Intensity-Modulated Radiation Therapy, Cisplatin, and Bevacizumab Followed by Carboplatin and Paclitaxel in Treating Patients Who Have Undergone Surgery for Endometrial Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01005329
• Collaborator: Radiation Therapy Oncology Group (Other)
• Enrollment: 34
• Locations: 41
• Arm: 1
• Actual Duration (Months): 46.5
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects of giving intensity-modulated radiation therapy together with cisplatin and bevacizumab followed by carboplatin and cisplatin and to see how well they work in treating patients who have undergone surgery for high-risk endometrial cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, 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, can block the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving intensity-modulated radiation therapy together with chemotherapy and bevacizumab after surgery may kill any tumor cells that remain after surgery.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Stage IA Uterine Corpus Cancer AJCC v7; Stage IB Uterine Corpus Cancer AJCC v7; Stage II Uterine Corpus Cancer AJCC v7; Stage IIIA Uterine Corpus Cancer AJCC v7; Stage IIIB Uterine Corpus Cancer AJCC v7; Stage IIIC Uterine Corpus Cancer AJCC v7; Stage IVA Uterine Corpus Cancer AJCC v7; Stage IVB Uterine Corpus Cancer AJCC v7	Biological: Bevacizumab; Drug: Carboplatin; Drug: Cisplatin; Radiation: Intensity-Modulated Radiation Therapy; Drug: Paclitaxel	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To assess the treatment-related, grade 3+, non-hematologic adverse-event rate within 90 days from the start of treatment with concurrent intensity-modulated radiotherapy, cisplatin, and bevacizumab followed by carboplatin and paclitaxel in patients with high-risk endometrial cancer.

SECONDARY OBJECTIVES:

1. To evaluate treatment-related adverse events occurring within 1 year from the start of treatment.

2. To evaluate all treatment-related adverse events. III. To evaluate disease-free and overall survival. IV. To evaluate local, regional, and distant failure.

OUTLINE:

Patients undergo pelvic intensity-modulated radiotherapy (IMRT) once daily, 5 days a week, for 5 weeks. Patients may also undergo optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Patients also receive concurrent cisplatin intravenously (IV) over 1 hour on days 1 and 29 and bevacizumab IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin IV over 1 hour and paclitaxel IV over 3 hours on day 1. Treatment with carboplatin and paclitaxel repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Postoperative Intensity Modulated Radiation Therapy (IMRT) With Concurrent Cisplatin and Bevacizumab Followed by Carboplatin and Paclitaxel for Patients With Endometrial Cancer
• Actual Study Start Date: Nov 6, 2009
• Actual Primary Completion Date: Jun 30, 2012
• Actual Study Completion Date: Sep 22, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (IMRT, cisplatin,bevacizumab,carboplatin,paclitaxel) Patients undergo pelvic IMRT once daily, 5 days a week, for 5 weeks. Patients may also undergo optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Patients also receive concurrent cisplatin IV over 1 hour on days 1 and 29 and bevacizumab IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin IV over 1 hour and paclitaxel IV over 3 hours on day 1. Treatment with carboplatin and paclitaxel repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab; Given IV; Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar FKB238 BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF ; Drug: Carboplatin; Given IV; Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo ; Drug: Cisplatin; Given IV; Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin ; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT Intensity Modulated RT Intensity-Modulated Radiotherapy ; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Treatment-related, Grade 3+, Non-hematologic Adverse Events Occuring Within 90 Days After Treatment Start [From start of treatment to 90 days]

   Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE, assigning Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

Secondary Outcome Measures

1. Percentage of Participants With Treatment-related, Grade 3+, Non-hematologic Adverse Events Occuring Within 1 Year After Treatment Start [From start of treatment to one year]

   Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE, assigning Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Adverse events reported as definitely, probably, or possibly related to study treatment.

2. Treatment-related Grade 3+ Adverse Events [From start of treatment to end of follow-up, up to 43.4 months; analysis occurred after all patients had been on study for at least one year.]

   The highest grade adverse event per patient reported as definitely, probably, or possibly related to study treatment is counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE, assigning Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

3. Overall Survival (Two-year Rate Reported) [From registration to two years]

   Failure was defined as death due to any cause. Patients alive at time of analysis were censored at the date of last contact. Survival rate at two years was estimated using the Kaplan-Meier method.

4. Disease-free Survival (Two-year Rate Reported) [From registration to two years]

   Failure was defined as pelvic failure (recurrence in the pelvis, which must be confirmed by histologic or cytologic biopsy of the recurrent lesion), distant failure (confirmed by histologic or cytologic biopsy of the recurrent lesion), or death due to any cause. Patients alive at time of analysis were censored at the date of last contact. Disease-free survival rate at two years was estimated using the Kaplan-Meier method.

