Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II-III Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies bevacizumab and intravenous (given into a vein) chemotherapy to see how well they work compared with bevacizumab and intraperitoneal (given into the abdominal cavity) chemotherapy in treating patients with stage II-III ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer. Monoclonal antibodies, such as bevacizumab, can block the ability of tumor cells to grow and spread by blocking the growth of new blood vessels necessary for tumor growth. 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. It is not yet known whether giving bevacizumab together with intravenous chemotherapy is more effective than giving bevacizumab together with intraperitoneal chemotherapy in treating patients with ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if one or both of the proposed intraperitoneal chemotherapy regimens improves the progression-free survival (PFS) event rate compared to standard intravenous chemotherapy for first-line treatment of patients diagnosed with advanced stage ovarian, peritoneal or fallopian tube cancer. II. If both intraperitoneal (IP) regimens significantly improve the PFS event rate compared to the standard regimen, then a second study objective is to determine whether IP cisplatin and intravenous (IV) paclitaxel on day one plus IP paclitaxel on day eight improves the PFS event rate when compared to the IP carboplatin and IV paclitaxel. SECONDARY OBJECTIVES: I. To determine if intraperitoneal chemotherapy reduces the overall death rate compared to standard intravenous chemotherapy. II. To assess the frequency and severity of adverse events as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. III. To compare the patient-reported outcomes on: Quality of Life (Function Assessment of Cancer Therapy-Ovarian-Trial Outcome Index [FACT-O-TOI]), Neuropathy (FACT-Gynecologic Oncology Group/Neurotoxicity [GOG/NTX4] scale), Abdominal discomfort (FACT-GOG/AD scale), Fatigue (FACIT-Fatigue scale), and Nausea (item from FACT-O-TOI). IV. To assess the frequency and the reasons for early discontinuation of the study treatments. TERTIARY OBJECTIVES: I. To bank deoxyribonucleic acid (DNA) from whole blood for research and examine the association between single nucleotide polymorphisms (SNPs) and measures of clinical outcome including overall survival, progression-free survival and adverse events. II. To bank archival tumor for research and examine the association between tumor markers and measures of clinical outcome including overall survival, progression-free survival and adverse events. III. Patients will be encouraged to enroll on the companion translational research protocol (CEM0703 under development). OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1 in courses 2-6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone in courses 7-22 in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive paclitaxel as in Arm I and carboplatin IP on day 1. Patients also receive bevacizumab as in Arm I. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone as in Arm I. ARM III: Patients receive paclitaxel IV over 3 hours on day 1, cisplatin IP on day 2, and paclitaxel IP on day 8. Patients also receive bevacizumab as in Arm I. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone as in Arm I. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Official Title
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A Phase III Clinical Trial of Bevacizumab With IV Versus IP Chemotherapy in Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma

Conditions
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Malignant Ovarian Brenner Tumor, Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Mucinous Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mucinous Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Adenocarcinoma, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Primary Peritoneal Clear Cell Adenocarcinoma, Primary Peritoneal Endometrioid Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Primary Peritoneal Transitional Cell Carcinoma, Primary Peritoneal Undifferentiated Carcinoma, Stage II Fallopian Tube Cancer AJCC v6 and v7, Stage II Ovarian Cancer AJCC v6 and v7, Stage IIA Fallopian Tube Cancer AJCC v6 and v7, Stage IIA Ovarian Cancer AJCC V6 and v7, Stage IIB Fallopian Tube Cancer AJCC v6 and v7, Stage IIB Ovarian Cancer AJCC v6 and v7, Stage IIC Fallopian Tube Cancer AJCC v6 and v7, Stage IIC Ovarian Cancer AJCC v6 and v7, Stage III Ovarian Cancer AJCC v6 and v7, Stage III Primary Peritoneal Cancer AJCC v7, Stage IIIA Ovarian Cancer AJCC v6 and v7, Stage IIIA Primary Peritoneal Cancer AJCC v7, Stage IIIB Ovarian Cancer AJCC v6 and v7, Stage IIIB Primary Peritoneal Cancer AJCC v7, Stage IIIC Ovarian Cancer AJCC v6 and v7, Stage IIIC Primary Peritoneal Cancer AJCC v7, Stage IV Fallopian Tube Cancer AJCC v6 and v7, Stage IV Ovarian Cancer AJCC v6 and v7, Stage IV Primary Peritoneal Cancer AJCC v7

