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Carboplatin, Paclitaxel and Gemcitabine Hydrochloride With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian, Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel (or Gemcitabine) Alone or in Combination With Bevacizumab (NSC #704865) Followed by Bevacizumab and Secondary Cytoreductive Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer. NCI-Supplied Agents: Bevacizumab (NSC #704865)

Status
Active, not recruiting
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00565851
Enrollment
1052
Registered
2007-11-30
Start date
2007-12-06
Completion date
2028-01-01
Last updated
2025-12-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Clear Cell Adenocarcinoma, 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, Mucinous Adenocarcinoma, Ovarian Brenner Tumor, Ovarian Clear Cell Adenocarcinofibroma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid 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, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Undifferentiated Carcinoma

Brief summary

This randomized phase III trial studies carboplatin, paclitaxel and gemcitabine hydrochloride when given together with or without bevacizumab after surgery to see how well it works in treating patients with ovarian, epithelial, primary peritoneal, or fallopian tube cancer that has come back. Drugs used in chemotherapy, such as carboplatin, paclitaxel and gemcitabine hydrochloride work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether combination chemotherapy is more effective when given with or without bevacizumab after surgery in treating patients with ovarian, epithelial, primary peritoneal, or fallopian tube cancer.

Detailed description

PRIMARY OBJECTIVES: I. To determine if surgical secondary cytoreduction in addition to adjuvant chemotherapy increases the duration of overall survival in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer. II. To determine if the addition of bevacizumab to the second-line and maintenance phases of treatment increases the duration of overall survival relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer. SECONDARY OBJECTIVES: I. To determine if the addition of bevacizumab to the second-line and maintenance phase of treatment increases the duration of progression-free survival relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer. II. To prospectively determine the incidence of carboplatin and paclitaxel hypersensitivity in these patients undergoing retreatment with both agents as first recurrence therapy. III. To determine if surgical secondary cytoreduction in addition to adjuvant chemotherapy increases quality of life (QOL) in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer, as measured by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) trial outcome index and Rand Short Form (SF)-36 physical functioning scale. IV. To determine if the addition of bevacizumab to the second-line and maintenance phases of treatment increases QOL relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum-sensitive epithelial ovarian, peritoneal primary or fallopian tube cancer. TRANSLATIONAL RESEARCH OBJECTIVES: I. To define molecular and biochemical profiles associated with the duration of progression-free survival in platinum-sensitive recurrent ovarian, peritoneal primary or fallopian tube carcinoma treated with combination chemotherapy with or without bevacizumab followed with or without maintenance bevacizumab therapy in the presence or absence of secondary surgical cytoreduction. II. To identify molecular determinants that predict sensitivity or resistance to carboplatin and paclitaxel with or without bevacizumab followed with or without maintenance bevacizumab therapy. 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 assigned to 1 of 4 treatment groups. Patients who are not candidates for surgical cytoreduction (i.e., those for whom complete cytoreduction in the estimation of the investigator is impossible or a medical infirmity precludes exploration and debulking) are eligible to receive chemotherapy after randomization. Patients who are eligible for surgery undergo abdominal exploration with cytoreduction. Patients are then randomized to 1 of 4 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours or docetaxel IV over 1 hour and carboplatin IV over 60 minutes on day 1. ARM II: Patients receive chemotherapy as in Arm I and bevacizumab IV over 30-90 minutes on day 1. ARM III: Patients receive gemcitabine hydrochloride IV over 60 minutes on days 1 and 8 and carboplatin as in Arm I. ARM IV: Patients receive gemcitabine hydrochloride IV as in Arm III, bevacizumab IV and carboplatin IV as in Arm II. In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with measurable disease achieving a clinical response (CR) receive 6-8 courses of therapy. Patients with stable disease or partial regression receive a maximum of 8 courses. Patients without measurable lesions as determined by a computed tomography (CT) scan prior to initiating study treatment continue therapy for 6 courses or, if cancer antigen (CA)-125 normalizes, for 2 courses beyond CA-125 normalization, whichever is greater. Patients in Arm II then receive a maintenance regimen comprising bevacizumab IV over 30-90 minutes. Treatment with bevacizumab alone repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years.

