Intraperitoneal vs Intravenous Chemotherapy Following Neoadjuvant Chemotherapy in Ovarian Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving them in different ways may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating patients with ovarian epithelial cancer, primary peritoneal cancer, and fallopian tube cancer. PURPOSE: This randomized phase II trial is comparing the side effects of three combination chemotherapy regimens and to see how well they work in treating patients with stage IIB, stage IIC, stage III, or stage IV ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.

Detailed Description
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OBJECTIVES: Primary To compare the efficacy of the selected IP chemotherapy regimen (Arm 3: IV paclitaxel and IP carboplatin plus day 8 IP paclitaxel) versus IV carboplatin plus paclitaxel (Arm 1) in patients with epithelial ovarian cancer optimally debulked at surgery following neoadjuvant intravenous chemotherapy. Nine month progressive rate post randomization is the primary endpoint for assessment of efficacy. Secondary To compare IP plus IV chemotherapy versus IV carboplatin plus paclitaxel with respect to progression free survival and overall survival. OUTLINE: This is a multicenter study. Patients are stratified according to cooperative group, residual disease (observable [e.g., macroscopic] disease that is evident at end of delayed primary debulking surgery vs no evidence of observable disease at end of delayed primary debulking surgery), reason for delayed primary debulking surgery at initial diagnosis (nonresectable disease vs other reasons), and timing of intraperitoneal catheter insertion (intra-operative catheter insertion vs post-operative insertion). Phase II: Patients are randomized to 1 of 3 treatment groups. ARM 1: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intravenous day 1; Paclitaxel 60 mg/m2 intravenous day 8. Cycles given Q 21 days x 3 cycles ARM 2: Paclitaxel 135 mg/m2 intravenous day 1 plus Cisplatin 75 mg/m2 intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles (Phase II cisplatin arm closed to accrual on 2014-Feb-03) ARM 3: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles. Patients also receive carboplatin IP on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Expanded Phase II: Patients are randomized to 1 of 2 treatment groups. Arm I: Patients receive paclitaxel and carboplatin as in phase II, arm I. Arm III: Patients receive paclitaxel and cisplatin as in phase II, arm II or paclitaxel and carboplatin as in phase II, arm III. Patients complete quality of life questionnaires EORTC QLQ-C30, ovarian cancer module (EORTC QLQ-OV28), and FACT/GOG-Ntx at baseline, on day 1 of courses 2 and 3, at 3, 6 and 12 months after completion of study treatment, and then annually until disease progression, death, or initiation of second-line therapy. After completion of study treatment, patients are followed at 6 weeks, every 3 months for 2 years, every 6 months for 2 years, and then annually until progression, death, or initiation of second-line therapy.

Official Title
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A Phase II Study of Intraperitoneal (IP) Plus Intravenous (IV) Chemotherapy Versus IV Carboplatin Plus Paclitaxel in Patients With Epithelial Ovarian Cancer Optimally Debulked at Surgery Following Neoadjuvant Intravenous Chemotherapy

