Carboplatin, Paclitaxel, and Bevacizumab With or Without Everolimus in Treating Patients With Metastatic Malignant Melanoma

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Completed
• CT.gov ID: NCT00976573
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 149
• Locations: 310
• Arms: 2
• Duration (Months): 65
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying how well carboplatin, paclitaxel, and bevacizumab work when given with or without everolimus in treating patients with malignant melanoma that has spread from where it started to other places in the body. Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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, may block the ability of tumor cells to grow and spread. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether combination chemotherapy given together with bevacizumab is more effective with or without everolimus in treating patients with metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma (Skin)	Biological: bevacizumab; Drug: carboplatin; Drug: everolimus; Drug: paclitaxel	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To assess whether there is sufficient promise of an impact of the addition of everolimus to the combination of carboplatin, paclitaxel, and bevacizumab on progression-free survival that it would be recommended for further testing in patients with metastatic malignant melanoma.

Secondary

• To estimate the confirmed tumor response rate of each of the treatment regimens.

• To estimate the distribution of overall survival (OS) time for each of the treatment regimens.

• To assess the impact on the safety profile of the addition of everolimus to the combination of carboplatin, paclitaxel, and bevacizumab.

OUTLINE: This is a multicenter study. Patients are stratified according to elevated LDH (above upper limit of normal) at baseline (yes vs no), location of metastatic disease (M1a [skin, subcutaneous tissue, or lymph node only] vs M1b [lung] vs M1c [other visceral sites]) and prior chemotherapy for metastatic disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15, paclitaxel IV over 60 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes on day

1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive everolimus orally (PO) once daily (QD) 3 times weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 149 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Carboplatin, Paclitaxel, Bevacizumab, With or Without Everolimus for Therapy of Metastatic Malignant Melanoma
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (bevacizumab, paclitaxel, and carboplatin) Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, paclitaxel IV over 60 minutes on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Drug: carboplatin; Given IV; Drug: paclitaxel; Given IV
Experimental: Arm II(bevacizumab, paclitaxel, carboplatin, and everolimus) Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive everolimus PO QD on 3 days a week. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Drug: carboplatin; Given IV; Drug: everolimus; Given orally; Drug: paclitaxel; Given IV

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Time from randomization to documentation of disease progression or death without documentation of progression;Up to 5 years]

   The primary endpoint is progression-free survival (PFS) defined as the time from randomization to documentation of disease progression or death without documentation of progression. The distribution of PFS times will be estimated using the Kaplan-Meier method. Progression is defined using the RECIST Criteria as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum of diameters recorded on study (this includes the baseline sum if that is the smallest on study) or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm of target lesions, or the appearance of one or more new lesions, unequivocal progression of existing non-target lesions, although unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Secondary Outcome Measures

1. Toxicity [Up to 5 years]

   For this secondary endpoint, toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The percentage of participants reporting a grade 3 or higher toxicity is reported. For a list of all reported adverse events, please refer to the Adverse Events Section below.

2. Confirmed Tumor Response Rate (Complete Response [CR] or Partial Response [PR]) According to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria [Up to 5 years]

   Confirmed Tumor Response: A confirmed tumor response is defined to be a CR or PR (by the RECIST criteria) noted as the objective status on 2 consecutive evaluations at least 8 weeks apart. The proportion of tumor responses will be estimated by the number of confirmed tumor responses divided by the total number of evaluable patients. A ninety percent confidence interval for the true proportion of confirmed tumor responses will be calculated assuming that the number of confirmed tumor responses follows a binomial distribution.

3. Overall Survival Time [up to 5 years]

   Overall survival time is defined as the time from registration to death due to any cause. The distribution of survival times will be estimated using the method of Kaplan-Meier.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologic proof of stage IV malignant melanoma not amenable to surgery; (biopsy can be of locoregional disease in setting of clinically evident stage IV disease, but primary tumor alone will not qualify)

• At most one prior chemotherapy based regimen for metastatic melanoma (no prior taxane-based regimens allowed); note: prior adjuvant non-taxane based chemotherapy and/or adjuvant immunotherapy are allowed; no limit on the number of prior biologic, immunologic or targeted therapies

• Measurable disease defined as at least one lesion whose longest diameter can be accurately measured as >= 2.0 cm with chest x-ray, or as >= 1.0 cm with computed tomography (CT) scan, CT component of a positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) scan; note: disease that is measurable by physical examination only is not eligible

• Life expectancy >= 4 months

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Absolute neutrophil count (ANC) >= 1500/mL

• Platelets (PLT) >= 100,000 x 10^9/L

• Hemoglobin (Hgb) >= 9 g/dL (patients may be transfused to meet this requirement)

• Total cholesterol =< 300 mg/dL and; (note: serum levels of cholesterol or triglycerides found to be elevated may be lowered with anti-lipid therapy, but must be documented to be below these levels prior to enrollment)

• Triglycerides =< 2.5 X upper limit of normal (ULN); (note: serum levels of cholesterol or triglycerides found to be elevated may be lowered with anti-lipid therapy, but must be documented to be below these levels prior to enrollment)

• Creatinine =< 1.5 x ULN

• Total bilirubin =< 1.5 mg/dL (exception: patients with documented Gilbert's syndrome are allowed to participate despite elevated bilirubin)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN

• Alkaline phosphatase =< 2.5 x ULN

• Urine protein:creatinine (UPC) ratio < 1.0 at screening OR

• Urine dipstick for proteinuria < 2+ (patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate =< 1 g of protein in 24 hours to be eligible)

• Negative pregnancy test done =< 7 days prior to registration/randomization, for women of childbearing potential only

• Ability to understand and the willingness to sign a written informed consent document

• Willing to return to a North Central Cancer Treatment Group (NCCTG) institution for follow-up

• Willing to provide mandatory blood samples for research purposes

• Willing to follow a diet low in fat and cholesterol while taking everolimus

• Willing to abstain from eating grapefruit or drinking grapefruit juice for the duration of the study

