Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This phase III clinical trial is studying two different dose schedules of paclitaxel to see how well they work in combination with carboplatin with or without bevacizumab in treating patients with stage II, III or IV ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving bevacizumab together with combination chemotherapy may kill more tumor cells. It is not yet known whether giving paclitaxel once every three weeks is more effective than giving paclitaxel once a week

Further Study Information

PRIMARY OBJECTIVES:

I. To determine if the weekly paclitaxel regimen increases the time until first progression or death (progression-free survival [PFS]) compared to the every-3-week paclitaxel regimen in patients with stage II, III or IV ovarian epithelial, primary peritoneal, or fallopian tube cancer who are receiving carboplatin with or without bevacizumab.

SECONDARY OBJECTIVES:

I. To determine if the weekly paclitaxel increases the duration of overall survival compared to the every-3-week paclitaxel when combined with carboplatin with or without bevacizumab.

II. To compare the weekly paclitaxel to the every-3-week paclitaxel with respect to the incidence of severe or serious adverse events when it is combined with carboplatin with or without bevacizumab.

III. To compare the weekly paclitaxel to the every-3-week paclitaxel with respect to patients' self-reported quality of life (QOL) as measured by the FACT-O-TOI, when paclitaxel is combined with carboplatin with or without bevacizumab (as of 02/08/2012, the QOL portion of this study is complete; patients enrolled after this date will not have QOL assessments).

TERTIARY OBJECTIVES:

I. To evaluate single nucleotide polymorphisms associated with PFS and toxicity in advanced-stage ovarian epithelial, primary peritoneal, and fallopian tube cancer using genome-wide association studies.* II. To evaluate genomic signatures in tumor tissues that are predictive for patient survival in advanced-stage ovarian epithelial, primary peritoneal, and fallopian tube cancer.* III. To evaluate the association between serum and plasma biomarkers and response to antiangiogenesis therapy in advanced-stage ovarian epithelial, primary peritoneal, and fallopian tube cancer.*

NOTE: *As of 02/08/2012, the translational research (TR) portion of this study is complete; patients enrolled after this date will not have TR specimens collected.

IMAGING PRIMARY OBJECTIVES:

I. To determine whether larger changes in the tumor perfusion parameters from baseline timepoint (T0) to early-therapy T2 are prognostic of higher PFS rate at 6 months (PFS-6) from enrollment in patients treated with weekly or every-3-week paclitaxel regimens, who are receiving carboplatin with or without bevacizumab.***

IMAGING SECONDARY OBJECTIVES:

I. To determine whether larger changes in tumor perfusion parameters from baseline T0 to intermediate T1 and from T1 to T2 are prognostic of higher PFS-6 in patients treated with weekly or every-3-week paclitaxel regimens, who are receiving carboplatin with or without bevacizumab.*** II. To determine whether larger changes in tumor perfusion parameters values from T0 to T1, T0 to T2, and T1 to T2 are prognostic of better overall survival in all treatment arms.*** III. To assess the association between changes in tumor perfusion parameters before and after chemotherapy initiation (T0 to T1) and subsequent best tumor response according to standard anatomic Response Evaluation Criteria in Solid Tumors (RECIST).*** IV. To assess the association between tumor perfusion parameters before chemotherapy and subsequent best tumor response according to RECIST, PFS-6, and overall survival.*** V. To test the assumption that tumor perfusion parameters are reliable, user-independent, and reproducible parameters of tumor microvascular characteristics; a subgroup of 15 patients will have repeat computed tomography (CT) perfusion studies at the intermediate T1.***

NOTE: ***Patients enrolled after February 8, 2012 must participate in the ACRIN 6695 component at ACRIN-qualified institutions.

OUTLINE: This is a multicenter study. Patients are stratified according to disease stage (II vs III vs IV), performance status (0 vs 1-2), inclusion of bevacizumab in the treatment regimen (yes vs no), and decision to use neoadjuvant chemotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms (beginning on 04-30-2012, the trial is no longer randomized and the chemotherapy regimen is selected and declared prior to enrolling in the study).

ARM I: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses.

ARM II: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses.