5. Pelvic Failure Rate (Two-year Rate Reported) [From registration to two years]

   Pelvic failure (PF) was defined as disease recurrence in the pelvis, including the pelvic or sacral lymph nodes, and required confirmation by histologic or cytologic biopsy of the recurrent lesion. Death was considered a competing risk. PF rates were estimated using the cumulative incidence method.

6. Distant Failure (Two-year Rate Reported) [From registration to two years]

   Distant Failure (DF) was defined as the appearance of distant metastasis. Death was considered a competing risk. DF rates were estimated using the cumulative incidence method.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed endometrial cancer, including 1 of the following cellular types:

• Endometrioid endometrial adenocarcinoma

• Clear cell carcinoma

• Papillary serous adenocarcinoma

• Adenosquamous cell carcinoma

• Other adenocarcinoma variant

• No carcinosarcoma

• Meets 1 of the following criteria:

• Grade 3 carcinoma with > 50% myometrial invasion (stage IC or IIA) (all papillary serous or clear cell carcinoma will be considered grade 3)

• Grade 2 or 3 carcinoma with any cervical stromal invasion (stage IIB)

• Known extra-uterine disease confined to the pelvis (stage III or IVA)

• Patients with stage III or IVA disease must have undergone computed tomography (CT) scan or positron emission tomography (PET)/CT scan of the abdomen and pelvis within the past 56 days

• Has undergone hysterectomy (i.e., total abdominal, vaginal, robotic-assisted, radical, or laparoscopic-assisted vaginal hysterectomy) and bilateral salpingo-oophorectomy within the past 56 days

• No positive common iliac or positive para-aortic nodal disease (defined as lymph nodes ? 2 cm in any dimension on CT scan or biopsy) or positive peritoneal cytology

• No evidence of metastatic extrauterine disease, gross or residual disease (not including pelvic nodal disease), or distant metastases

• Zubrod performance status 0-1

• Absolute neutrophil count (ANC) ? 1,500/mm^3 (without growth factor support)

• Platelet count ? 100,000/mm^3

• Hemoglobin ? 10 g/dL (transfusion allowed)

• Total bilirubin ? 1.5 times upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2 times ULN

• Serum creatinine ? 1.5 mg/dL

• Urine protein:creatinine ratio ? 0.5 OR urine protein < 1,000 mg on 24-hour urine collection

• International normalized ratio (INR) < 1.5 (for patients treated with warfarin within the past 14 days)

• Not nursing

• No neuropathy ? Common Terminology Criteria for Adverse Events (CTCAE) grade 1

• No ototoxicity > CTCAE grade 2

• No serious, active comorbidity, including any of the following:

• Unstable angina and/or New York Heart Association (NYHA) class II-IV congestive heart failure requiring hospitalization within the past 12 months

• Transmural myocardial infarction within the past 12 months

• Acute bacterial or fungal infection requiring IV antibiotics

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition (human immunodeficiency virus [HIV] testing is not required)

• Active gastrointestinal (GI) ulcers, GI bleeding, inflammatory bowel disease, or GI obstruction

• Inadequately controlled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg and/or diastolic BP > 90 mm Hg on antihypertensive medications

• Significant vascular disease, including aortic aneurysm, aortic dissection, or arteriovenous malformation within the past 12 months

• Serious cardiac arrhythmia on medication (well-controlled atrial fibrillation on medication allowed)

• Serious non-healing wound, ulcer, or bone fracture

• No history of hypertensive crisis or hypertensive encephalopathy

• No stroke/cerebrovascular event within the past 12 months

• No arterial thromboembolic events, including transient ischemic attack or clinically symptomatic peripheral artery disease within the past 12 months

• No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 6 months

• No other invasive malignancies within the past 3 years other than nonmelanomatous skin cancer

• No significant trauma within the past 28 days

• No mental status changes or bladder problems that would preclude the ability to comply with bladder-filling instructions

• No mental or psychiatric illness that would preclude giving informed consent

• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• No prior allergic reaction to bevacizumab, cisplatin, carboplatin, or paclitaxel

• No concurrent erythropoietin, St. John's wort, therapeutic anticoagulants, aminoglycoside antibiotics, or amifostine

• No prior organ transplantation

• No prior external-beam radiotherapy to the pelvis resulting in overlapping of radiotherapy fields

• No prior systemic chemotherapy for uterine cancer

• Prior chemotherapy for a different cancer is allowed

• No prior therapy with anti-vascular endothelial growth factor (VEGF) compounds

• More than 28 days since prior major surgical procedure requiring open biopsy incision

• No concurrent surgery (except for vascular access device placement or procedures that do not require significant incision)