Interventions

BIOLOGICALBevacizumab

Given IV

DRUGCarboplatin

Given IV

DRUGDocetaxel

Given IV

DRUGGemcitabine Hydrochloride

Given IV

OTHERLaboratory Biomarker Analysis

Correlative studies

DRUGPaclitaxel

Given IV

OTHERQuality-of-Life Assessment

Ancillary studies

Sponsors

NRG Oncology
CollaboratorOTHER
National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

* Patients enrolled after August 28, 2011 must be candidates for cytoreductive surgery and consent to have their surgical treatment determined by randomization * Patients must have histologic diagnosis of epithelial ovarian carcinoma, peritoneal primary or fallopian tube carcinoma, which is now recurrent * 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.) * Patients must have had a complete response to front-line platinum-taxane therapy (at least three cycles) * A complete response to front-line chemotherapy must include: negative physical exam, negative pelvic exam and normalization of CA125, if elevated at baseline; although not required, any radiographic assessment of disease status (e.g. CT, magnetic resonance imaging \[MRI\], positron emission tomography \[PET\]/CT, etc) obtained following the completion of primary therapy should be considered negative for disease * All patients must have also had a treatment-free interval without clinical evidence of progressive disease of at least 6 months from completion of front-line chemotherapy (both platinum and taxane); front-line therapy may have included a biologic agent (i.e. bevacizumab) * Front-line treatment may include maintenance therapy following complete clinical or pathological response; however, maintenance cytotoxic chemotherapy must be discontinued for a minimum of 6 months prior to documentation of recurrent disease; patients receiving maintenance biological therapy or hormonal therapy are ELIGIBLE provided their recurrence is documented more than 6 months from primary cytotoxic chemotherapy completion (includes maintenance chemotherapy) AND a minimum 4 weeks has elapsed since their last infusion of biological therapy * Patients must have clinically evident recurrent disease for the purpose of this study * Measurable disease (Response Evaluation Criteria in Solid Tumors \[RECIST\]) is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be more than or equal to 20 mm when measured by conventional techniques, MRI or CT, or more than or equal to 10 mm when measured by spiral CT * Absolute neutrophil count (ANC) greater than or equal to 1,500/mm\^3, equivalent to Common Toxicity Criteria for Adverse Events version (v)4.0 (CTCAE) grade 1 * Platelets greater than or equal to 100,000/mm\^3 (CTCAE grade 0-1) * Creatinine (non-isotope dilution mass spectrometry \[IDMS\]) =\< 1.5 x institutional upper limit normal (ULN), CTCAE grade 1 * Total bilirubin =\< 1.5 ULN (CTCAE grade 1) * Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) =\< 2.5 times the upper limit of normal in the absence of liver metastasis; SGOT/AST \< 5.0 times ULN in the presence of liver metastasis * Alkaline phosphatase =\< 2.5 times the upper limit of normal in the absence of liver metastasis; alkaline phosphatase \< 5.0 times ULN in the presence of liver metastasis * This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients must have a urine protein-to-creatinine ratio (UPCR) \< 1.0 mg/dL * This eligibility criterion does not apply to patients enrolled after August 28, 2011; patients who are not candidates for surgical cytoreduction are eligible for the chemotherapy randomization; patients are not considered candidates for surgical cytoreduction if complete cytoreduction in the estimation of the investigator is impossible or a medical infirmity precludes exploration and debulking * Patients must have met the pre-entry requirements as specified * Patients must have signed an approved informed consent and authorization permitting release of personal health information * Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2