Exclusion Criteria

• Prior treatment with agents disrupting vascular endothelial growth factor (VEGF) activity (i.e., bevacizumab, VEGF-trap, anti-VEGF receptor [R] monoclonal antibody [Mab]) or targeting VEGFR (e.g. sunitinib, sorafenib)

• Prior treatment with an mTOR inhibitor for melanoma (sirolimus, temsirolimus, everolimus)

• Brain metastases per MRI or CT at any time prior to registration; note: patients that have had primary therapy for brain metastasis (i.e. surgical resection, whole brain radiation, or stereotactic radiation therapy [SRT] even if stable) are not eligible

• Other investigational agents =< 4 weeks prior to registration/randomization

• Chemotherapy treatment =< 3 weeks prior to registration/randomization

• Any biologic, immunologic or targeted therapy =< 2 weeks prior to registration/randomization

• Major surgical procedure, open biopsy, or significant traumatic injury =< 4 weeks prior to registration/randomization

• Fine needle aspirations or core biopsies =< 7 days prior to registration/randomization

• Planned/or anticipated major surgical procedure during the course of the study

• Other medical conditions including but not limited to:

• History of liver disease such as cirrhosis, chronic active hepatitis, chronic persistent hepatitis or hepatitis B or C

• Active infection requiring parenteral antibiotics

• Poorly controlled high blood pressure (>=150 mm Hg systolic and/or 100 mmHg diastolic) despite treatment

• New York Heart Association class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Myocardial infarction or unstable angina =< 6 months prior to registration/randomization

• Clinically significant peripheral vascular disease

• Deep venous thrombosis or pulmonary embolus =< 1 year of registration/randomization and/or ongoing need for full-dose oral or parenteral anticoagulation

• Ongoing anti-platelet treatment other than low-dose aspirin (i.e., aspirin 81 mg orally [p.o.] daily)

• Active bleeding or pathological conditions that carry high risk of bleeding (e.g., known esophageal varices, etc.)

• Serious, non-healing wound (including wounds healing by secondary intention), ulcer or bone fracture

• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess =< 6 months prior to registration/randomization

• History of central nervous system (CNS) disease (e.g., primary brain tumor, vascular abnormalities, etc.), clinically significant stroke or transient ischemic attack (TIA) =< 6 months prior to registration/randomization, seizures not controlled with standard medical therapy

• Radiographically documented tumor invading major blood vessels

• History of hypertensive crisis or hypertensive encephalopathy

• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

• Severely impaired lung function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air

• A known history of human immunodeficiency virus (HIV) seropositivity

• Any of the following as this regimen may be harmful to a developing fetus or nursing child:

• Pregnant women

• Nursing women

• Men and women of reproductive potential who are not using effective birth control methods must use highly effective contraception throughout the trail and for 6 months after last study treatment

• Existence of peripheral sensory neuropathy >= grade 2

• History of other malignancy =< 5 years with the exception of basal cell or squamous cell carcinoma of the skin, treated with local resection only, or carcinoma in situ (e.g. of the cervix, breast, prostate, etc.)

• =< 4 weeks since last day of adjuvant radiation therapy prior to registration or =< 2 weeks since last day of palliative radiation therapy; NOTE: patients who have had > 25% of their functional bone marrow irradiated are not eligible for this trial

• Active or recent history of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) =< 30 days prior to registration

• Known hypersensitivity to any of the components of the everolimus, bevacizumab, carboplatin, or paclitaxel

• Current use of drugs that are known to be strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); note: if these agents are discontinued, everolimus therapy can begin >= 7 days after discontinuation of such agent

• Positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests

• Planned immunization with attenuated live vaccines =< 7 days prior to registration or during study period; note: close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Contra Costa Regional Medical Center	Martinez	California	United States	94553-3156
3	El Camino Hospital Cancer Center	Mountain View	California	United States	94040
4	Bay Area Breast Surgeons, Incorporated	Oakland	California	United States	94609
5	CCOP - Bay Area Tumor Institute	Oakland	California	United States	94609
6	Larry G Strieff MD Medical Corporation	Oakland	California	United States	94609
7	Tom K Lee, Incorporated	Oakland	California	United States	94609
8	Doctors Medical Center - San Pablo Campus	San Pablo	California	United States	94806
9	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
10	Boulder Community Hospital	Boulder	Colorado	United States	80301-9019
11	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
12	St. Anthony Central Hospital	Denver	Colorado	United States	80204
13	Porter Adventist Hospital	Denver	Colorado	United States	80210
14	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
15	St. Joseph Hospital	Denver	Colorado	United States	80218
16	Rose Medical Center	Denver	Colorado	United States	80220
17	Swedish Medical Center	Englewood	Colorado	United States	80110
18	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
19	Front Range Cancer Specialists	Fort Collins	Colorado	United States	80528
20	North Colorado Medical Center	Greeley	Colorado	United States	80631
21	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
22	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80501
23	McKee Medical Center	Loveland	Colorado	United States	80539
24	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
25	North Suburban Medical Center	Thornton	Colorado	United States	80229
26	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
27	Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center	Hartford	Connecticut	United States	06105
28	Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
29	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
30	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
31	Ella Milbank Foshay Cancer Center at Jupiter Medical Center	Jupiter	Florida	United States	33458
32	Lakeland Regional Cancer Center at Lakeland Regional Medical Center	Lakeland	Florida	United States	33805
33	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
34	John B. Amos Cancer Center	Columbus	Georgia	United States	31904
35	Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center	Boise	Idaho	United States	83706
36	Rush-Copley Cancer Care Center	Aurora	Illinois	United States	60504
37	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
38	St. Joseph Medical Center	Bloomington	Illinois	United States	61701
39	Illinois CancerCare - Canton	Canton	Illinois	United States	61520
40	Illinois CancerCare - Carthage	Carthage	Illinois	United States	62321
41	Eureka Community Hospital	Eureka	Illinois	United States	61530
42	Illinois CancerCare - Eureka	Eureka	Illinois	United States	61530
43	Galesburg Clinic, PC	Galesburg	Illinois	United States	61401
44	Illinois CancerCare - Havana	Havana	Illinois	United States	62644
45	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois	United States	61443
46	La Grange Memorial Hospital	La Grange	Illinois	United States	60525
47	Illinois CancerCare - Macomb	Macomb	Illinois	United States	61455
48	Trinity Cancer Center at Trinity Medical Center - 7th Street Campus	Moline	Illinois	United States	61265
49		Moline	Illinois	United States	61265
50	Illinois CancerCare - Monmouth	Monmouth	Illinois	United States	61462
51	OSF Holy Family Medical Center	Monmouth	Illinois	United States	61462
52	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
53	Community Cancer Center	Normal	Illinois	United States	61761
54	Illinois CancerCare - Community Cancer Center	Normal	Illinois	United States	61761
55	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
56	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
57	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois	United States	61554
58	Illinois CancerCare - Pekin	Pekin	Illinois	United States	61603
59	Proctor Hospital	Peoria	Illinois	United States	61614
60	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
61	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
62	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
63	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
64	Illinois CancerCare - Peru	Peru	Illinois	United States	61354
65	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
66	Illinois CancerCare - Princeton	Princeton	Illinois	United States	61356
67	Illinois CancerCare - Spring Valley	Spring Valley	Illinois	United States	61362
68	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
69	Elkhart Clinic, LLC	Elkhart	Indiana	United States	46514-2098
70	Michiana Hematology-Oncology, PC - Elkhart	Elkhart	Indiana	United States	46514
71	Elkhart General Hospital	Elkhart	Indiana	United States	46515
72	St. Francis Hospital Cancer Care Services	Indianapolis	Indiana	United States	46237
73	Howard Community Hospital	Kokomo	Indiana	United States	46904
74	Center for Cancer Therapy at LaPorte Hospital and Health Services	La Porte	Indiana	United States	46350
75	Saint Anthony Memorial Health Centers	Michigan City	Indiana	United States	46360
76	Michiana Hematology-Oncology, PC - South Bend	Mishawaka	Indiana	United States	46545-1470
77	Saint Joseph Regional Medical Center	Mishawaka	Indiana	United States	46545-1470
78	Michiana Hematology Oncology PC - Plymouth	Plymouth	Indiana	United States	46563
79	Reid Hospital & Health Care Services	Richmond	Indiana	United States	47374
80	CCOP - Northern Indiana CR Consortium	South Bend	Indiana	United States	46601
81	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
82	Michiana Hematology Oncology PC - La Porte	Westville	Indiana	United States	46391
83	McFarland Clinic, PC	Ames	Iowa	United States	50010
84		Bettendorf	Iowa	United States	52722
85	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa	United States	52403
86	Mercy Regional Cancer Center at Mercy Medical Center	Cedar Rapids	Iowa	United States	52403
87	Medical Oncology and Hematology Associates - West Des Moines	Clive	Iowa	United States	50325
88	Mercy Cancer Center - West Lakes	Clive	Iowa	United States	50325
89	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309
90	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
91	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa	United States	50309
92	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa	United States	50314
93	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
94	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
95	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
96	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
97	McCreery Cancer Center at Ottumwa Regional	Ottumwa	Iowa	United States	52501
98	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
99	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51102
100	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
101	Methodist West Hospital	West Des Moines	Iowa	United States	50266-7700
102	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
103	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
104	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
105	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
106	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
107	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
108	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
109	Cancer Center of Kansas, PA - Liberal	Liberal	Kansas	United States	67901
110	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
111	Menorah Medical Center	Overland Park	Kansas	United States	66209
112	Saint Luke's Hospital - South	Overland Park	Kansas	United States	66213
113	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
114	CCOP - Kansas City	Prairie Village	Kansas	United States	66208
115	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
116	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67401
117	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
118	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
119	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
120	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
121	CCOP - Wichita	Wichita	Kansas	United States	67214
122	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
123	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
124	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
125	Hickman Cancer Center at Bixby Medical Center	Adrian	Michigan	United States	49221
126	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
127	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan	United States	48106
128	Battle Creek Health System Cancer Care Center	Battle Creek	Michigan	United States	49017
129	Mecosta County Medical Center	Big Rapids	Michigan	United States	49307
130	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
131	Green Bay Oncology, Limited - Escanaba	Escanaba	Michigan	United States	49431
132	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
133	Hurley Medical Center	Flint	Michigan	United States	48503
134	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
135	CCOP - Grand Rapids	Grand Rapids	Michigan	United States	49503
136	Lacks Cancer Center at Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
137	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
138	Dickinson County Healthcare System	Iron Mountain	Michigan	United States	49801
139	Foote Memorial Hospital	Jackson	Michigan	United States	49201
140	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
141	St. Mary Mercy Hospital	Livonia	Michigan	United States	48154
142	Community Cancer Center of Monroe	Monroe	Michigan	United States	48162
143	Mercy Memorial Hospital - Monroe	Monroe	Michigan	United States	48162
144	Mercy General Health Partners	Muskegon	Michigan	United States	49444
145	St. Joseph Mercy Oakland	Pontiac	Michigan	United States	48341-2985
146	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan	United States	48060
147	Spectrum Health Reed City Hospital	Reed City	Michigan	United States	49677
148	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan	United States	48601
149	Lakeland Regional Cancer Care Center - St. Joseph	Saint Joseph	Michigan	United States	49085
150	Lakeside Cancer Specialists, PLLC	Saint Joseph	Michigan	United States	49085
151	Munson Medical Center	Traverse City	Michigan	United States	49684
152	St. John Macomb Hospital	Warren	Michigan	United States	48093
153	MeritCare Bemidji	Bemidji	Minnesota	United States	56601
154	St. Joseph's Medical Center	Brainerd	Minnesota	United States	56401
155	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
156	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
157	Essentia Health - Duluth Clinic	Duluth	Minnesota	United States	55805-1983
158	CCOP - Duluth	Duluth	Minnesota	United States	55805