• No concurrent warfarin at doses > 1 mg/day

• Concurrent prophylactic low molecular weight heparin allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
2	John Muir Medical Center-Walnut Creek	Walnut Creek	California	United States	94598
3	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
4	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
5	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
6	Integrated Community Oncology Network-Florida Cancer Center Beaches	Jacksonville Beach	Florida	United States	32250
7	Baptist MD Anderson Cancer Center	Jacksonville	Florida	United States	32207
8	Integrated Community Oncology Network-Southside Cancer Center	Jacksonville	Florida	United States	32207
9	University of Florida Health Science Center - Jacksonville	Jacksonville	Florida	United States	32209
10	Baptist Medical Center South	Jacksonville	Florida	United States	32258
11	21st Century Oncology-Orange Park	Orange Park	Florida	United States	32073
12	21st Century Oncology-Palatka	Palatka	Florida	United States	32177
13	Bay Medical Center	Panama City	Florida	United States	32401
14	Integrated Community Oncology Network-Flager Cancer Center	Saint Augustine	Florida	United States	32086
15	Northwestern University	Chicago	Illinois	United States	60611
16	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
17	Saint Vincent Anderson Regional Hospital/Cancer Center	Anderson	Indiana	United States	46016
18	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
19	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
20	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
21	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland	United States	21044
22	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
23	Henry Ford Hospital	Detroit	Michigan	United States	48202
24	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
25	Elliot Hospital	Manchester	New Hampshire	United States	03103
26	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
27	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
28	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
29	Summa Barberton Hospital	Barberton	Ohio	United States	44203
30	Flower Hospital	Sylvania	Ohio	United States	43560
31	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
32	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
33	Radiation Therapy Oncology Group	Philadelphia	Pennsylvania	United States	19103
34	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
35	M D Anderson Cancer Center	Houston	Texas	United States	77030
36	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
37	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia	United States	26003
38	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
39	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
40	McGill University Department of Oncology	Montreal	Quebec	Canada	H2W 1S6
41	Pamela Youde Nethersole Eastern Hospital	Chai Wan		Hong Kong

Sponsors and Collaborators

• National Cancer Institute (NCI)
• Radiation Therapy Oncology Group

Investigators

• Principal Investigator: Akila Viswanathan, Radiation Therapy Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01005329
• Other Study ID Numbers: NCI-2011-01982; NCI-2011-01982; CDR0000657979; RTOG-0921; RTOG 0921; RTOG-0921; U10CA021661
• First Posted: Oct 30, 2009
• Last Update Posted: Mar 15, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Adenocarcinoma; Endometrial Neoplasms; Cystadenocarcinoma, Serous; Adenocarcinoma, Clear Cell; Carcinoma, Adenosquamous; Paclitaxel; Bevacizumab; Cisplatin; Carboplatin; Albumin-Bound Paclitaxel; Antineoplastic Agents, Immunological; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	34
COMPLETED	30
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV AUC 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Overall Participants	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	30 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Treatment-related, Grade 3+, Non-hematologic Adverse Events Occuring Within 90 Days After Treatment Start
Description	Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE, assigning Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time Frame	From start of treatment to 90 days

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV AUC 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Number (90% Confidence Interval) [percentage of participants]	23.3 77.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chemoradiation (IMRT), Chemotherapy
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		The rate of the acute specified AEs (adverse events) from previous (and prior to ClinicalTrials.gov requirements) Radiation Therapy Oncology Group (RTOG) trial 9708 of RT + cisplatin was 44% and the hypothesis is that the addition of bevacizumab to IMRT + cisplatin will not increase this rate beyond 60%. This study was designed with a 1-sided, upper bound confidence interval to estimate this AE rate. Twenty-seven evaluable patients were required to have 95% confidence that the true grade 3+ non-hematologic treatment-related AE rate is not greater than 60%. Please note that this is a 95% ONE-SIDED confidence bound which is equivalent to the upper bound of a two-sided 90% confidence interval.

2. Secondary Outcome

Title	Percentage of Participants With Treatment-related, Grade 3+, Non-hematologic Adverse Events Occuring Within 1 Year After Treatment Start
Description	Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE, assigning Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Adverse events reported as definitely, probably, or possibly related to study treatment.
Time Frame	From start of treatment to one year

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Number (95% Confidence Interval) [percentage of participants]	43.3 144.3%

3. Secondary Outcome

Title	Treatment-related Grade 3+ Adverse Events
Description	The highest grade adverse event per patient reported as definitely, probably, or possibly related to study treatment is counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE, assigning Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time Frame	From start of treatment to end of follow-up, up to 43.4 months; analysis occurred after all patients had been on study for at least one year.