Exclusion criteria

* Patients who have received more than one previous regimen of chemotherapy (maintenance is not considered a second regimen) * Patients receiving concurrent immunotherapy, or radiotherapy * Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded * Patients whom have already undergone secondary cytoreduction for recurrent disease are excluded * Patients with a prior histologic diagnosis of borderline, low malignant potential (grade 0) epithelial carcinoma that was surgically resected and who subsequently developed an unrelated, new invasive epithelial ovarian or peritoneal primary cancer are eligible provided that they meet the criteria listed above * Patients who require parenteral hydration or nutrition and have evidence of partial bowel obstruction or perforation * Patients who have received prior chemotherapy for any abdominal or pelvic tumor (other than ovarian, fallopian tube, and primary peritoneal) are excluded * 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; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other International Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions * Patients with uncontrolled infection * Patients with concurrent severe medical problems unrelated to the malignancy that would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy * Patients with \>= grade 2 peripheral neuropathy * Patients with a history of allergic reactions to carboplatin and/or paclitaxel or chemically similar compounds; patients with allergic (hypersensitivity) reactions to these chemotherapeutic agents are NOT excluded IF they were successfully retreated following a desensitization program or protocol * This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies * Patients of childbearing potential, not practicing adequate contraception, patients who are pregnant or patients who are nursing are not eligible for this trial; to date, no fetal studies in animal or humans have been performed; the possibility of harm to a fetus is likely; bevacizumab specifically inhibits VEGF, which is responsible for the formation of new blood vessels during development, and antibodies can cross the placenta; therefore, bevacizumab should not be administered to pregnant women; in addition, there are unknown immediate and long-term consequences of chemotherapy administration to these women; in addition, surgical exploration as mandated by randomization during pregnancy may cause imminent mortal consequences; further, it is not known whether bevacizumab is excreted in human milk; because many drugs are excreted in human milk, bevacizumab should not be administered to nursing women; subjects will be apprised of the large potential risk to a developing fetus * Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, 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 * This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with active bleeding or pathologic conditions that carry high risk of bleeding such as a known bleeding disorder, coagulopathy, or tumor involving major vessels * This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with a history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases or a history of stroke within 5 years of the first date of treatment on this study * This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with clinically significant cardiovascular disease; this includes: * Patients with significant cardiac conduction abnormalities, i.e. PR interval \> 0.24 seconds (sec) or 2nd or 3rd degree atrioventricular (AV) block * Uncontrolled hypertension, defined as systolic \> 150 mm Hg or diastolic \> 90 mm Hg * Myocardial infarction, cardiac arrhythmia 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 * Grade II or greater peripheral vascular disease (exception: episodes of ischemia \< 24 hours \[hrs\] in duration, that are managed non-surgically and without permanent deficit) * History of cerebrovascular attack (CVA) within six months * This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients who have had a major surgical procedure, open biopsy, dental extractions or other dental surgery/procedure that results in an open wound, or significant traumatic injury within 28 days prior to the first date of treatment on this study, or anticipation of need for major surgical procedure during the course of the study; patients with placement of vascular access device or core biopsy within 7 days prior to the first date of treatment on this study * Patients undergoing pre-treatment secondary cytoreduction will undergo therapy with bevacizumab on cycle #2 * Patients undergoing pre-treatment surgery for purposes other than cytoreduction may also participate provided they meet eligibility; patients randomized to arms containing bevacizumab must wait a minimum of 28 days since that procedure to begin protocol treatment; patients who undergo an uncomplicated port placement must wait a minimum of 7 days to begin protocol treatment

Design outcomes

Primary

MeasureTime frameDescription
To Determine if Surgical Secondary Cytoreduction in Addition to Adjuvant Chemotherapy Increases the Duration of Overall Survival in Patients With Recurrent Platinum Sensitive Epithelial Ovarian Cancer, Peritoneal Primary or Fallopian Tube CancerThe time frame is 82.5 months (median duration of follow-up)The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs \> 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method.
To Determine if the Addition of Bevacizumab Increases the Duration of Overall Survival Relative to Second-line Paclitaxel and Carboplatin Alone in Patients With Recurrent Platinum Sensitive Epithelial Ovarian, Peritoneal Primary or Fallopian Tube CancerThe time frame is 82.5 months (median duration of follow-up).The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs \> 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method.