159	Miller - Dwan Medical Center	Duluth	Minnesota	United States	55805
160	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
161	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
162	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
163	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
164	Minnesota Oncology - Maplewood	Maplewood	Minnesota	United States	55109
165	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
166	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
167	Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
168	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
169	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
170	Coborn Cancer Center	Saint Cloud	Minnesota	United States	56303
171	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
172	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
173	United Hospital	Saint Paul	Minnesota	United States	55102
174	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
175	Regions Hospital Cancer Care Center	St. Paul	Minnesota	United States	55101
176	Lakeview Hospital	Stillwater	Minnesota	United States	55082
177	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
178	Willmar Cancer Center at Rice Memorial Hospital	Willmar	Minnesota	United States	56201
179	Minnesota Oncology - Woodbury	Woodbury	Minnesota	United States	55125
180	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
181	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri	United States	65203
182	Goldschmidt Cancer Center	Jefferson City	Missouri	United States	65109
183	Saint Luke's Cancer Institute at Saint Luke's Hospital	Kansas City	Missouri	United States	64111
184	North Kansas City Hospital	Kansas City	Missouri	United States	64116
185	Heartland Hematology Oncology Associates, Incorporated	Kansas City	Missouri	United States	64118
186	Research Medical Center	Kansas City	Missouri	United States	64132
187	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
188	Mercy Clinic Cancer and Hematology - Rolla	Rolla	Missouri	United States	65401
189	Saint Joseph Oncology, Incorporated	Saint Joseph	Missouri	United States	64507
190	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
191	Missouri Baptist Cancer Center	Saint Louis	Missouri	United States	63131
192	CCOP - Cancer Research for the Ozarks	Springfield	Missouri	United States	65804
193	St. John's Regional Health Center	Springfield	Missouri	United States	65804
194	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
195	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
196	St. Vincent Healthcare Cancer Care Services	Billings	Montana	United States	59101
197	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana	United States	59102
198	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
199	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
200	St. James Healthcare Cancer Care	Butte	Montana	United States	59701
201	Benefis Sletten Cancer Institute	Great Falls	Montana	United States	59405
202	St. Peter's Hospital	Helena	Montana	United States	59601
203	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
204	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana	United States	59807-7877
205	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana	United States	59807
206	Cancer Resource Center - Lincoln	Lincoln	Nebraska	United States	68510
207	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
208	Immanuel Medical Center	Omaha	Nebraska	United States	68122
209	Alegant Health Cancer Center at Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
210	Lakeside Hospital	Omaha	Nebraska	United States	68130
211	Creighton University Medical Center	Omaha	Nebraska	United States	68131-2197
212	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
213	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
214	Charles R. Wood Cancer Center at Glens Falls Hospital	Glens Falls	New York	United States	12801
215	Randolph Hospital	Asheboro	North Carolina	United States	27203-5400
216	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina	United States	27534
217	Moses Cone Regional Cancer Center at Wesley Long Community Hospital	Greensboro	North Carolina	United States	27403-1198
218	Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
219	Kinston Medical Specialists	Kinston	North Carolina	United States	28501
220	FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center	Pinehurst	North Carolina	United States	28374
221	Annie Penn Cancer Center	Reidsville	North Carolina	United States	27320
222	Iredell Memorial Hospital	Statesville	North Carolina	United States	28677
223	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota	United States	58501
224	Mid Dakota Clinic, PC	Bismarck	North Dakota	United States	58501
225	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota	United States	58502
226	MeritCare Broadway	Fargo	North Dakota	United States	58102
227	Altru Cancer Center at Altru Hospital	Grand Forks	North Dakota	United States	58201
228	Wood County Oncology Center	Bowling Green	Ohio	United States	43402
229	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
230	Riverside Methodist Hospital Cancer Care	Columbus	Ohio	United States	43214-3998
231	CCOP - Columbus	Columbus	Ohio	United States	43215
232	Grant Medical Center Cancer Care	Columbus	Ohio	United States	43215
233	Mount Carmel Health - West Hospital	Columbus	Ohio	United States	43222
234	Doctors Hospital at Ohio Health	Columbus	Ohio	United States	43228
235	Grandview Hospital	Dayton	Ohio	United States	45405
236	Good Samaritan Hospital	Dayton	Ohio	United States	45406
237	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
238	Samaritan North Cancer Care Center	Dayton	Ohio	United States	45415
239	CCOP - Dayton	Dayton	Ohio	United States	45420
240	Grady Memorial Hospital	Delaware	Ohio	United States	43015
241	Community Cancer Center	Elyria	Ohio	United States	44035
242	Hematology Oncology Center	Elyria	Ohio	United States	44035
243	Blanchard Valley Medical Associates	Findlay	Ohio	United States	45840
244	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
245	Wayne Hospital	Greenville	Ohio	United States	45331
246	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
247	Fairfield Medical Center	Lancaster	Ohio	United States	43130
248	Lima Memorial Hospital	Lima	Ohio	United States	45804
249	Strecker Cancer Center at Marietta Memorial Hospital	Marietta	Ohio	United States	45750
250	Northwest Ohio Oncology Center	Maumee	Ohio	United States	43537-1839
251	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
252	Licking Memorial Cancer Care Program at Licking Memorial Hospital	Newark	Ohio	United States	43055
253	St. Charles Mercy Hospital	Oregon	Ohio	United States	43616
254	Toledo Clinic - Oregon	Oregon	Ohio	United States	43616
255	Southern Ohio Medical Center Cancer Center	Portsmouth	Ohio	United States	45662
256	Community Hospital of Springfield and Clark County	Springfield	Ohio	United States	45505
257	Flower Hospital Cancer Center	Sylvania	Ohio	United States	43560
258	Mercy Hospital of Tiffin	Tiffin	Ohio	United States	44883
259	Toledo Hospital	Toledo	Ohio	United States	43606
260	St. Vincent Mercy Medical Center	Toledo	Ohio	United States	43608
261	Medical University of Ohio Cancer Center	Toledo	Ohio	United States	43614
262	St. Anne Mercy Hospital	Toledo	Ohio	United States	43623
263	Toledo Clinic, Incorporated - Main Clinic	Toledo	Ohio	United States	43623
264	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
265	Fulton County Health Center	Wauseon	Ohio	United States	43567
266	Mount Carmel St. Ann's Cancer Center	Westerville	Ohio	United States	43081
267	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385
268	Genesis - Good Samaritan Hospital	Zanesville	Ohio	United States	43701
269	Cancer Care Associates - Norman	Norman	Oklahoma	United States	73071
270	Cancer Care Associates - Mercy Campus	Oklahoma City	Oklahoma	United States	73120
271	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
272	Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest	Allentown	Pennsylvania	United States	18105
273	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
274	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania	United States	18201
275	Guthrie Cancer Center at Guthrie Clinic Sayre	Sayre	Pennsylvania	United States	18840
276	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
277	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
278	Cancer Centers of the Carolinas - Faris Road	Greenville	South Carolina	United States	29605
279	Cancer Centers of the Carolinas - Grove Commons	Greenville	South Carolina	United States	29605
280	Greenville Hospital Cancer Center	Greenville	South Carolina	United States	29605
281	CCOP - Greenville	Greenville	South Carolina	United States	29615
282	Cancer Centers of the Carolinas - Greer Medical Oncology	Greer	South Carolina	United States	29650
283	Cancer Centers of the Carolinas - Seneca	Seneca	South Carolina	United States	29672
284	Cancer Centers of the Carolinas - Spartanburg	Spartanburg	South Carolina	United States	29307
285	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
286	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
287	Danville Regional Medical Center	Danville	Virginia	United States	24541
288	Fredericksburg Oncology, Incorporated	Fredericksburg	Virginia	United States	22401
289	Mary Babb Randolph Cancer Center at West Virginia University Hospitals	Morgantown	West Virginia	United States	26506
290	Center for Cancer Treatment & Prevention at Sacred Heart Hospital	Eau Claire	Wisconsin	United States	54701
291	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin	United States	54701
292	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54301-3526
293	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin	United States	54303
294	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin	United States	54303
295	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
296	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601
297	Holy Family Memorial Medical Center Cancer Care Center	Manitowoc	Wisconsin	United States	54221-1450
298	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
299	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
300	Saint Joseph's Hospital	Marshfield	Wisconsin	United States	54449
301	Marshfield Clinic - Lakeland Center	Minocqua	Wisconsin	United States	54548
302	Green Bay Oncology, Limited - Oconto Falls	Oconto Falls	Wisconsin	United States	54154
303	Ministry Medical Group at Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
304	Marshfield Clinic - Indianhead Center	Rice Lake	Wisconsin	United States	54868
305	St. Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
306	Marshfield Clinic at Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
307	Saint Michael's Hospital Cancer Center	Stevens Point	Wisconsin	United States	54481
308	Green Bay Oncology, Limited - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
309	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
310	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)

