Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal Cancer, or Fallopian Tube Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	GOG-0218 NCT00262847

Special Category: NCI Web site featured trial, CTSU trial

Objectives

Primary

1. Compare the overall survival of patients with stage III or stage IV ovarian epithelial, primary peritoneal cancer, or fallopian tube cancer treated with carboplatin and paclitaxel vs carboplatin, paclitaxel, and concurrent bevacizumab with vs without extended bevacizumab.

Secondary

1. Compare the duration of progression-free survival of patients treated with these regimens.
2. Compare the incidence of severe toxicity of these regimens in these patients.
3. Compare the quality of life of patients treated with these regimens.

Tertiary

1. Determine the relationship between angiogenic markers and clinical outcome (tumor response, progression-free survival, and overall survival) in patients treated with these regimens.
2. Determine the predictive value of a set of genes whose expression correlates with survival of these patients.
3. Bank whole blood for research.
4. Determine if genetic variations in genes associated with essential hypertension including WNK lysine deficient protein kinase 1 (WNK1), G protein-coupled receptor kinase 4 (GRK4), and kallikrein B (KLKB1) predict which patients are likely to develop bevacizumab-induced hypertension.

Entry Criteria

Disease Characteristics:

• Histologically confirmed ovarian epithelial, primary peritoneal*, or fallopian tube cancer
  • Stage III with any gross (macroscopic or palpable) residual disease OR stage IV disease

   [Note: May have co-existing fallopian tube carcinoma in-situ so long as the primary origin of invasive tumor is ovarian or peritoneal.]

• The following histologic epithelial cell types are allowed provided the histologic features of the tumor are compatible with a primary müllerian epithelial adenocarcinoma:
  • Serous adenocarcinoma
  • Endometrioid adenocarcinoma
  • Mucinous adenocarcinoma
  • Undifferentiated carcinoma
  • Clear cell adenocarcinoma
  • Mixed epithelial carcinoma
  • Transitional cell carcinoma
  • Malignant Brenner tumor
  • Adenocarcinoma not otherwise specified
• No borderline ovarian epithelial tumor (formerly "tumors of low malignant potential")
  • Prior diagnosis of a borderline tumor that was surgically resected and an unrelated, new, invasive ovarian epithelial or primary peritoneal cancer that subsequently develops is allowed provided there was no prior chemotherapy for any ovarian tumor
• No recurrent invasive ovarian epithelial cancer treated with surgery only (e.g., stage IA or IB low-grade epithelial ovarian or fallopian tube cancer)
• No synchronous primary endometrial cancer or prior primary endometrial cancer unless all of the following criteria are met:
  • Stage ≤ IB
  • Superficial myometrial invasion without vascular or lymphatic invasion
  • No poorly differentiated subtypes (i.e., papillary serous, clear cell, or other FIGO grade 3 lesions)
• Must have undergone surgery for ovarian epithelial, primary peritoneal, or fallopian tube cancer in the past 1-12 weeks AND have tissue available for histologic evaluation
  • Patients with stage III disease in which the largest maximal diameter of any residual tumor implant a the completion of initial surgery is ≤ 1 cm will be defined as "optimal" (all others will be defined as "suboptimal")
• Measurable or nonmeasurable disease
• No tumor involving active major vessels
• No prior or concurrent CNS disease, including primary brain tumor or brain metastases

Prior/Concurrent Therapy:

Biologic therapy

• No prior targeted therapy for ovarian epithelial or peritoneal primary cancer, including, but not limited to, any of the following:
  • Vaccines
  • Antibodies
  • Tyrosine kinase inhibitors
• No prior bevacizumab
• No other prior antivascular endothelial growth factors (VEGF)
• No other concurrent biologic therapy

Chemotherapy

• See Disease Characteristics
• No prior chemotherapy for abdominal or pelvic tumor including neoadjuvant chemotherapy for their ovarian or primary peritoneal cancer
• More than 3 years since prior adjuvant chemotherapy for localized breast cancer AND patient remains free of recurrent or metastatic disease
• No other concurrent chemotherapy

Endocrine therapy

• Ovarian estrogen with or without progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time allowed
  • No progestins for management of anorexia while on study-directed therapy or prior to disease progression
• No prior hormonal therapy for ovarian, peritoneal primary, or fallopian tube cancer
• No concurrent hormonal therapy

Radiotherapy

• More than 3 years since prior radiotherapy for localized cancer of the breast, head and neck, or skin AND patient remains free of recurrent or metastatic disease
• No prior radiotherapy to the abdominal cavity or pelvis
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• At least 4 weeks since prior major surgical procedure or open biopsy
• At least 1 week since prior core biopsy
• No concurrent major surgery including abdominal surgery (laparotomy or laparoscopy) prior to disease progression (e.g., colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or second look surgery

Other

• No prior cancer therapy that would preclude study treatment
• No concurrent consolidation or maintenance therapy
• No other concurrent cytotoxic or anticancer therapy
• No concurrent amifostine or other protective reagents