Secondary

MeasureTime frameDescription
Summary of Adverse Events (CTCAE Version 4.0)During treatment period and up to 100 days after stopping the study treatment, a median duration of 82.5 monthsNumber of treated patients with at least one adverse event reported (assessed by Common Terminology Criteria for Adverse Events (version 4.0))
Patient Reported Quality of Life (Chemotherapy Analysis)1. Prior to cycle 1 (baseline), 2. Prior to cycle 3 (6 weeks post cycle 1), 3. Prior to cycle 6 (15 weeks post cycle 1), 4. 6 months post cycle 1, 5. 12 months post cycle 1.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-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL.
Progression-free Survival (Chemotherapy Analysis)Radiographic assessment of disease was conducted during chemotherapy and then every 6 months during the maintenance / surveillance phaseProgression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause.
Patient Reported Quality of Life (Surgery Analysis)1. Prior to surgery, 2. 6 weeks post-surgery, 3. 15 weeks post-surgery, 4. 6 months post-surgery, 5. 12 months post-surgery.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-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL.
Patient Reported Physical Functioning (Surgery Analysis)1. Prior to surgery (baseline), 2. 6 weeks post-surgery, 3. 15 weeks post-surgery 4. 6 months post-surgery, 5. 12 months post-surgeryPatient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning. This measure was completed by US patients only.
Patient Reported Physical Function (Chemotherapy Analysis)1. Prior to cycle 1 (baseline), 2. Prior to cycle 3 (6 weeks post cycle 1), 3. Prior to cycle 6 (15 weeks post cycle 1), 4. 6 months post cycle 1, 5. 12 months post cycle 1.Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning Subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning.
Progression Free Survival (Surgery Analysis)Radiographic assessment of disease (in patients with measurable and non-measurable disease) was conducted Every three months for two years and then every 6 months after completion of chemotherapy during the maintenance/surveillance phase.Progression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause.

Countries

Japan, South Korea, United States

Participant flow

Recruitment details

At the beginning of the study participants could be randomized to chemotherapy. On August 29, 2011 randomization to chemotherapy ended and participants could only be randomized to surgery.

Participants by arm

ArmCount
Arm I (no Surgery; Carboplatin and Paclitaxel)
Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients are not in secondary cytoreductive surgery portion of study. Carboplatin: Given IV Docetaxel: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Quality-of-Life Assessment: Ancillary studies
316
Arm II (no Surgery; Carboplatin, Paclitaxel and Bevacizumab)
Patients receive chemotherapy as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days. Patients are not in secondary cytoreductive surgery portion of study. Bevacizumab: Given IV Carboplatin: Given IV Docetaxel: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Quality-of-Life Assessment: Ancillary studies
456
Arm III (Surgery; Carboplatin and Paclitaxel)
Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery. Carboplatin: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Quality-of-Life Assessment: Ancillary studies
33
Arm IV (Surgery; Carboplatin, Paclitaxel and Bevacizumab)
Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery. Bevacizumab: Given IV Carboplatin: Given IV Docetaxel: Given IV Laboratory Biomarker Analysis: Correlative studies Paclitaxel: Given IV Quality-of-Life Assessment: Ancillary studies
165
Arm V (no Surgery; Carboplatin and Gemcitabine)
Patients receive carboplatin as in arm I. Patients receive gemcitabine. Treatment repeats every 21 days. Patients do not receive secondary cytoreductive surgery. Carboplatin: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies
6
Arm VI (no Surgery; Carboplatin, Gemcitabine and Bevacizumab))
Patients receive carboplatin as in arm I and bevacizumab IV over 30-90 minutes on day 1. Patients receive gemcitabine. Treatment repeats every 21 days. Patients do not receive secondary cytoreductive surgery. Bevacizumab: Given IV Carboplatin: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies
34
Arm VII (Surgery; Carboplatin and Gemcitabine)
Patients receive carboplatin as in arm I. Patients receive gemcitabine. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery. Carboplatin: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies
5
Arm VIII (Surgery; Carboplatin, Gemcitabine and Bevacizumab))
Patients receive carboplatin as in arm I and bevacizumab IV over 30-90 minutes on day 1. Patients receive gemcitabine. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery. Bevacizumab: Given IV Carboplatin: Given IV Gemcitabine Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies
37
Total1,052