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Carboplatin
* Drug: Carboplatin
* Drug: Cisplatin
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Drug: Paclitaxel
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, stage II, III, or IV with either optimal (=< 1 cm residual disease) or suboptimal residual disease; in the event of a higher priority Phase III Gynecologic Oncology Group (GOG) protocol becoming available for suboptimal and/or stage IV patients, the eligibility of this study will narrow and exclude those patients at those participating institutions (11/02/2009) Note: patients with suboptimal disease/and or stage IV will not be eligible as of April 1, 2011; they should be enrolled on GOG-0262 (03/14/11) All patients must have a procedure for determining diagnosis of epithelial ovarian, fallopian tube, primary peritoneal, with appropriate tissue for histologic evaluation; the minimum surgery required is an abdominal surgery providing tissue for histologic evaluation and establishing and documenting the primary site and stage, as well as a maximal effort at tumor debulking; if additional surgery was performed, it should have been in accordance with appropriate surgery for ovarian or peritoneal carcinoma described in the GOG Surgical Procedures Manual (https://www.gog.fccc.edu/manuals/pdf/surgman.pdf) (11/02/2009)(08/16/2010) Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S.); however, the histologic features of the tumor must be compatible with a primary Müllerian epithelial adenocarcinoma; if doubt exists, it is recommended that the investigator should have the slides reviewed by an independent pathologist prior to entry; patients may have co-existing endometrial cancer so long as the primary origin of invasive tumor is ovarian or peritoneal; Note: patients with mucinous, low grade and clear cell disease are eligible unless there is a higher priority GOG trial open (11/02/2009) (08/16/2010) Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl, equivalent to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) grade 1; this ANC cannot have been induced or supported by granulocyte colony stimulating factors Platelets greater than or equal to 100,000/mcl Creatinine no greater than institutional upper limits of normal (03/29/10) Bilirubin less than or equal to 1.5 x upper limit of normal (ULN) (CTCAE grade 1) Alanine aminotransferase (ALT), aspartate aminotransferase (AST) less than or equal to 2.5 x ULN (CTCAE grade 1) Alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE grade 1) Neuropathy (sensory and motor) less than or equal to CTCAE grade 1 Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) =< 1.5 times the upper limit of normal (heparin, Lovenox or alternative anticoagulants are acceptable); this corresponds to CTCAE version 3.0 grade 1 one or less (11/02/2009) (03/29/10) Patients with a GOG performance status of 0, 1, or 2 Patients must be entered and treated within 12 weeks of their most recent surgery performed for the combined purpose of diagnosis, staging and/or cytoreduction; the first cycle of chemotherapy should not be given until at least seven days after the most recent major surgery, which allows 4 weeks to have elapsed prior to the first bevacizumab dose; (placement of venous or peritoneal access devices will be considered minor surgery) (03/29/10) Patients who have met the pre-entry requirements specified An approved informed consent and authorization permitting release of personal health information must be signed by the patient or guardian Patients in this trial may receive ovarian estrogen +/- progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time, but high dose progestin as an appetite stimulant should be avoided (03/29/10) Exclusion Criteria: Patients with a current diagnosis of borderline epithelial ovarian tumor (formerly tumors of low malignant potential) or recurrent invasive epithelial ovarian cancer treated with surgery only (such as those with stage IA or IB low grade lesions) are not eligible; patients with a prior diagnosis of a borderline tumor that was surgically resected and who subsequently develop an unrelated, new invasive epithelial ovarian or peritoneal primary cancer are eligible, provided that they have not received prior chemotherapy for any ovarian tumor Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies are excluded if there is any evidence of the