Investigators

• Study Chair: Robert McWilliams, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00976573
• Other Study ID Numbers: NCCTG-N0879; NCI-2011-01968; CDR0000654465
• First Posted: Sep 14, 2009
• Last Update Posted: Apr 4, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Alliance for Clinical Trials in Oncology: Stage IV Skin Melanoma; recurrent melanoma
• Additional relevant MeSH terms: Melanoma; Paclitaxel; Bevacizumab; Carboplatin; Everolimus

Study Results

Participant Flow

Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)	Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	75	74
COMPLETED	71	71
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)	Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)	Total
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	75	74	149
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	58	59
Sex: Female, Male (Count of Participants)
Female	21 28%	33 44.6%	54 36.2%
Male	54 72%	41 55.4%	95 63.8%
Region of Enrollment (participants) [Number]
United States	75 100%	74 100%	149 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	The primary endpoint is progression-free survival (PFS) defined as the time from randomization to documentation of disease progression or death without documentation of progression. The distribution of PFS times will be estimated using the Kaplan-Meier method. Progression is defined using the RECIST Criteria as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum of diameters recorded on study (this includes the baseline sum if that is the smallest on study) or the appearance of one or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm of target lesions, or the appearance of one or more new lesions, unequivocal progression of existing non-target lesions, although unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Time Frame	Time from randomization to documentation of disease progression or death without documentation of progression;Up to 5 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis population: All participants enrolled are included in the primary analysis.

Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)	Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	75	74
Median (95% Confidence Interval) [months]	5.6	5.1

2. Secondary Outcome

Title	Toxicity
Description	For this secondary endpoint, toxicity is defined as a grade 3 or higher adverse events that is classified as either possibly, probably, or definitely related to study treatment. The assignment of attribution to study treatment and grade (or degree of severity) of the adverse event are classified using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The percentage of participants reporting a grade 3 or higher toxicity is reported. For a list of all reported adverse events, please refer to the Adverse Events Section below.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Participants who completed the study (specified in the Participant Flow) are included.

Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)	Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	71	71
Neutropenia	35 46.7%	58 78.4%
Leukopenia	17 22.7%	24 32.4%
Fatigue	11 14.7%	17 23%

3. Secondary Outcome

Title	Confirmed Tumor Response Rate (Complete Response [CR] or Partial Response [PR]) According to Response Evaluation Criteria in Solid Tumors (RECIST) Criteria
Description	Confirmed Tumor Response: A confirmed tumor response is defined to be a CR or PR (by the RECIST criteria) noted as the objective status on 2 consecutive evaluations at least 8 weeks apart. The proportion of tumor responses will be estimated by the number of confirmed tumor responses divided by the total number of evaluable patients. A ninety percent confidence interval for the true proportion of confirmed tumor responses will be calculated assuming that the number of confirmed tumor responses follows a binomial distribution.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis population: All participants enrolled are included.

Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)	Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	75	74
Number (95% Confidence Interval) [percentage of patients]	13	23

4. Secondary Outcome

Title	Overall Survival Time
Description	Overall survival time is defined as the time from registration to death due to any cause. The distribution of survival times will be estimated using the method of Kaplan-Meier.
Time Frame	up to 5 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis population: All participants enrolled are included.

Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)	Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	75	74
Median (95% Confidence Interval) [months]	14.5	10.8

Adverse Events

Time Frame	Adverse events are assessed less than or equal to 14 days prior to registration, prior to each cycle of treatment, at discontinuation of study treatment, and during observation 28-42 days after discontinuation of study treatment; Up to 5 years.
Adverse Event Reporting Description	The CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. All graded adverse events are reported. Patients who completed the study (as specified in the Participant Flow) and had adverse events assessed are included below.
Arm/Group Title	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)		Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
Arm/Group Description	Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15, 80 mg/m^2 paclitaxel IV over 60 minutes on days 1, 8, and 15, and AUC 5 carboplatin IV over 30 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.		Patients receive bevacizumab, paclitaxel, and carboplatin as in Arm I. Patients also receive 5 mg everolimus PO QD three times weekly (e.g. Monday, Wednesday, Friday). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)		Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)		Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/71 (16.9%)		18/71 (25.4%)
Blood and lymphatic system disorders
Anemia	0/71 (0%)	0	1/71 (1.4%)	1
Gastrointestinal disorders
Abdominal pain	1/71 (1.4%)	1	1/71 (1.4%)	1
Diarrhea	0/71 (0%)	0	1/71 (1.4%)	1
Gastric perforation	1/71 (1.4%)	1	0/71 (0%)	0
Jejunal perforation	0/71 (0%)	0	1/71 (1.4%)	1
Nausea	1/71 (1.4%)	1	2/71 (2.8%)	2
Vomiting	1/71 (1.4%)	2	1/71 (1.4%)	1
General disorders
Death NOS	0/71 (0%)	0	1/71 (1.4%)	1
Fatigue	2/71 (2.8%)	2	1/71 (1.4%)	1
Fever	0/71 (0%)	0	1/71 (1.4%)	1
Flu like symptoms	1/71 (1.4%)	1	0/71 (0%)	0
Non-cardiac chest pain	0/71 (0%)	0	1/71 (1.4%)	1
Immune system disorders
Allergic reaction	0/71 (0%)	0	1/71 (1.4%)	1
Anaphylaxis	1/71 (1.4%)	1	0/71 (0%)	0
Infections and infestations
Sepsis	0/71 (0%)	0	2/71 (2.8%)	2
Urinary tract infection	0/71 (0%)	0	2/71 (2.8%)	2
Wound infection	0/71 (0%)	0	1/71 (1.4%)	1
Injury, poisoning and procedural complications
Hip fracture	1/71 (1.4%)	1	0/71 (0%)	0
Investigations
Lymphocyte count decreased	1/71 (1.4%)	1	0/71 (0%)	0
Neutrophil count decreased	4/71 (5.6%)	4	5/71 (7%)	5
Platelet count decreased	2/71 (2.8%)	2	2/71 (2.8%)	2
White blood cell decreased	2/71 (2.8%)	2	1/71 (1.4%)	1
Metabolism and nutrition disorders
Dehydration	0/71 (0%)	0	1/71 (1.4%)	1
Hypertriglyceridemia	0/71 (0%)	0	2/71 (2.8%)	2
Hypokalemia	0/71 (0%)	0	1/71 (1.4%)	1
Hypophosphatemia	0/71 (0%)	0	1/71 (1.4%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/71 (1.4%)	1	0/71 (0%)	0
Generalized muscle weakness	0/71 (0%)	0	2/71 (2.8%)	2
Pain in extremity	0/71 (0%)	0	1/71 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/71 (1.4%)	1	1/71 (1.4%)	1
Nervous system disorders
Dizziness	0/71 (0%)	0	1/71 (1.4%)	1
Dysarthria	0/71 (0%)	0	1/71 (1.4%)	1
Headache	2/71 (2.8%)	3	0/71 (0%)	0
Intracranial hemorrhage	1/71 (1.4%)	1	1/71 (1.4%)	1
Seizure	1/71 (1.4%)	1	1/71 (1.4%)	1
Stroke	0/71 (0%)	0	1/71 (1.4%)	2
Renal and urinary disorders
Acute kidney injury	0/71 (0%)	0	2/71 (2.8%)	2
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/71 (0%)	0	1/71 (1.4%)	1
