Paclitaxel, Polyglutamate Paclitaxel, or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Peritoneal Cancer, or Fallopian Tube Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies paclitaxel to see how well it works compared to polyglutamate paclitaxel or observation only in treating patients with stage III or stage IV ovarian epithelial, peritoneal cancer, or fallopian tube cancer. Drugs used in chemotherapy, such as paclitaxel and polyglutamate paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Paclitaxel and polyglutamate paclitaxel may also stop the growth of ovarian epithelial or peritoneal cancer by blocking blood flow to the tumor. Sometimes, after treatment, the tumor may not need additional treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether paclitaxel is more effective than polyglutamate paclitaxel or observation only in treating ovarian epithelial, peritoneal, or fallopian tube cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether CT-2103 (polyglutamate paclitaxel) or paclitaxel, administered to women with advanced ovarian, primary peritoneal or fallopian tube cancer who have attained a clinically-defined complete response to primary platinum/taxane-based chemotherapy (consolidation/maintenance therapy) will reduce the death rate, compared to re-treatment at the time of documented disease progression. II. To determine if, in this clinical setting, CT-2103 produces a more favorable toxicity profile (with a particular focus on peripheral neuropathy as measured by the Gynecologic Oncology Group [GOG] NTX4) and superior quality-of-life (as measured by the Functional Assessment of Cancer Therapy-Ovarian [FACT-O]), compared to paclitaxel. SECONDARY OBJECTIVES: I. To explore the relationship between expression of several of the angiogenic markers and overall survival or progression-free survival in patients randomized to CT-2103, paclitaxel, or no treatment. II. To assess the association among the various tissue and serum markers of angiogenesis, and compare the ability of different combinations of these markers to predict patient outcome including overall survival and progression-free survival in patients randomized to CT-2103, paclitaxel, or no treatment. III. To bank deoxyribonucleic acid (DNA) from whole blood for research and evaluate the association between single nucleotide polymorphisms (SNPs) and measures of clinical outcome including overall survival, progression-free survival and adverse events. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive polyglutamate paclitaxel intravenously (IV) over 10-20 minutes on day 1. ARM II: Patients receive paclitaxel IV over 3 hours on day 1. ARM III: Patients receive no further anticancer treatment until evidence of disease progression. In arms I and II, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 10 years.

Official Title
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A Randomized Phase III Trial of Maintenance Chemotherapy Comparing 12, Monthly Cycles of Single Agent Paclitaxel or CT-2103 Versus No Treatment Until Documented Relapse in Women With Advanced Ovarian, Primary Peritoneal or Fallopian Tube Cancer Who Achieve a Complete Clinical Response to Primary Platinum/Taxane Chemotherapy

Conditions
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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 Serous Adenocarcinoma, Stage IIIA Fallopian Tube Cancer AJCC v7, Stage IIIA Ovarian Cancer AJCC v6 and v7, Stage IIIA Primary Peritoneal Cancer AJCC v7, Stage IIIB Fallopian Tube Cancer AJCC v7, Stage IIIB Ovarian Cancer AJCC v6 and v7, Stage IIIB Primary Peritoneal Cancer AJCC v7, Stage IIIC Fallopian Tube 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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* Other: Clinical Observation
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Drug: Paclitaxel Poliglumex
* Procedure: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a histologic diagnosis of primary peritoneal carcinoma, or stage III or IV epithelial ovarian or fallopian tube carcinoma, with either optimal (=< 1 cm residual disease) or suboptimal residual disease following initial surgery; all patients must have had appropriate surgery for ovarian, primary peritoneal or fallopian tube carcinoma with appropriate tissue available for histologic evaluation to confirm diagnosis and stage 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 tumor Adenocarcinoma not otherwise specified (NOS) Patients must have completed treatment within the past 12 weeks with at least 5 cycles and not more than 8 cycles of a platinum (IV or intraperitoneal [IP]) and paclitaxel or docetaxel-based combination chemotherapy and have no symptoms suggestive of persistent cancer, normal (no evidence of cancer) computed tomography (CT) scan of the abdomen/pelvis and normal cancer antigen 125 (CA-125) following this therapy Patients treated with neo-adjuvant platinum-taxane chemotherapy for a presumptive diagnosis of stage III or IV epithelial ovarian, primary peritoneal or, fallopian tube (by paracentesis, percutaneous biopsy or open biopsy) are eligible provided that they have undergone interval abdominal surgery after at least one but no more than six cycles of standard chemotherapy; such surgery must meet the same criteria as for those undergoing up front surgery, including tissue diagnosis for confirmation of primary tumor site and stage III or IV disease; also, patients must have received at least two cycles after interval abdominal surgery Absolute neutrophil count >= 1,500/ul, equivalent to Common Toxicity Criteria (CTCAE version [v]3.0) grade 1 Platelet count >= 100,000/ul Creatinine =< 1.5 times institutional upper limit of normal (ULN), CTCAE v3.0 grade 1 Bilirubin =< 1.5 times ULN, (CTCAE v3.0 grade 1) Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5 times ULN (CTCAE