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003FG004FG005FG006FG007
Chemotherapy AssignmentNever Initiated Chemotherapy993180202
Chemotherapy AssignmentStill On Chemotherapy0140180101

Baseline characteristics

CharacteristicArm III (Surgery; Carboplatin and Paclitaxel)Arm IV (Surgery; Carboplatin, Paclitaxel and Bevacizumab)Arm V (no Surgery; Carboplatin and Gemcitabine)Arm I (no Surgery; Carboplatin and Paclitaxel)Arm VI (no Surgery; Carboplatin, Gemcitabine and Bevacizumab))Arm VII (Surgery; Carboplatin and Gemcitabine)Arm II (no Surgery; Carboplatin, Paclitaxel and Bevacizumab)Arm VIII (Surgery; Carboplatin, Gemcitabine and Bevacizumab))Total
Age, Continuous58.7 years
STANDARD_DEVIATION 10
57.1 years
STANDARD_DEVIATION 10.5
72.1 years
STANDARD_DEVIATION 7.4
60.9 years
STANDARD_DEVIATION 10
58.7 years
STANDARD_DEVIATION 8.2
60.7 years
STANDARD_DEVIATION 9.3
59.0 years
STANDARD_DEVIATION 10.3
61.1 years
STANDARD_DEVIATION 9.5
59.4 years
STANDARD_DEVIATION 10.2
Age, Customized
40 - 49 years
6 Participants37 Participants0 Participants40 Participants6 Participants1 Participants68 Participants6 Participants164 Participants
Age, Customized
< 40 years
0 Participants7 Participants0 Participants4 Participants0 Participants0 Participants14 Participants0 Participants25 Participants
Age, Customized
50 - 59 years
11 Participants57 Participants1 Participants102 Participants14 Participants1 Participants170 Participants9 Participants365 Participants
Age, Customized
60 - 69 years
10 Participants44 Participants0 Participants111 Participants12 Participants2 Participants143 Participants13 Participants335 Participants
Age, Customized
70 - 79 years
6 Participants19 Participants5 Participants52 Participants2 Participants1 Participants54 Participants9 Participants148 Participants
Age, Customized
≥ 80 years
0 Participants1 Participants0 Participants7 Participants0 Participants0 Participants7 Participants0 Participants15 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
0 Participants6 Participants0 Participants14 Participants0 Participants0 Participants22 Participants4 Participants46 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
30 Participants155 Participants6 Participants272 Participants34 Participants5 Participants409 Participants32 Participants943 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
3 Participants4 Participants0 Participants30 Participants0 Participants0 Participants25 Participants1 Participants63 Participants
Histology
Clear Cell
1 Participants5 Participants0 Participants13 Participants0 Participants0 Participants14 Participants0 Participants33 Participants
Histology
Endometrioid
0 Participants9 Participants1 Participants25 Participants2 Participants0 Participants24 Participants2 Participants63 Participants
Histology
Mucinous
0 Participants0 Participants0 Participants2 Participants0 Participants0 Participants2 Participants0 Participants4 Participants
Histology
Other
2 Participants9 Participants0 Participants24 Participants2 Participants1 Participants33 Participants0 Participants71 Participants
Histology
Serous
30 Participants142 Participants5 Participants252 Participants30 Participants4 Participants383 Participants35 Participants881 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants1 Participants0 Participants0 Participants5 Participants0 Participants6 Participants
Race (NIH/OMB)
Asian
6 Participants101 Participants0 Participants39 Participants14 Participants1 Participants136 Participants10 Participants307 Participants
Race (NIH/OMB)
Black or African American
1 Participants4 Participants1 Participants15 Participants3 Participants1 Participants17 Participants2 Participants44 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants0 Participants1 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants3 Participants0 Participants6 Participants0 Participants0 Participants3 Participants0 Participants12 Participants
Race (NIH/OMB)
White
26 Participants57 Participants5 Participants255 Participants17 Participants3 Participants294 Participants25 Participants682 Participants
Region of Enrollment
Japan
0 Participants7 Participants0 Participants12 Participants0 Participants0 Participants24 Participants0 Participants43 Participants
Region of Enrollment
Russia
0 Participants1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants
Region of Enrollment
South Korea
4 Participants90 Participants0 Participants20 Participants11 Participants0 Participants108 Participants9 Participants242 Participants
Region of Enrollment
United States
29 Participants67 Participants6 Participants284 Participants23 Participants5 Participants324 Participants28 Participants766 Participants
Sex: Female, Male
Female
33 Participants165 Participants6 Participants316 Participants34 Participants5 Participants456 Participants37 Participants1052 Participants
Sex: Female, Male
Male
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
EG006
affected / at risk
EG007
affected / at risk
deaths
Total, all-cause mortality
253 / 316299 / 45628 / 3356 / 1654 / 614 / 344 / 521 / 37
other
Total, other adverse events
304 / 316376 / 45629 / 3377 / 1653 / 69 / 343 / 59 / 37
serious
Total, serious adverse events
37 / 316104 / 4561 / 3324 / 1650 / 61 / 342 / 52 / 37