Voice alteration	1/71 (1.4%)	1	0/71 (0%)	0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	1/71 (1.4%)	1	0/71 (0%)	0
Skin ulceration	1/71 (1.4%)	1	0/71 (0%)	0
Vascular disorders
Hematoma	0/71 (0%)	0	1/71 (1.4%)	1
Hypertension	1/71 (1.4%)	1	1/71 (1.4%)	1
Lymphedema	0/71 (0%)	0	1/71 (1.4%)	1
Thromboembolic event	1/71 (1.4%)	1	2/71 (2.8%)	2
Other (Not Including Serious) Adverse Events
	Arm A (Bevacizumab, Paclitaxel, and Carboplatin)		Arm B (Bevacizumab, Paclitaxel, Carboplatin, and Everolimus)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/71 (100%)		71/71 (100%)
Blood and lymphatic system disorders
Anemia	63/71 (88.7%)	357	59/71 (83.1%)	332
Febrile neutropenia	0/71 (0%)	0	2/71 (2.8%)	2
Leukocytosis	0/71 (0%)	0	1/71 (1.4%)	1
Cardiac disorders
Atrial fibrillation	1/71 (1.4%)	1	1/71 (1.4%)	1
Cardiac arrest	1/71 (1.4%)	1	0/71 (0%)	0
Heart failure	0/71 (0%)	0	1/71 (1.4%)	1
Left ventricular systolic dysfunction	0/71 (0%)	0	1/71 (1.4%)	1
Myocardial infarction	0/71 (0%)	0	1/71 (1.4%)	1
Pericardial effusion	1/71 (1.4%)	1	0/71 (0%)	0
Sinus tachycardia	1/71 (1.4%)	1	1/71 (1.4%)	1
Endocrine disorders
Adrenal insufficiency	0/71 (0%)	0	1/71 (1.4%)	1
Hypothyroidism	0/71 (0%)	0	1/71 (1.4%)	1
Eye disorders
Blurred vision	1/71 (1.4%)	1	2/71 (2.8%)	2
Dry eye	1/71 (1.4%)	1	0/71 (0%)	0
Eye disorders - Other, specify	0/71 (0%)	0	1/71 (1.4%)	1
Gastrointestinal disorders
Abdominal pain	24/71 (33.8%)	51	24/71 (33.8%)	47
Bloating	0/71 (0%)	0	1/71 (1.4%)	1
Constipation	9/71 (12.7%)	11	5/71 (7%)	7
Diarrhea	7/71 (9.9%)	12	10/71 (14.1%)	16
Duodenal ulcer	1/71 (1.4%)	1	0/71 (0%)	0
Dyspepsia	4/71 (5.6%)	4	2/71 (2.8%)	6
Dysphagia	1/71 (1.4%)	1	2/71 (2.8%)	2
Flatulence	0/71 (0%)	0	1/71 (1.4%)	1
Gastric hemorrhage	1/71 (1.4%)	1	0/71 (0%)	0
Hemorrhoids	1/71 (1.4%)	1	2/71 (2.8%)	3
Ileus	1/71 (1.4%)	1	0/71 (0%)	0
Mucositis oral	3/71 (4.2%)	11	8/71 (11.3%)	11
Nausea	40/71 (56.3%)	152	46/71 (64.8%)	129
Pancreatitis	0/71 (0%)	0	1/71 (1.4%)	2
Toothache	1/71 (1.4%)	1	1/71 (1.4%)	1
Vomiting	22/71 (31%)	46	25/71 (35.2%)	52
General disorders
Death NOS	1/71 (1.4%)	1	1/71 (1.4%)	1
Edema limbs	1/71 (1.4%)	1	1/71 (1.4%)	1
Fatigue	68/71 (95.8%)	408	67/71 (94.4%)	352
Fever	14/71 (19.7%)	19	15/71 (21.1%)	16
Infusion related reaction	2/71 (2.8%)	7	0/71 (0%)	0
Infusion site extravasation	0/71 (0%)	0	2/71 (2.8%)	2
Non-cardiac chest pain	1/71 (1.4%)	1	0/71 (0%)	0
Pain	0/71 (0%)	0	1/71 (1.4%)	1
Immune system disorders
Allergic reaction	10/71 (14.1%)	14	7/71 (9.9%)	8
Anaphylaxis	0/71 (0%)	0	1/71 (1.4%)	1
Infections and infestations
Anorectal infection	0/71 (0%)	0	1/71 (1.4%)	1
Bladder infection	1/71 (1.4%)	1	0/71 (0%)	0
Catheter related infection	2/71 (2.8%)	3	0/71 (0%)	0
Device related infection	0/71 (0%)	0	1/71 (1.4%)	1
Infections and infestations - Other, specify	1/71 (1.4%)	1	1/71 (1.4%)	1
Lip infection	1/71 (1.4%)	1	1/71 (1.4%)	1
Lung infection	1/71 (1.4%)	1	0/71 (0%)	0
Peripheral nerve infection	0/71 (0%)	0	1/71 (1.4%)	1
Rash pustular	0/71 (0%)	0	1/71 (1.4%)	1
Sepsis	1/71 (1.4%)	1	3/71 (4.2%)	3
Sinusitis	1/71 (1.4%)	3	2/71 (2.8%)	6
Skin infection	2/71 (2.8%)	2	5/71 (7%)	7
Soft tissue infection	1/71 (1.4%)	2	0/71 (0%)	0
Tooth infection	1/71 (1.4%)	1	1/71 (1.4%)	1
Upper respiratory infection	1/71 (1.4%)	3	3/71 (4.2%)	4
Urinary tract infection	1/71 (1.4%)	3	2/71 (2.8%)	2
Vulval infection	0/71 (0%)	0	1/71 (1.4%)	2
Wound infection	2/71 (2.8%)	2	1/71 (1.4%)	1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify	1/71 (1.4%)	1	0/71 (0%)	0
Wound dehiscence	1/71 (1.4%)	4	3/71 (4.2%)	9
Investigations
Alanine aminotransferase increased	0/71 (0%)	0	3/71 (4.2%)	3
Alkaline phosphatase increased	0/71 (0%)	0	3/71 (4.2%)	4
Aspartate aminotransferase increased	0/71 (0%)	0	3/71 (4.2%)	3
Blood bilirubin increased	0/71 (0%)	0	1/71 (1.4%)	1
CD4 lymphocytes decreased	2/71 (2.8%)	2	1/71 (1.4%)	2
Cholesterol high	0/71 (0%)	0	6/71 (8.5%)	13
Creatinine increased	2/71 (2.8%)	3	2/71 (2.8%)	2
Investigations - Other, specify	1/71 (1.4%)	2	0/71 (0%)	0
Lipase increased	0/71 (0%)	0	1/71 (1.4%)	1
