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

Study Overview
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Brief Summary
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RATIONALE: Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving pemetrexed together with cisplatin and paclitaxel and giving them in different ways may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of intraperitoneal pemetrexed when given together with intraperitoneal cisplatin and paclitaxel in treating patients with stage III ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.

Detailed Description
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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.

Official Title
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Phase I Open Label Trial of Alimta® Plus Cisplatin and Paclitaxel Given Intraperitoneally (IP) as First Line Treatment for Women With Stage III Ovarian Cancer

Conditions
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Fallopian Tube Cancer, Ovarian Cancer, Peritoneal Cavity Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: paclitaxel
* Drug: pemetrexed disodium
* Other: biologic sample preservation procedure


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Receiving Treatment<br>Dose escalation of day 1 i.p. pemetrexed disodium accrued three patients to each of five dose levels (60-1,000 mg/m2), along with day 2 i.p. cisplatin (75 mg/m2) and day 8 i.p. paclitaxel (60 mg/m2) with a biologic sample preservation procedure | Drug: cisplatin<br>* IP cisplatin will be administered on day 2 of each cycle at 75mg per m2 and IP paclitaxel will be administered at 60mg per m2 on day 8 of each cycle. Courses will be repeated every 21 days for up to 6 cycles<br>* Other names: IP cisplatin;Drug: paclitaxel<br>* IP cisplatin will be administered on day 2 of each cycle at 75mg per m2 and IP paclitaxel will be administered at 60mg per m2 on day 8 of each cycle. Courses will be repeated every 21 days for up to 6 cycles<br>* Other names: IP paclitaxel;Drug: pemetrexed disodium<br>* Escalate doses in groups of 3 patients to 60mg per m2, 120 mg per m2, 500 mg per m2, 750 mg per m2, 1000 mg per m2<br>* Other names: Alimta;Other: biologic sample preservation procedure<br>* Plasma samples will be collected on the 1st course at baseline, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours (if possible) and 24 hours after the first IP Alimta® dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated Dose of Pemetrexed With a Day 2 i.p. Cisplatin (75 mg/m2) and Day 8 i.p. Paclitaxel (60 mg/m2) | If none of the initial 3 patients on a dose level experienced a dose-limiting toxicity (DLT) after the first cycle of therapy, then the dose was escalated to the next level. If 2 or more patients on any dose level experienced a DLT, then the maximum tolerated dose would be determined to be the next lower dose level. | 18 months | 
| Patients That Completed at Least 6 Courses of Therapy of Pemetrexed Along With Day 2 i.p. Cisplatin (75 mg/m2) and Day 8 i.p. Paclitaxel (60 mg/m2)at the Determined Maximum Tolerated Dose | If none of the initial 3 patients on a dose level experienced a dose-limiting toxicity (DLT) after the first cycle of therapy, then the dose was escalated to the next level. If 2 or more patients on any dose level experienced a DLT, then the Maximum Tolerance Dose (MTD) would be determined to be the next lower dose level. | 18 months | 
| Patients Experienced Grade >=3 Toxicity at Dose Level 5 (1,000 mg/m2 IP Pemetrexed) | Toxicity was assessed by NCI Common Toxicity Criteria for Adverse Effects v3.0 | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 18 Months as Assessed by Cancer Antigen 125 | Progression was evaluated with posttreatment CT scans and measured changes in cancer antigen 125 levels 6 months after the initiation of the treatment regimen, or within one month after discontinuation of treatment if stopped early. Cancer antigen 125 response in evaluable patients (N=13) was analyzed using the modified Gynecologic Cancer Intergroup (GCIG) criteria. There was one evaluable patient by Response Evaluation Criteria in Solid Tumors(RECIST) criteria | 18 months | 
| Overall Survival |  | Average Length of follow-up 788 days | 
| Pharmacokinetics (Mean Cmax, ug/mL)for Different Dosages of Pemetrexed | Cmax levels were found through plasma collected between 0.5 to 4 hours and at 24 hours after initiation of intraperitoneal administration | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III ovarian epithelial cancer, recurrent ovarian epithelial cancer, peritoneal cavity cancer, fallopian tube cancer