• Dose-limiting toxicity and maximum tolerated dose (MTD) of vatalanib when administered with pemetrexed disodium as measured by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
• Overall toxicity incidence as well as toxicity profiles as measured by dose level, patient, and primary disease site as measured by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
• Pharmacokinetics of treatment, including AUC, C-max, half-life, and clearance obtained at different time points on day 1 of each course, in patients treated at the MTD [ Designated as safety issue: Yes ]
• Expression of functionally relevant polymorphisms in genes that encode proteins involved in the transport and activation of pemetrexed disodium in patients treated at the MTD [ Designated as safety issue: Yes ]
• Correlation of expression of these polymorphisms with clinical outcomes (toxicity, response, or progression status) in patients treated at the MTD [ Designated as safety issue: Yes ]
• Relation of gene expression and polymorphisms to the intracellular content of pemetrexed disodium [ Designated as safety issue: No ]

• Dose-limiting toxicity and maximum tolerated dose of vatalanib as measured by NCI CTCAE v3.0
• Overall toxicity incidence as well as toxicity profiles by dose level, patient, and primary disease site as measured by NCI CTCAE v3.0
• Pharmacokinetics, in patients treated at the maximum tolerated dose (MTD) in cohort II, including AUC, C-max, half-life, and clearance obtained at different time points on day 1 of each course
• Expression of functionally relevant polymorphisms in genes that encode proteins involved in the transport and activation of pemetrexed disodium in patients treated at the MTD in cohort II
• Correlation of expression of these polymorphisms with clinical outcomes (toxicity, response, or progression status) in patients treated at the MTD in cohort II
• Relation of gene expression and polymorphisms to the intracellular content of pemetrexed disodium

• Response (complete and partial response, stable and progressive disease) in patients with measurable disease [ Designated as safety issue: No ]
• Response profile as measured by dose level and by primary disease site [ Designated as safety issue: No ]

• Response (complete and partial response, stable and progressive disease) in patients with measurable disease as assessed by modified RECIST
• Response profile by dose level and by primary disease site

RATIONALE: Vatalanib and pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vatalanib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving vatalanib together with pemetrexed disodium may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vatalanib when given together with pemetrexed disodium in treating patients with advanced solid tumors.

OBJECTIVES:

• Determine the dose-limiting toxicity and maximum tolerated dose (MTD) of vatalanib when administered with pemetrexed disodium in patients with advanced solid tumors.
• Determine the toxicities of this regimen in these patients.
• Assess the pharmacokinetic interaction of this regimen when administered at the MTD.
• Assess the intracellular content of pemetrexed disodium polyglutamates as a measure of activity of pemetrexed disodium transport and activation enzymes in the MTD expansion group.
• Assess polymorphisms and gene expression of pemetrexed disodium target genes and genes encoding enzymes involved in the transport, activation, and inactivation of pemetrexed disodium.
• Correlate haplotype-tagged single nucleotide polymorphisms (SNPs) or gene expression levels with intracellular levels of pemetrexed disodium polyglutamates, toxicity, and/or efficacy of pemetrexed disodium in the MTD expansion group.

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

• Group I (dose escalation): Patients receive pemetrexed disodium IV over 10 minutes on day 1 and oral vatalanib twice daily on days 1-21.

Cohorts of 3-6 patients receive escalating doses of vatalanib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT) during the first 3 weeks of treatment.

• 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. Patients who experience unacceptable toxicity without progressive disease may be retreated at a lower dose.

Patients treated at the MTD (group II) undergo blood collection periodically for pharmacokinetic and pharmacogenetic analysis, including polyglutamation, gene expression, and polymorphism studies using mass spectrometry and high-performance liquid chromatography (HPLC). Genes of interest include reduced folate carrier (RFC-1), MRP, folate receptor, BCRP, FPGS, methylenetetrahydrofolate reductase (MTHFR), methionine synthase, methylthioadenosine phosphorylase, TS, DHFR, and GARFT.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

• Drug: pemetrexed disodium
• Drug: vatalanib

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