Conditions
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Fallopian Tube Cancer, Metastatic Cancer, Ovarian Cancer, Peritoneal Cavity Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: cisplatin
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed ovarian epithelial, primary serous type peritoneal, or fallopian tube carcinoma Patients with ovarian cancer of the clear cell histology are eligible. Histologic confirmation is preferably by biopsy or limited excision prior to neo-adjuvant treatment. If the diagnosis prior to neo-adjuvant chemotherapy is based on cytology, histologic confirmation is required prior to randomization. Histologic confirmation can be obtained at the time of debulking surgery by intra-operative frozen section, thus permitting intra-operative randomization, or by final pathologic review of the resected specimen if randomization is to be performed following debulking surgery. Initial FIGO stage IIB-III disease Stage IV disease allowed provided the only criterion for stage IV disease is the presence of a pleural effusion confirmed to be associated with positive cytology for ovarian cancer Completed ≥ 3 but no more than 4 courses of platinum-based neoadjuvant chemotherapy prior to the first debulking surgery Meets the following criteria for surgical treatment prior to randomization: Initial Diagnosis: No debulking surgery was attempted or completed. The patient's first cytoreductive (debulking) surgery must be after neoadjuvant chemotherapy (Delayed Primary Debulking). The delayed primary debulking surgery must be completed no more than 4 weeks after commencing administering of the last cycle of neoadjuvant chemotherapy and must be completed no more than 6 weeks prior to randomization. Surgery will include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and any additional procedures required to achieve maximal cytoreduction with residual disease of 1 cm or less as assessed by the surgeon at the end of surgery. Delayed primary debulking surgery must be completed no more than 4 weeks after the last course of neoadjuvant chemotherapy and must be completed no more than 6 weeks prior to randomization Surgery will include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and any additional procedures required to achieve maximal cytoreduction with residual disease of ≤ 1 cm as assessed by the surgeon at the end of surgery No borderline ovarian tumors (i.e., tumors of low malignant potential) alone No mucinous tumor PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 12 weeks Granulocyte count ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Serum creatinine ≤ upper limit of normal (ULN) OR > ULN to ≤ 1.25 ULN provided measured creatinine clearance is > 60 mL/min Serum bilirubin normal AST/ALT ≤ 2.5 times ULN Fertile patients must use effective contraception Able (i.e., sufficiently fluent) and willing to complete the quality of life questionnaires Accessible for treatment and follow-up No history of other malignancy, except adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years No uncontrolled atrial or ventricular arrhythmias including second or third degree heart block unless managed with implanted pacemaker Patients with a history of first degree heart block are eligible No documented myocardial infarction within the past 6 months preceding randomization (pretreatment ECG evidence only of infarct will not exclude patients) No diagnosis of bowel obstruction No serious illness or medical condition which would not permit the patient to be managed according to protocol including, but not limited to, any of the following: Prior allergic reactions to drugs containing cremophor or to compounds chemically related to cisplatin, paclitaxel, or carboplatin Symptomatic congestive heart failure within the past 6 months or other conditions which would lead to a contraindication of a high-volume saline diuresis History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent Active uncontrolled infection Persistent peripheral neuropathy or hearing loss ≥ grade 2 resulting from prior therapy Extensive intraperitoneal adhesion intra- or post-operatively which would impede intraperitoneal treatment delivery PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior therapy for ovarian cancer, except for neoadjuvant platinum-based chemotherapy and surgery No concurrent intraperitoneal adhesion barriers No other concurrent anticancer treatment, including cytotoxic agents, biological response modifiers, immunotherapy, anticancer hormone therapy, or investigational drug therapy No other concurrent experimental drugs or anticancer therapy

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IV carboplatin + IV paclitaxel<br>ARM 1: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intravenous day 1; Paclitaxel 60 mg/m2 intravenous day 8. Cycles given Q 21 days x 3 cycles | Drug: carboplatin<br>* Carboplatin AUC 5 if measured GFR or AUC6 if calculated GFR intravenous or intraperitoneal.<br>Drug: paclitaxel<br>* Paclitaxel 135 mg/m2 intravenous day 1 plus Paclitaxel 60 mg/m2 intraperitoneal or intravenously day 8. Cycles given Q 21 days x 3 cycles<br>|
| Active Comparator: IP cisplatin + IV/IP paclitaxel<br>ARM 2: Paclitaxel 135 mg/m2 intravenous day 1 plus Cisplatin 75 mg/m2 intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles (Phase II cisplatin arm closed to accrual on 2014-FEB-03) | Drug: cisplatin<br>* Cisplatin 75 mg/m2 intraperitoneal day 1<br>Drug: paclitaxel<br>* Paclitaxel 135 mg/m2 intravenous day 1 plus Paclitaxel 60 mg/m2 intraperitoneal or intravenously day 8. Cycles given Q 21 days x 3 cycles<br>|
| Active Comparator: IP carboplatin + IV/IP paclitaxel<br>ARM 3: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles | Drug: carboplatin<br>* Carboplatin AUC 5 if measured GFR or AUC6 if calculated GFR intravenous or intraperitoneal.<br>Drug: paclitaxel<br>* Paclitaxel 135 mg/m2 intravenous day 1 plus Paclitaxel 60 mg/m2 intraperitoneal or intravenously day 8. Cycles given Q 21 days x 3 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 9-month Progression Rate Post-randomization | It is defined as proportion of patients who had progressed at or before 9 months after randomization, i.e., the time from the randomization to the date when the first observation of disease progression (earliest of the date when the first CA 125 meets progression definition and the date of first objective relapse or progression, defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, recorded) has been documented or when death due to any cause has been observed was less than or equal to 9 months. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Time from the day of randomization until the time when first observation of disease progression (earliest of the dates of first CA125 which meets progression definition and first objective relapse or progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, has been documented or when death due to any cause has been observed. | During the study with median follow-up of 33 months | 
| Overall Survival | Time from the day of randomization to death from any cause. | During the study with median follow-up of 33 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peritoneal cavity cancer, fallopian tube cancer, stage II ovarian epithelial cancer, stage III ovarian epithelial cancer, stage IV ovarian epithelial cancer, malignant pleural effusion, ovarian clear cell cystadenocarcinoma, ovarian clear cell tumor with proliferating activity