Outcome results

Primary

To Determine if Surgical Secondary Cytoreduction in Addition to Adjuvant Chemotherapy Increases the Duration of Overall Survival in Patients With Recurrent Platinum Sensitive Epithelial Ovarian Cancer, Peritoneal Primary or Fallopian Tube Cancer

The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs \> 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method.

Time frame: The time frame is 82.5 months (median duration of follow-up)

Population: All patients who were eligible for the surgery analysis (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol)

ArmMeasureValue (MEDIAN)
No Cytoreductive SurgeryTo Determine if Surgical Secondary Cytoreduction in Addition to Adjuvant Chemotherapy Increases the Duration of Overall Survival in Patients With Recurrent Platinum Sensitive Epithelial Ovarian Cancer, Peritoneal Primary or Fallopian Tube Cancer64.7 Months
Cytoreductive SurgeryTo Determine if Surgical Secondary Cytoreduction in Addition to Adjuvant Chemotherapy Increases the Duration of Overall Survival in Patients With Recurrent Platinum Sensitive Epithelial Ovarian Cancer, Peritoneal Primary or Fallopian Tube Cancer50.6 Months
Primary

To Determine if the Addition of Bevacizumab Increases the Duration of Overall Survival Relative to Second-line Paclitaxel and Carboplatin Alone in Patients With Recurrent Platinum Sensitive Epithelial Ovarian, Peritoneal Primary or Fallopian Tube Cancer

The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs \> 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method.

Time frame: The time frame is 82.5 months (median duration of follow-up).

Population: All patients who were enrolled between December 10, 2007 and August 26, 2011 and received paclitaxel and carboplatin (with or without bevacizumab) (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

ArmMeasureValue (MEDIAN)
No Cytoreductive SurgeryTo Determine if the Addition of Bevacizumab Increases the Duration of Overall Survival Relative to Second-line Paclitaxel and Carboplatin Alone in Patients With Recurrent Platinum Sensitive Epithelial Ovarian, Peritoneal Primary or Fallopian Tube Cancer37.3 Months
Cytoreductive SurgeryTo Determine if the Addition of Bevacizumab Increases the Duration of Overall Survival Relative to Second-line Paclitaxel and Carboplatin Alone in Patients With Recurrent Platinum Sensitive Epithelial Ovarian, Peritoneal Primary or Fallopian Tube Cancer42.2 Months
Secondary

Patient Reported Physical Function (Chemotherapy Analysis)

Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning Subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning.

