Vatalanib and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of PTK/ZK
and pemetrexed disodium when given in combination.

II. To describe the toxicities associated with the combination of PTK/ZK with pemetrexed
disodium.

III. To evaluate the pharmacokinetic interaction of combination of PTK/ZK with pemetrexed
disodium at the MTD (Group II).

IV. To evaluate the intracellular content of pemetrexed disodium polyglutamates as a measure
of activity of pemetrexed disodium transport and activation enzymes in the MTD expansion
cohort (Group II).

V. To evaluate polymorphisms and gene expression of pemetrexed disodium target genes, and
genes encoding enzymes involved in the transport, activation, and inactivation of pemetrexed
disodium, and correlate haplotype-tagged SNPs or gene expression levels with intracellular
levels of pemetrexed disodium polyglutamates, toxicity and/or efficacy or pemetrexed disodium
in Group II.

VI. To evaluate pharmacogenetic, metabolic and clinical markers that may predict for
hypertension induced by anti-VEGF therapy.

OUTLINE:

This is a dose-escalation study of vatalanib. Patients are assigned to 1 of 2 treatment
groups.

GROUP I (dose escalation, closed to accrual 12/18/2007): Patients receive pemetrexed disodium
IV over 10 minutes on day 1 and oral vatalanib twice daily on days 1-21.

GROUP II (MTD expansion group): Patients receive pemetrexed disodium IV on day 1, as in group
I. Patients also receive oral vatalanib at the MTD twice daily on days 8-21 during course 1
and on days 1-21 during all subsequent courses.

In both groups, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Inclusion Criteria:

- Willingness to return to Mayo Clinic Rochester for follow up

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry, duration of study
participation, and for at least 30 days after the last administration of study
medication

- ECOG performance status (PS) 0, 1, or 2

- Histologic proof of advanced solid tumor that has no known standard therapy that is
potentially curative or definitely capable of extending life expectancy upon
registration.

- Mandatory translational research (MTD patients only): willingness to provide the
biologic specimens as required by the protocol; willingness to undergo brachial artery
ultrasound measurements

- ANC >= 1500/uL

- Hgb >= 9 g/dL

- PLT >= 100,000/uL

- AST =< 3 x ULN or AST =< 5 x ULN if liver involvement

- Calculated creatinine clearance >= 45 ml/min

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Random urine protein:osmolality ratio =< 0.40 OR total urinary protein =< 500 mg and
measured creatinine clearance (CrCl) >= 45 mL/min from a 24-hour urine collection

- Patients should have no contraindications to the intake of folic acid, vitamin B12 or
dexamethasone

- For patients with pleural/peritoneal/pericardial effusions: If patient is asymptomatic
but the effusion volume is approximated to be > 500 mL or produces measurable
objective changes related to the effusion (e.g., echocardiographic ventricular
compression, hypoxia on pulse oximetry, etc.), effusion should be drained

- Able to permanently discontinue aspirin dose of >=1.3 grams/day >=10 days before
through >= 10 days after pemetrexed disodium treatment

- Life expectancy >= 12 weeks

Exclusion Criteria:

- Symptomatic, untreated, or uncontrolled CNS metastases or seizure disorder; patients
with CNS metastases treated with whole brain radiation (WBRT) may be enrolled after
completion of WBRT; patients may begin chemotherapy as early as the next day after
WBRT

- Any clinically significant infection

- Active, bleeding diathesis or on any anticoagulant

- HIV-positive patients receiving combination anti-retroviral therapy because of
possible pharmacokinetic interactions with PTK/ZK

- Chemotherapy =< 3 weeks prior to registration

- Radiation to >= 30% of bone marrow

- Immunotherapy =< 2 weeks prior to registration

- Chronic renal disease

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

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

- Greater than (>) normal risk of bleeding or on any anticoagulant

- Pregnant, nursing, or positive pregnancy test =< 7 days prior to registration for
women of childbearing potential

- Symptomatic serosal effusion (>= CTCAE v3.0 grade 2 dyspnea that is not amenable to
drainage prior to registration)

- Mitomycin C/nitrosoureas, bevacizumab =< 6 weeks prior to registration

- Biologic therapy =< 2 weeks prior to registration

- Other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, or any ancillary
therapy considered investigational (utilized for a non-FDA approved indication and in
the context of a research investigation) =< 4 weeks prior to registration

- Prolonged QTc (> 450 msec for males and > 470 msec for females) or known history of
congenital or acquired prolonged QTc syndrome

- Serious condition that, in the opinion of the investigator, would compromise the
patient's ability to complete the study

- Prior therapy with monoclonal antibody to VEGF, VEGF trap, small molecules with
receptor tyrosine kinase activity against VEGFR, antisense oligonucleotide therapy
against VEGF mRNA is allowed

- Full field radiation therapy =< 4 weeks prior to registration or limited field
radiation therapy =< 2 weeks prior to registration (the site of previous radiotherapy
should have evidence of progressive disease if this is the only site of disease)

- Men or women of childbearing potential who are unwilling to employ adequate
contraception (a barrier method of birth control) (oral, implantable, or injectable
contraceptives may be affected by cytochrome p450 interactions and are, therefore, not
considered effective for this study)

- a) Labile hypertension, or history of poor compliance with antihypertensive medication

- d) Myocardial infarction =< 6 months prior to registration

- h) History of deep venous thrombosis or pulmonary embolism =< 2 years prior to
registration

- Current use of the following drugs: amiodarone; anticoagulants (e.g., warfarin);
anti-retroviral therapy (e.g., ritonavir); carbamazepine; chlorpromazine; cisapride;
clarithromycin; clopidogrel; disopyramide; droperidol; erythromycin; fondaparinux;
haloperidol; heparin; itraconazole; ketoconazole

- Current use of the following drugs: methadone; oral contraceptives; phenobarbital;
phenytoin; procainamide; products containing grapefruit juice; quinidine; rifabutin;
rifampin; sotalol; sparfloxacin; St. John's Wort; thioridazine

- i) Patients who require chronic treatment with PPI (e.g., omeprazole, lansoprazole,
etc.) or H2 antagonist (e.g., ranitidine, famotidine, etc.)

- Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury =< 4
weeks prior to registration; minor surgery =< 2 weeks prior to registration; insertion
of a vascular access device is not considered major or minor surgery in this regard

- b) Angina pectoris

- c) History of congestive heart failure =< 3 months prior to registration, unless
ejection fraction > 45%

- f) Diabetes

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

- Patients who have received prior treatment using pemetrexed disodium-containing
regimens =< 12 months prior to registration

- Any of the following concurrent severe and/or uncontrolled medical conditions:

- e) Cardiac arrhythmia