Patients in both arms may receive optional** bevacizumab IV over 30-90 minutes on day 1 beginning in course 2. Courses of bevacizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: **Before enrolling onto this study, each patient chooses whether the study treatment will include concurrent and maintenance bevacizumab.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Eligibility Criteria

Inclusion Criteria:

• Patients must have measurable disease; at least one target lesion must have a minimum length of 1 cm in both the long and short axis (determined at the local site); for primary surgery patients, if no radiographic evidence of measurable disease is obtained prior to registration this can be based on surgical findings; imaging then would need to be completed in the 14 days between Gynecology Oncology Group (GOG) registration and chemotherapy initiation

• Histologically confirmed ovarian epithelial, primary peritoneal, or fallopian tube cancer

• Stage II -IV suboptimally debulked (any residual disease > 1 cm); International Federation of Gynecology and Obstetrics (FIGO) stage is assessed following the completion of initial abdominal surgery, appropriate imaging studies and with appropriate tissue available 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; 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

• The following histologic epithelial cell types are eligible:

• Serous

• Endometrioid

• Clear cell

• Mucinous adenocarcinoma

• Undifferentiated carcinoma

• Mixed epithelial carcinoma

• Transitional cell carcinoma

• Malignant Brenner tumor

• Adenocarcinoma not otherwise specified

• Histologic features of the tumor must be compatible with a primary Müllerian epithelial adenocarcinoma; patients may have co-existing fallopian tube carcinoma in-situ so long as the primary origin of invasive tumor is ovarian, peritoneal or fallopian tube; of note, patients with clear cell and mucinous tumors will be eligible unless there is a higher priority protocol

• For patients undergoing neoadjuvant chemotherapy (NAC) with interval cytoreductive surgery (ICS), a core tissue (not fine needle aspiration) biopsy is required; the tissue must be consistent with a müllerian origin; patients will require documentation of at least stage II or extraovarian sites of disease acquired via imaging or surgery (without attempt at cytoreduction)

• Patients will not be eligible for therapy on other clinical trials evaluating consolidation or maintenance therapy

• Absolute neutrophil count (ANC) >= 1,500/mm^3 (not induced or supported by granulocyte colony-stimulating factors)

• Platelet count >= 100,000/mm^3

• Creatinine =< 1.5 times upper limit of normal (ULN)

• Bilirubin =< 1.5 times ULN

• Serum glutamic oxalo-acetic transaminase (SGOT) =< 3 times ULN

• Alkaline phosphatase =< 2.5 times ULN

• Neuropathy (sensory or motor) >= Common Terminology Criteria for Adverse Events (CTCAE) grade 1

• GOG performance status 0-2

• Patients must be entered within 12 weeks of diagnostic/staging surgery

• An approved informed consent and authorization permitting release of personal health information and must be signed by the patient or guardian

• Patients who elect to receive bevacizumab must meet the following criteria:

• Patients in this trial may receive ovarian estrogen and/or progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time, but not high-dose progestins for management of anorexia while on protocol-directed therapy or prior to disease progression due to thrombophlebitis risk

• Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thromboembolus)

• Heparin, lovenox or alternative anticoagulants are acceptable

• Partial prothrombin time (PTT) < 1.2 times ULN

• American College of Radiology Imaging Network (ACRIN) 6695 imaging study:

• Patients enrolled after February 8, 2012 must participate in the ACRIN 6695 component at ACRIN-qualified institutions

• At least one target lesion must have a minimum length of 1 cm in both the long and short axis (as determined by the local site), at least half of the target lesion must have attenuation greater than or equal to 10 Hounsfield Units (HU) on the unenhanced (computed tomography (CT), and at least half of the lesion must have maximum enhancement greater than or equal to 5 HU in the perfusion CT scan (as determined by the American College of Radiology [ACR] Imaging Core Lab)

Exclusion Criteria:

• Patients with a current diagnosis of borderline epithelial ovarian tumor (formerly "tumors of low malignant potential") or recurrent invasive epithelial ovarian, primary peritoneal or fallopian tube cancer treated with surgery only (such as patients with stage I-A or I-B low grade epithelial ovarian or fallopian tube cancers) 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, peritoneal primary or fallopian tube cancer are eligible, provided that they have not received prior chemotherapy for any ovarian tumor

• Synchronous primary endometrial cancer or a history of primary endometrial cancer, unless all of the following conditions are met:

• Stage not greater than Ia

• Grade 1 or 2

• No more than superficial myometrial invasion

• No vascular or lymphatic invasion

• No poorly differentiated subtypes, including papillary serous, clear cell, or other FIGO grade 3 lesions

• Prior radiotherapy to any portion of the abdominal cavity or pelvis

• Prior radiotherapy for localized cancer of the breast, head and neck, or skin is allowed provided that it was completed > 3 years ago and that the patient remains free of recurrent or metastatic disease

• Prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant chemotherapy for ovarian, primary peritoneal, or fallopian tube cancer