v3.0 grade 1) Alkaline phosphatase =< 2.5 times ULN (CTCAE v3.0 grade 1) Neuropathy (sensory and motor) less than or equal to CTCAE v3.0 grade 1 Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 Patients must have signed an approved informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization Patients must complete pre-entry assessments Exclusion Criteria: Patients with a current diagnosis of epithelial ovarian or fallopian tube tumor of low malignant potential (LMP) (Borderline carcinomas) are not eligible; patients with a prior diagnosis of a low malignant potential tumor that was surgically resected and who subsequently develop invasive adenocarcinoma are eligible, provided that they have not received prior chemotherapy for their ovarian LMP tumor Germ cell tumors, sex cord-stromal tumors, carcinosarcomas, mixed mullerian tumors or carcinosarcomas, metastatic carcinomas from other sites to the ovary and low malignant potential tumors including so called micropapillary serous carcinomas are not eligible 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 3 years prior to registration, and the patient remains free of recurrent or metastatic disease Patients who have received investigational therapies, and/or biological therapies (i.e. Bevacizumab or Erlotinib) for their epithelial ovarian, primary peritoneal or fallopian tube cancers or for any other abdominal or pelvic tumor, are not excluded; however, biologics cannot be continued concurrent with the GOG-012 maintenance treatment (or observation); patients who have received prior chemotherapy for any other abdominal or pelvic tumor (except as noted above) are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than 3 years prior to registration, and that the patient remains free of recurrent or metastatic disease 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 I-B Less than 3 mm invasion without vascular or lymphatic invasion No poorly differentiated subtypes, including papillary serous, clear cell, or other Federation of Gynecology and Obstetrics (FIGO) Grade 3 lesions With the exception of non-melanoma skin cancer and other specific malignancies as noted above, patients with other invasive malignancies who had (or have) any evidence of the other cancer present within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy are excluded Patients with acute hepatitis, or known chronic hepatitis Patients with an active infection that requires antibiotics Patients with ongoing gastrointestinal bleeding requiring blood product support Patients whose circumstances at the time of entry onto the protocol would not permit completion of study or required follow up Patients with unstable angina or those who have had a myocardial infarction within the past six months; patients with evidence of abnormal cardiac conduction (e.g. bundle branch block, heart block) are eligible if their disease has been stable for the past six months Patients are excluded who have had prior therapy with CT-2103 Patients with active bleeding or an unexplained prothrombin time (PT) or partial thromboplastin time (PTT) > institutional upper limit normal (ULN) Patients who are pregnant or nursing are excluded; patients who may become pregnant must practice an effective method of birth control
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 poliglumex)<br>Patients receive polyglutamate paclitaxel IV over 10-20 minutes on day 1.Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel Poliglumex<br>* Given IV<br>* Other names: Xyotax;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Active Comparator: Arm II (paclitaxel)<br>Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Other: Arm III (observation)<br>Patients receive no further anticancer treatment until evidence of disease progression. | Other: Clinical Observation<br>* Undergo observation<br>* Other names: observation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: 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 |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last follow-up were censored on the date of last contact. | All patients were followed (with physical exams and histories) every three months for the first two years, then every six months for the next three years and then annually for the next five years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) was defined as the number of months between study enrollment and the date of first clinical, biochemical, or radiological evidence of progression or death due to any cause. Patients who were alive without progression at the time of analysis were censored on the date of the last tumor assessment. | Progression was assessed every 8 weeks for the first 15 months, then every 3 months, up to 14.2 years. | 
| Frequency and Severity of Adverse Effects Assessed by CTCAE v3.0 | Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy among adverse event terms with at least 4 patients reporting. | Measured within 6 months of enrollment; through all cycles of chemotherapy and up to 30 days after the last cycle of chemotherapy. Up to 10 cycles of chemotherapy were allowed. Cycles were to be repeated every 3 weeks. | 
| Patient-Reported Quality of Life (QOL) | Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-En TOI is a scale for assessing general QOL of ovarian cancer patients. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL. | 1. Prior to treatment 2. Prior to cycle 3 3. Prior to cycle 5 4. Prior to cycle 7 5. Prior to cycle 12 6. 12 months post treatment | 
| Patient-Reported Peripheral Neuropathy Symptoms | Patient reported peripheral neuropathy symptoms was measured with the Functional Assessment of Cancer Therapy/ Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms. | 1. Prior to treatment 2. Prior to cycle 3 3. Prior to cycle 5 4. Prior to cycle 7 5. Prior to cycle 12 6. 12 months post treatment |