other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy (11/02/2009) Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease Patients who have received prior chemotherapy for any abdominal or pelvic tumor including neo-adjuvant chemotherapy for their ovarian or primary peritoneal cancer are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: stage not greater than IB; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other FIGO grade 3 lesions Patients with acute hepatitis or active infection that requires parenteral antibiotics Patients with serious non-healing wound, ulcer, or bone fracture; this includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days; patients with granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are eligible but require weekly wound examinations Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels Patients with history or evidence upon physical examination of major central nervous system (CNS) disease (for example: primary brain tumor, metastatic cancer in the brain, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident [CVA, stroke], transient ischemic attack [TIA] or subarachnoid hemorrhage within six months of the first date of treatment on this study) (11/02/2009) (03/29/10) Patients with clinically significant cardiovascular disease; this includes: Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mmHg Myocardial infarction or unstable angina < 6 months prior to registration New York Heart Association (NYHA) grade II or greater congestive heart failure Serious cardiac arrhythmia requiring medication; this does not include asymptomatic atrial fibrillation with controlled ventricular rate, or past history of supraventricular tachycardia controlled with medications and that is asymptomatic (03/29/10) CTCAE grade 2 or greater peripheral vascular disease (at least brief (< 24 hrs) episodes of ischemia managed non-surgically and without permanent deficit) Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies; patients with known allergy to Cremophor or polysorbate 80 Patients with clinically significant proteinuria; urine protein should be screened by urine protein-creatinine ratio (UPCR); patients must have a UPCR < 1.0 to allow participation in the study Patients with or with anticipation of invasive procedures as defined below: Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the first date of bevacizumab therapy (cycle 2) Major surgical procedure anticipated during the course of the study; this includes, but is not limited to abdominal surgery (laparotomy or laparoscopy) prior to disease progression, such as colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or second look surgery Core biopsy, within 7 days prior to the first date of bevacizumab therapy (cycle 2) Patients with GOG performance grade of 3 or 4 Patients who are pregnant or nursing; patients of childbearing potential must agree to use contraceptive measures during study therapy and for at least six months after completion of bevacizumab therapy Patients who have received prior therapy with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab Patients with clinical symptoms or signs of gastrointestinal obstruction and/ or those who require parenteral hydration and/or nutrition; patients with history or current diagnosis of inflammatory bowel disease are not eligible (12/20/10) Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study; examples of this would be: persistent gastrointestinal symptoms resulting from clostridia difficile enterocolitis or bowel surgery which may increase gastrointestinal toxicity from bevacizumab; or hearing loss or neuropathy which would prevent tolerance to cisplatin, and paclitaxel administration; the investigator should feel free to consult the Study Chair or Study Co-Chairs for uncertainty in this regard (12/20/10) Patients with metastatic tumor in the parenchyma of the liver or lungs with proximity to large vessels which could make the patient as high risk of lethal hemorrhage during treatment with bevacizumab (i.e. hemoptysis, liver rupture) (11/02/2009)

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 |
| --- | --- |