Patient Characteristics:

Performance status

• GOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm³ without induction or support by granulocyte colony stimulating factors
• Platelet count ≥ 100,000/mm³
• No active bleeding
• No known bleeding disorder or coagulopathy

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN
• INR ≤ 1.5 (2-3 with stable-dose therapeutic warfarin for management of venous thrombosis including pulmonary thromboembolus)
• PTT < 1.2 times ULN
• No acute hepatitis

Renal

• Creatinine ≤ 1.5 times ULN
• Urine protein:creatinine ratio < 1.0

  OR

• Urine protein < 1 g/24-hr urine collection

Cardiovascular

• No New York Heart Association class II-IV congestive heart failure
• No myocardial infarction or unstable angina within the past 6 months
• No uncontrolled hypertension (i.e., blood pressure > 150/90 mm Hg)
• No serious cardiac arrhythmia requiring medication except for patients with asymptomatic atrial fibrillation with a controlled ventricular rate
• No other clinically significant cardiovascular disease
• No clinically significant peripheral vascular disease ≥ grade 2
• No history of cerebral vascular accident, transient ischemic attack, or subarachnoid hemorrhage within the past 6 months

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No neuropathy (sensory and motor) > grade 1
• No known hypersensitivity to Chinese hamster ovary cell products or recombinant human or humanized antibodies
• No other malignancy within the past 5 years except nonmelanoma skin cancer
• No active infection that requires parenteral antibiotics
• No serious nonhealing wound, ulcer, or bone fracture
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
  • Granulating incisions healing by secondary intention with no evidence of fascial dehiscence or infection are allowed
• No other pathological condition that would confer a high risk of bleeding
• No uncontrolled seizures
• No significant traumatic injury within the past 4 weeks
• No clinical symptoms or signs of gastrointestinal obstruction that require parenteral hydration and/or nutrition
• No other medical history or condition that, in the opinion of the investigator, would preclude study participation

Expected Enrollment

A total of 2,000 patients will be accrued for this study.

Outcomes

Progression-free survival measured by RECIST Criteria and Modified Rustin Criteria for CA-125 at baseline, prior to every other course of therapy, every 3 months for 2 years, every 6 months for 3 years, and then annually during follow-up

Overall survival
Severe toxicity and serious adverse events by NCI Common Toxicity Criteria version 3 at baseline, every course of therapy, every 3 months for 2 years, every 6 months for 3 years, and then annually during follow-up
Quality of life by Functional Assessment of Cancer Therapy-Ovarian (Fact-O) at baseline, prior to courses 4, 7, 13, and 21, and then at 6 months after study completion
Translational objectives by angiogenic markers and gene arrays at baseline
Response rate

Outline

This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to stage of disease (III vs IV) or initial performance status (0 vs 1 vs 2). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Beginning in course 2, patients also receive placebo IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses. Beginning in course 7, patients receive placebo alone IV over 30-90 minutes on day 1. Treatment with placebo repeats every 21 days for up to 22 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive paclitaxel and carboplatin as in arm I. Beginning in course 2, patients also receive bevacizumab IV over 30-90 minutes on day 1.Treatment repeats every 21 days for 6 courses. Beginning in course 7, patients receive placebo alone IV over 30-90 minutes on day 1. Treatment with placebo repeats every 21 days for up to 22 courses in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive paclitaxel and carboplatin as in arm I. Beginning in course 2, patients also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses. Beginning in course 7, patients receive bevacizumab alone IV over 30-90 minutes on day 1. Treatment with bevacizumab repeats every 21 days for up to 22 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, before courses 4, 7, 13, and 21, and then at 6 months after study completion.

After completion of study treatment, patients are followed periodically for at least 5 years.

Trial Contact Information

Trial Lead Organizations

Gynecologic Oncology Group

Robert Burger, MD, Protocol chair		Ph: 714-456-7971 Email: raburger@uci.edu
Gini Fleming, MD, Protocol co-chair		Ph: 773-702-6712; 888-824-0200 Email: gfleming@medicine.bsd.uchicago.edu

Related Information

Featured trial article

Registry Information
Official Title		A Phase III Trial of Carboplatin and Paclitaxel Plus Placebo Versus Carboplatin and Paclitaxel Plus Concurrent Bevacizumab (NSC # 704865, IND #7921) Followed By Placebo, Versus Carboplatin and Paclitaxel Plus Concurrent and Extended Bevacizumab, in Women With Newly Diagnosed, Previously Untreated, Suboptimal Advanced Stage Epithelial Ovarian, Primary Peritoneal Cancer, or Fallopian Tube Cancer
Trial Start Date		2005-09-26
Trial Completion Date		2008-10-11 (estimated)
Registered in ClinicalTrials.gov		NCT00262847
Date Submitted to PDQ		2005-11-01
Information Last Verified		2009-07-02
NCI Grant/Contract Number		CA27469

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