Alimta® Plus Cisplatin & Paclitaxel Given Intraperitonelly; First Line Tx Stage III Ovarian Cancer

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose (MTD) of combination therapy comprising
intraperitoneal (IP) pemetrexed disodium in combination with IP cisplatin and
paclitaxel in patients with optimally debulked stage III ovarian epithelial cancer,
primary peritoneal cancer, or fallopian tube cancer in relation to the percentage of
patients completing at least 6 courses of treatment.

- To determine the toxicity and the tolerability of this regimen in these patients.

Secondary

- To observe 80% of these patients progression free at 18 months after initiation of
chemotherapy.

- To determine, as an exploratory endpoint, the median overall survival of patients
treated with this regimen.

- To investigate the pharmacokinetics of this regimen at the determined MTD in these
patients.

- To conduct correlative studies on tumor tissue and blood from these patients.

OUTLINE: This is a dose-escalation study of pemetrexed disodium.

Patients receive pemetrexed disodium intraperitoneally (IP) on day 1, cisplatin IP on day 2,
and paclitaxel IP on day 8. Treatment repeats every 21 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity. At least 10 patients are treated at
the maximum-tolerated dose (MTD).

Whole blood samples and tumor tissue specimens are obtained from patients at baseline and
banked for future DNA, RNA, and protein studies related to prediction of disease progression
and treatment resistance. Plasma and intraperitoneal fluid samples may also be collected
from patients treated at the MTD for pharmacokinetic analysis of plasma concentrations of
pemetrexed disodium by high-performance liquid chromatography (HPLC) or mass
spectrometry-HPLC.

After completion of study therapy, patients are followed periodically.

DISEASE CHARACTERISTICS:

- Histologically or pathologically confirmed ovarian epithelial carcinoma, primary
peritoneal carcinoma, or fallopian tube carcinoma

- Stage III disease

- Meets 1 of the following criteria:

- No prior treatment and no more than 6 months since primary surgery

- Platinum-sensitive at second-look surgery with no prior cisplatin therapy

- Must have been optimally debulked to less than 2-cm residual individual tumor plaques
or, if suboptimally debulked at first surgery, had chemical debulking

- No mixed Müllerian tumor or borderline ovarian tumor

- No Central nervous system (CNS) or brain metastases

PATIENT CHARACTERISTICS:

- Gynecologic Oncology Group performance status 0-2

- White blood cell count(WBC) ≥ 3,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Serum bilirubin ≤ 2 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST)and alanine aminotransferase (ALT) ≤ 2.5 times upper
limit of normal

- Creatinine clearance ≥ 45 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception during and for 3 months
after discontinuation of study drug

- No psychological, familial, sociological, or geographical conditions that do not
permit medical follow-up or compliance with the study protocol

- No unstable or preexisting major medical conditions, except cancer-related
abnormalities

- No medical life-threatening complications of their malignancies

- No known severe and/or uncontrolled concurrent medical disease (e.g., uncontrolled
diabetes, uncontrolled chronic renal or liver disease, active uncontrolled infection,
or HIV)

- No serious active uncontrolled infections

- No inadequately controlled hypertension (defined as systolic blood pressure ≥ 150 mm
Hg and/or diastolic blood pressure ≥ 100 mm Hg on antihypertensive medications)

- No New York Heart Association grade II-IV congestive heart failure

- No weight loss between 5 to ≤ 10% within the past 14 days that is not related to
ascites or paracentesis

- No prior hypertensive crisis or hypertensive encephalopathy

- No myocardial infarction, cerebrovascular accident, transient ischemic attack, or
unstable angina within the past 6 months

- No evidence of uncontrollable nausea

- No clinically significant or symptomatic peripheral vascular disease (e.g., aortic
aneurysm or aortic dissection)

- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess

- No pre-existing clinically significant hearing loss

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer, cervical carcinoma in situ, or adequately treated stage I
or II cancer from which the patient is in complete remission

- No known hypersensitivity to any component of pemetrexed disodium

- Able to take folic acid, vitamin B_12, and dexamethasone according to protocol

- No presence of third-space fluid that cannot be controlled by drainage

- No inability to comply with study and/or follow-up procedures

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- May have received up to 4 courses of carboplatin and paclitaxel IV as neoadjuvant
chemotherapy for advanced, unresectable disease

- Concurrent low-dose aspirin therapy (i.e., 325 mg/day) allowed

- Concurrent ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) with
short elimination half-lives allowed provided ≥ 1 of the following criteria is met:

- Creatinine clearance (CrCl) > 80 mL/min (i.e., normal renal function)

- CrCl 45-79 mL/min (i.e., mild to moderate renal insufficiency) AND NSAID dosing
interrupted for a period of 2 days before, during, and 2 days after
administration of pemetrexed disodium

- Concurrent NSAIDs or salicylates with long half-lives (e.g., naproxen, piroxicam,
diflunisal, or nabumetone) allowed provided NSAID dosing is interrupted for at least
5 days before, during, and 2 days after administration of pemetrexed disodium

- No concurrent antineoplastic or antitumor agents not part of the study therapy (i.e.,
chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy)

- No other concurrent investigational agents