) are allowed provided
the following criterion is met:

- NSAID dosing is interrupted for at least 5 days before, the day of, and 2 days
after administration of pemetrexed disodium

- No concurrent prophylactic granulocyte colony-stimulating growth factors

- No concurrent products that stimulate thrombopoiesis

- Concurrent epoetin alpha allowed

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent use of the following drugs:

- Amiodarone

- Anticoagulants (e.g., warfarin)

- Antiretroviral therapy (e.g., ritonavir)

- Carbamazepine

- Chlorpromazine

- Cisapride

- Clarithromycin

- Clopidogrel bisulfate

- Disopyramide phosphate

- Droperidol

- Erythromycin

- Fondaparinux sodium

- Haloperidol

- Heparin

- Itraconazole

- Ketoconazole

- Methadone

- Oral contraceptives

- Phenobarbital

- Phenytoin

- Procainamide

- Products containing grapefruit juice

- Quinidine

- Rifabutin

- Rifampin

- Sotalol

- Sparfloxacin

- Hypericum perforatum (St. John's wort)

- Thioridazine