Time frame: 1. Prior to cycle 1 (baseline), 2. Prior to cycle 3 (6 weeks post cycle 1), 3. Prior to cycle 6 (15 weeks post cycle 1), 4. 6 months post cycle 1, 5. 12 months post cycle 1.

Population: Provided baseline and at least one follow-up assessments (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

ArmMeasureGroupValue (LEAST_SQUARES_MEAN)Dispersion
No Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)Prior to cycle 373.2 score on a scaleStandard Error 2.1
No Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)6 months post cycle 171.6 score on a scaleStandard Error 2.2
No Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)Prior to cycle 671.5 score on a scaleStandard Error 2.2
No Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)12 months post cycle 171.8 score on a scaleStandard Error 2.2
No Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)Prior to cycle 1 (baseline)71.5 score on a scaleStandard Error 1.6
Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)12 months post cycle 170.7 score on a scaleStandard Error 2.2
Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)Prior to cycle 1 (baseline)69.4 score on a scaleStandard Error 1.7
Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)Prior to cycle 369.8 score on a scaleStandard Error 2.1
Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)Prior to cycle 664.6 score on a scaleStandard Error 2.2
Cytoreductive SurgeryPatient Reported Physical Function (Chemotherapy Analysis)6 months post cycle 170.2 score on a scaleStandard Error 2.1
Secondary

Patient Reported Physical Functioning (Surgery Analysis)

Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning. This measure was completed by US patients only.

Time frame: 1. Prior to surgery (baseline), 2. 6 weeks post-surgery, 3. 15 weeks post-surgery 4. 6 months post-surgery, 5. 12 months post-surgery

Population: US patients who provided baseline and ≥ 1 follow-up assessments (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol).

ArmMeasureGroupValue (LEAST_SQUARES_MEAN)Dispersion
No Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)6 weeks post-surgery73.2 score on a scaleStandard Error 2.1
No Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)6 months post-surgery71.6 score on a scaleStandard Error 2.2
No Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)15 weeks post-surgery71.5 score on a scaleStandard Error 2.2
No Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)12 months post-surgery71.8 score on a scaleStandard Error 2.2
No Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)Prior to surgery (baseline)73.4 score on a scaleStandard Error 2.3
Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)12 months post-surgery70.7 score on a scaleStandard Error 2.2
Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)Prior to surgery (baseline)71.7 score on a scaleStandard Error 2.3
Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)6 weeks post-surgery69.8 score on a scaleStandard Error 2.1
Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)15 weeks post-surgery64.6 score on a scaleStandard Error 2.2
Cytoreductive SurgeryPatient Reported Physical Functioning (Surgery Analysis)6 months post-surgery70.2 score on a scaleStandard Error 2.1
Secondary

Patient Reported Quality of Life (Chemotherapy Analysis)

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-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL.

Time frame: 1. Prior to cycle 1 (baseline), 2. Prior to cycle 3 (6 weeks post cycle 1), 3. Prior to cycle 6 (15 weeks post cycle 1), 4. 6 months post cycle 1, 5. 12 months post cycle 1.

Population: Provided baseline and at least one follow-up assessment (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

ArmMeasureGroupValue (LEAST_SQUARES_MEAN)Dispersion
No Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)Prior to cycle 374.2 score on a scaleStandard Error 1
No Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)6 months post cycle 177.1 score on a scaleStandard Error 1
No Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)Prior to cycle 673.3 score on a scaleStandard Error 1
No Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)12 months post cycle 177.0 score on a scaleStandard Error 1.1
No Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)Prior to cycle 1 (baseline)75.8 score on a scaleStandard Error 0.8
Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)12 months post cycle 177.8 score on a scaleStandard Error 1
Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)Prior to cycle 1 (baseline)75.3 score on a scaleStandard Error 0.9
Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)Prior to cycle 373.4 score on a scaleStandard Error 0.9
Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)Prior to cycle 672.3 score on a scaleStandard Error 1
Cytoreductive SurgeryPatient Reported Quality of Life (Chemotherapy Analysis)6 months post cycle 177.2 score on a scaleStandard Error 1
Secondary

Patient Reported Quality of Life (Surgery Analysis)

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-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL.