Lymphocyte count decreased	5/71 (7%)	14	7/71 (9.9%)	13
Lymphocyte count increased	1/71 (1.4%)	1	1/71 (1.4%)	1
Neutrophil count decreased	49/71 (69%)	177	59/71 (83.1%)	209
Platelet count decreased	47/71 (66.2%)	177	50/71 (70.4%)	196
Weight gain	1/71 (1.4%)	12	2/71 (2.8%)	2
Weight loss	2/71 (2.8%)	3	5/71 (7%)	23
White blood cell decreased	54/71 (76.1%)	217	55/71 (77.5%)	215
Metabolism and nutrition disorders
Anorexia	8/71 (11.3%)	14	13/71 (18.3%)	23
Dehydration	7/71 (9.9%)	8	4/71 (5.6%)	4
Hyperglycemia	1/71 (1.4%)	1	3/71 (4.2%)	3
Hyperkalemia	0/71 (0%)	0	1/71 (1.4%)	1
Hypertriglyceridemia	1/71 (1.4%)	1	11/71 (15.5%)	34
Hyperuricemia	0/71 (0%)	0	1/71 (1.4%)	1
Hypoalbuminemia	0/71 (0%)	0	6/71 (8.5%)	6
Hypocalcemia	0/71 (0%)	0	3/71 (4.2%)	7
Hypoglycemia	0/71 (0%)	0	1/71 (1.4%)	1
Hypokalemia	0/71 (0%)	0	1/71 (1.4%)	2
Hypomagnesemia	1/71 (1.4%)	3	0/71 (0%)	0
Hyponatremia	4/71 (5.6%)	7	2/71 (2.8%)	2
Hypophosphatemia	3/71 (4.2%)	5	2/71 (2.8%)	11
Musculoskeletal and connective tissue disorders
Arthralgia	19/71 (26.8%)	41	24/71 (33.8%)	60
Back pain	4/71 (5.6%)	4	2/71 (2.8%)	2
Bone pain	0/71 (0%)	0	1/71 (1.4%)	1
Flank pain	1/71 (1.4%)	1	0/71 (0%)	0
Generalized muscle weakness	3/71 (4.2%)	3	5/71 (7%)	6
Muscle weakness lower limb	1/71 (1.4%)	1	1/71 (1.4%)	1
Musculoskeletal and connective tissue disorder - Other, specify	0/71 (0%)	0	1/71 (1.4%)	1
Myalgia	14/71 (19.7%)	28	25/71 (35.2%)	66
Pain in extremity	2/71 (2.8%)	6	1/71 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	2/71 (2.8%)	3	0/71 (0%)	0
Nervous system disorders
Cognitive disturbance	2/71 (2.8%)	2	1/71 (1.4%)	1
Dizziness	1/71 (1.4%)	1	2/71 (2.8%)	2
Dysesthesia	0/71 (0%)	0	1/71 (1.4%)	1
Dysgeusia	3/71 (4.2%)	7	7/71 (9.9%)	12
Headache	1/71 (1.4%)	3	3/71 (4.2%)	3
Hypersomnia	1/71 (1.4%)	1	0/71 (0%)	0
Intracranial hemorrhage	1/71 (1.4%)	1	1/71 (1.4%)	1
Memory impairment	1/71 (1.4%)	1	0/71 (0%)	0
Olfactory nerve disorder	0/71 (0%)	0	1/71 (1.4%)	1
Paresthesia	1/71 (1.4%)	9	0/71 (0%)	0
Peripheral motor neuropathy	2/71 (2.8%)	2	0/71 (0%)	0
Peripheral sensory neuropathy	36/71 (50.7%)	190	29/71 (40.8%)	159
Presyncope	0/71 (0%)	0	1/71 (1.4%)	1
Seizure	0/71 (0%)	0	1/71 (1.4%)	1
Psychiatric disorders
Anxiety	2/71 (2.8%)	2	1/71 (1.4%)	1
Confusion	1/71 (1.4%)	1	0/71 (0%)	0
Depression	1/71 (1.4%)	1	1/71 (1.4%)	1
Insomnia	3/71 (4.2%)	4	2/71 (2.8%)	6
Renal and urinary disorders
Acute kidney injury	1/71 (1.4%)	1	0/71 (0%)	0
Hematuria	0/71 (0%)	0	1/71 (1.4%)	1
Proteinuria	14/71 (19.7%)	24	14/71 (19.7%)	31
Renal and urinary disorders - Other, specify	0/71 (0%)	0	1/71 (1.4%)	1
Urinary tract obstruction	0/71 (0%)	0	1/71 (1.4%)	1
Reproductive system and breast disorders
Irregular menstruation	0/71 (0%)	0	1/71 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/71 (1.4%)	2	0/71 (0%)	0
Dyspnea	8/71 (11.3%)	28	2/71 (2.8%)	2
Epistaxis	3/71 (4.2%)	3	1/71 (1.4%)	3
Pneumonitis	0/71 (0%)	0	1/71 (1.4%)	2
Pneumothorax	0/71 (0%)	0	1/71 (1.4%)	1
Pulmonary edema	1/71 (1.4%)	1	0/71 (0%)	0
Respiratory failure	0/71 (0%)	0	1/71 (1.4%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	0/71 (0%)	0	1/71 (1.4%)	2
Sinus disorder	0/71 (0%)	0	1/71 (1.4%)	1
Sore throat	1/71 (1.4%)	1	1/71 (1.4%)	2
Skin and subcutaneous tissue disorders
Alopecia	13/71 (18.3%)	32	21/71 (29.6%)	73
Bullous dermatitis	0/71 (0%)	0	1/71 (1.4%)	1
Dry skin	0/71 (0%)	0	2/71 (2.8%)	3
Hyperhidrosis	2/71 (2.8%)	3	0/71 (0%)	0
Nail loss	1/71 (1.4%)	2	0/71 (0%)	0
Pruritus	0/71 (0%)	0	1/71 (1.4%)	1
Rash acneiform	1/71 (1.4%)	1	0/71 (0%)	0
Rash maculo-papular	0/71 (0%)	0	3/71 (4.2%)	3
Skin ulceration	1/71 (1.4%)	4	1/71 (1.4%)	1
Vascular disorders
Flushing	0/71 (0%)	0	1/71 (1.4%)	1
Hot flashes	0/71 (0%)	0	1/71 (1.4%)	1
Hypertension	39/71 (54.9%)	190	37/71 (52.1%)	205
Hypotension	1/71 (1.4%)	1	5/71 (7%)	5
Peripheral ischemia	1/71 (1.4%)	2	0/71 (0%)	0
Thromboembolic event	4/71 (5.6%)	5	5/71 (7%)	9
Vascular disorders - Other, specify	0/71 (0%)	0	1/71 (1.4%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.