| Experimental: Arm I (paclitaxel, carboplatin, bevacizumab)<br>Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1 in courses 2-6. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone in courses 7-22 in the absence of disease progression or unacceptable toxicity. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (paclitaxel, bevacizumab, carboplatin IP)<br>Patients receive paclitaxel as in Arm I and carboplatin IP on day 1. Patients also receive bevacizumab as in Arm I. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone as in Arm I. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Carboplatin<br>* Given IP<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm III (paclitaxel IP, bevacizumab, cisplatin IP)<br>Patients receive paclitaxel IV over 3 hours on day 1, cisplatin IP on day 2, and paclitaxel IP on day 8. Patients also receive bevacizumab as in Arm I. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone as in Arm I. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Drug: Cisplatin<br>* Given IP<br>* Other names: Platosin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Drug: Paclitaxel<br>* Given IP<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival | Estimate the median duration of progression-free survival in months. Progression is 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. | Progression-free survival is measured from date of randomization until first indication of progression based on RECIST criteria or death from any cause, or if progression-free at last contact, the date of last disease assessment up to 10 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Adverse Events by Treatment Group, as Defined by NCI CTCAE (Common Terminology Criteria for Adverse Events Version 3.0) Version 3.0 | Eligible and treated patients. CTCAE includes grades 1-5. Grade refers to the severity of the adverse event. Grades 0 listed should be interpreted to mean there were no subjects in the arm with a toxicity to report. Grade 1 toxicities are mild; asymptomatic or mild symptoms. Grade 2 toxicities are moderate; minimal, local or noninvasive intervention indicated. Grade 3 toxicities are severe or medically significant but not immediately life-threatening. Grade 4 toxicities are life threatening. Grade 5 is death related to adverse event. | During treatment and up to 30 days after end of treatment | 
| Overall Survival | Estimate the median duration of overall survival in months. | Up to 10 years | 
| Patient Reported Quality of Life (QOL) | QOL was measured with the FACT-O TOI score. Means at baseline are raw means. Scores are reported at all time points in the outcome measure table. FACT-O TOI is Trial outcome index (TOI) of the Functional assessment of cancer therapy (FACT) for ovarian cancer (FACT-O). The FACT-O TOI is composed of three subscales; Physical Well Being (PWB) ( 7 items), and Ovarian Cancer subscale (OCS) (12 items). Each item in the FACT-O TOI are scored using a 5 point scale (0=not at all; 1=a little bit; 2=somewhat;3=quite a bit;4=very much). A subscale score is computed as long as more thatn 50% of subscale items have been answered. A total score of the FACT-O items provide valid responses and all three subscales have valid scores. A score of the FACT-) TOI is ranged 0-104 with a larger score indicating a more preferred state of health-related quality of life (HRQOL). | Time points: Baseline, prior to cycle 4, prior to cycle 7, prior to cycle 13, prior to cycle 21, up to 84 weeks post starting treatment | 
| Patient Reported Neurotoxicity (Ntx) | The FACT/GOG-NTX subscale (short version) contains 4 items measuring sensory neuropathy. Each item is scored using a 5 point Likert scale (0=not at all; 1=a little bit;2=somewhat;3=quite a bit; 4=very much). For each item, reversal was performed prior to score calculation so that a large score suggests less symptoms. According to the FACIT measurement system, the subscale score was calculated as the summation of the individual item scores if more than 50% of a subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the subscale. The Ntx subscale score ranges from 0-16 with a large subscale score suggesting less symptom or better QOL. | Time points: Baseline, prior to cycle 4, prior to cycle 7, prior to cycle 13, prior to cycle 21, 84 weeks post starting treatment | 
| Patient Reported Fatigue | Patient reported fatigue as measured with the Functional Assessment of Chronic Illness Therapy- Fatigue scale (FACIT-Fatigue). The FACIT-Fatigue contains 13 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative items, reversal was performed prior to score calculation. According to the FACIT measurement system, the Fatigue score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The FACIT-Fatigue score ranges 0-52 with a large score suggesting less fatigue. | Time points: Baseline, prior to cycle 4, prior to cycle 7, prior to cycle 13, prior to cycle 21, 84 weeks post starting treatment | 
| Patient Reported Nausea | Nausea was measured with the a single item ,' I have nausea' from the FACT-O TOI, and was scored using a 5 point scale (0=not at all; 1=a little bit; 2=somewhat;3=quite a bit;4=very much) | Time points: Baseline, prior to cycle 4, prior to cycle 7, prior to cycle 13, prior to cycle 21, 84 weeks post starting treatment |