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

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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


- 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

- Assess polymorphisms and gene expression of pemetrexed disodium target genes and genes
encoding enzymes involved in the transport, activation, and inactivation of pemetrexed

- 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.

Inclusion Criteria


- 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


- 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

- Labile hypertension or history of poor compliance with antihypertensive

- Angina pectoris

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

- Myocardial infarction within the past 6 months

- Cardiac arrhythmia

- Diabetes

- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the

- 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


- 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

- 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

- 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

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicity and maximum tolerated dose (MTD) of vatalanib when administered with pemetrexed disodium as measured by NCI CTCAE v3.0

Safety Issue:


Principal Investigator

Julian Molina, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

May 2007

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms



Mayo Clinic Rochester, Minnesota  55905