Time frame: 1. Prior to surgery, 2. 6 weeks post-surgery, 3. 15 weeks post-surgery, 4. 6 months post-surgery, 5. 12 months post-surgery.

Population: Provided baseline and at least one follow-up assessment (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol).

ArmMeasureGroupValue (LEAST_SQUARES_MEAN)Dispersion
No Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)6 weeks post-surgery69.3 score on a scaleStandard Error 1.3
No Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)6 months post-surgery72.6 score on a scaleStandard Error 1.3
No Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)15 weeks post-surgery68.7 score on a scaleStandard Error 1.3
No Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)12 months post-surgery74.0 score on a scaleStandard Error 1.4
No Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)Prior to surgery74.5 score on a scaleStandard Error 1
Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)12 months post-surgery75.6 score on a scaleStandard Error 1.3
Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)Prior to surgery74.2 score on a scaleStandard Error 1
Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)6 weeks post-surgery68.4 score on a scaleStandard Error 1.3
Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)15 weeks post-surgery68.8 score on a scaleStandard Error 1.3
Cytoreductive SurgeryPatient Reported Quality of Life (Surgery Analysis)6 months post-surgery73.5 score on a scaleStandard Error 1.3
Secondary

Progression-free Survival (Chemotherapy Analysis)

Progression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause.

Time frame: Radiographic assessment of disease was conducted during chemotherapy and then every 6 months during the maintenance / surveillance phase

Population: All patients who were enrolled and eligible for the chemotherapy analysis (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

ArmMeasureValue (MEDIAN)
No Cytoreductive SurgeryProgression-free Survival (Chemotherapy Analysis)10.4 Months
Cytoreductive SurgeryProgression-free Survival (Chemotherapy Analysis)13.8 Months
Secondary

Progression Free Survival (Surgery Analysis)

Progression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause.

Time frame: Radiographic assessment of disease (in patients with measurable and non-measurable disease) was conducted Every three months for two years and then every 6 months after completion of chemotherapy during the maintenance/surveillance phase.

Population: All randomized patients who were eligible for the surgery analysis (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol).

ArmMeasureValue (MEDIAN)
No Cytoreductive SurgeryProgression Free Survival (Surgery Analysis)16.2 Months
Cytoreductive SurgeryProgression Free Survival (Surgery Analysis)18.9 Months
Secondary

Summary of Adverse Events (CTCAE Version 4.0)

Number of treated patients with at least one adverse event reported (assessed by Common Terminology Criteria for Adverse Events (version 4.0))

Time frame: During treatment period and up to 100 days after stopping the study treatment, a median duration of 82.5 months

Population: Eligible and treated participants

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
No Cytoreductive SurgerySummary of Adverse Events (CTCAE Version 4.0)304 Participants
Cytoreductive SurgerySummary of Adverse Events (CTCAE Version 4.0)376 Participants
Arm III (Surgery; Carboplatin and Paclitaxel)Summary of Adverse Events (CTCAE Version 4.0)29 Participants
Arm IV (Surgery; Carboplatin, Paclitaxel and Bevacizumab)Summary of Adverse Events (CTCAE Version 4.0)77 Participants
Arm V (no Surgery; Carboplatin and Gemcitabine)Summary of Adverse Events (CTCAE Version 4.0)3 Participants
Arm VI (no Surgery; Carboplatin, Gemcitabine and Bevacizumab))Summary of Adverse Events (CTCAE Version 4.0)9 Participants
Arm VII (Surgery; Carboplatin and Gemcitabine)Summary of Adverse Events (CTCAE Version 4.0)3 Participants
Arm VIII (Surgery; Carboplatin, Gemcitabine and Bevacizumab))Summary of Adverse Events (CTCAE Version 4.0)9 Participants

Source: ClinicalTrials.gov · Data processed: Mar 10, 2026