• Prior adjuvant chemotherapy for localized breast cancer allowed provided that it was completed > 3 years ago and that the patient remains free of recurrent or metastatic disease

• Prior targeted therapy (including, but not limited to, vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of ovarian epithelial, fallopian tube, or primary peritoneal cancer

• Prior therapy with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab

• Acute hepatitis or active infection that requires parenteral antibiotics

• 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

• With the exception of non-melanoma skin cancer, patients with other invasive malignancies who had (or have) any evidence of the other cancer present within the last five years or whose previous cancer treatment contraindicates this protocol therapy

• Clinically significant cardiovascular disease, including:

• Myocardial infarction or unstable angina within the past 6 months

• New York Heart Association (NYHA) class II or greater congestive heart failure

• Serious cardiac arrhythmia requiring medication (this does not include asymptomatic, atrial fibrillation with controlled ventricular rate)

• Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study

• Patients with known allergy to cremophor or polysorbate 80

• Exclusions for patients who elect to receive bevacizumab:

• * 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 central nervous system (CNS) disease, including primary brain tumor, 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

• Patients with CTCAE Grade 2 or greater peripheral vascular disease [at least brief (< 24 hours) episodes of ischemia managed non-surgically and without permanent deficit]

• Patients with a history of CVA within six months

• * Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies

• * Patients with clinically significant proteinuria; patients must have a urine protein-creatinine ratio (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, secondary cytoreductive surgery, or second look surgery

• Any tissue biopsy, such as a core biopsy, within 7 days prior to the first date of bevacizumab therapy (cycle 2)

• * Patients with clinical symptoms or signs of gastrointestinal obstruction AND who require parenteral hydration and/or nutrition

• * Patients with metastatic tumor in the parenchyma of the liver or lungs with proximity to large vessels which could make the patients at high risk of lethal hemorrhage during treatment with bevacizumab (ie. hemoptysis, liver rupture)

• ACRIN 6695 exclusions:

• Patients with contraindication to iodinated contrast for perfusion CT imaging

• Patients who receive metformin within 48 hours before perfusion CT imaging

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

John Chan

Principal Investigator

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Warner Huh	Ph: 205-934-0309
Arizona
	Phoenix
	St. Joseph's Hospital and Medical Center
		John H Farley	Ph: 877-602-4111
	Tucson
	Arizona Cancer Center at UMC Orange Grove
		Michael A. Bookman	Ph: 520-626-9008
	Arizona Cancer Center at University Medical Center North
		Michael A. Bookman	Ph: 520-626-9008
California
	Los Angeles
	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
		Bobbie J Rimel	Ph: 310-423-8965
			Email: info@ccadmin.wustl.edu
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		John K Chan	Ph: 877-827-3222
Colorado
	Aurora
	University of Colorado Cancer Center at UC Health Sciences Center
		Susan Davidson	Ph: 720-848-0650
Connecticut
	New Britain
	George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus
		James S. Hoffman	Ph: 860-224-5660
Kentucky
	Louisville
	University of Louisville School of Medicine
		Lynn P Parker	Ph: 866-530-5516
Missouri
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		David Gardner Mutch	Ph: 800-600-3606
			Email: info@ccadmin.wustl.edu
New Mexico
	Albuquerque
	University of New Mexico Cancer Center
		Carolyn Y. Muller	Ph: 505-272-6972
North Carolina
	Durham
	Duke Cancer Institute
		Angeles Alvarez Secord	Ph: 888-275-3853
Ohio
	Columbus
	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
		David M O'Malley	Ph: 866-627-7616
			Email: osu@emergingmed.com
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Robert S. Mannel	Ph: 405-271-4272
			Email: julie-traylor@ouhsc.edu
Pennsylvania
	Philadelphia
	Abramson Cancer Center of the University of Pennsylvania
		Stephen C. Rubin	Ph: 215-746-7406
	Fox Chase Cancer Center - Philadelphia
		Lainie P Martin	Ph: 215-728-4790
Rhode Island
	Providence
	Women and Infants Hospital of Rhode Island
		Paul A. DiSilvestro	Ph: 401-274-1122
Texas
	Dallas
	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
		David Scott Miller	Ph: 214-648-7097
	Houston
	Univeristy of Texas M.D. Anderson Cancer Center
		Robert L. Coleman	Ph: 713-792-3245
Virginia
	Charlottesville
	University of Virginia Cancer Center
		Susan C Modesitt	Ph: 434-243-6143
Wisconsin
	Madison
	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
		David M Kushner	Ph: 877-405-6866

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01167712
Information obtained from ClinicalTrials.gov on April 04, 2013