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Grade 0	1 3.3%
Grade 1	0 0%
Grade 2	8 26.7%
Grade 3	12 40%
Grade 4	9 30%
Grade 5	0 0%

4. Secondary Outcome

Title	Overall Survival (Two-year Rate Reported)
Description	Failure was defined as death due to any cause. Patients alive at time of analysis were censored at the date of last contact. Survival rate at two years was estimated using the Kaplan-Meier method.
Time Frame	From registration to two years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Number (95% Confidence Interval) [percentage of participants]	96.7 322.3%

5. Secondary Outcome

Title	Disease-free Survival (Two-year Rate Reported)
Description	Failure was defined as pelvic failure (recurrence in the pelvis, which must be confirmed by histologic or cytologic biopsy of the recurrent lesion), distant failure (confirmed by histologic or cytologic biopsy of the recurrent lesion), or death due to any cause. Patients alive at time of analysis were censored at the date of last contact. Disease-free survival rate at two years was estimated using the Kaplan-Meier method.
Time Frame	From registration to two years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Number (95% Confidence Interval) [percentage of participants]	79.1 263.7%

6. Secondary Outcome

Title	Pelvic Failure Rate (Two-year Rate Reported)
Description	Pelvic failure (PF) was defined as disease recurrence in the pelvis, including the pelvic or sacral lymph nodes, and required confirmation by histologic or cytologic biopsy of the recurrent lesion. Death was considered a competing risk. PF rates were estimated using the cumulative incidence method.
Time Frame	From registration to two years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Number (95% Confidence Interval) [percentage of participants]	0 0%

7. Secondary Outcome

Title	Distant Failure (Two-year Rate Reported)
Description	Distant Failure (DF) was defined as the appearance of distant metastasis. Death was considered a competing risk. DF rates were estimated using the cumulative incidence method.
Time Frame	From registration to two years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV area under the curve (AUC) 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	30
Median (95% Confidence Interval) [percentage of participants]	17.0 56.7%

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given serious adverse event (SAE) are counted only once for that SAE. The same methodology was applied for non-SAE adverse events (AE).
Arm/Group Title	Chemoradiation (IMRT), Chemotherapy
Arm/Group Description	Pelvic intensity-modulated radiation therapy (IMRT) once daily, 5 days a week, for 5 weeks (45 Gy in 25 fractions) with optional nodal boost radiotherapy and/or vaginal brachytherapy boost. Concurrent cisplatin (CISPT) 50 mg/m^2 IV over 1 hour on days 1 and 29 and bevacizumab (BEV) 5mg/kg IV over 30-90 minutes on days 1, 15, and 29. Beginning 4-6 weeks after completing IMRT, cisplatin, and bevacizumab, patients receive carboplatin (CBCDA) IV AUC 5 over 1 hour and paclitaxel (PTX) IV 135 mg/m^2 over 3 hours on day 1 and every every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Chemoradiation (IMRT), Chemotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Chemoradiation (IMRT), Chemotherapy
	Affected / at Risk (%)	# Events
Total	8/30 (26.7%)
Blood and lymphatic system disorders
Anemia	2/30 (6.7%)
Febrile neutropenia	1/30 (3.3%)
Gastrointestinal disorders
Diarrhea	1/30 (3.3%)
Esophageal pain	1/30 (3.3%)
Infections and infestations
Skin infection	1/30 (3.3%)
Urinary tract infection	1/30 (3.3%)
Investigations
Lymphocyte count decreased	2/30 (6.7%)
Neutrophil count decreased	2/30 (6.7%)
Platelet count decreased	1/30 (3.3%)
White blood cell decreased	1/30 (3.3%)
Metabolism and nutrition disorders
Hypoalbuminemia	1/30 (3.3%)
Hypokalemia	1/30 (3.3%)
Hyponatremia	1/30 (3.3%)
Nervous system disorders
Neuralgia	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/30 (3.3%)
Vascular disorders
Thromboembolic event	1/30 (3.3%)
Other (Not Including Serious) Adverse Events
	Chemoradiation (IMRT), Chemotherapy
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Anemia	22/30 (73.3%)
Blood and lymphatic system disorders - Other, specify	2/30 (6.7%)
Cardiac disorders
Chest pain - cardiac	1/30 (3.3%)
Palpitations	2/30 (6.7%)
Sinus tachycardia	2/30 (6.7%)
Ear and labyrinth disorders
Ear pain	3/30 (10%)
Hearing impaired	4/30 (13.3%)
Tinnitus	5/30 (16.7%)
Eye disorders
Blurred vision	8/30 (26.7%)
Eye disorders - Other, specify	1/30 (3.3%)
Eye pain	1/30 (3.3%)
Floaters	2/30 (6.7%)
Photophobia	1/30 (3.3%)
Gastrointestinal disorders
Abdominal pain	9/30 (30%)
Anal mucositis	1/30 (3.3%)
Anal pain	3/30 (10%)
Bloating	7/30 (23.3%)
Constipation	18/30 (60%)
Dental caries	1/30 (3.3%)
Diarrhea	22/30 (73.3%)
Dry mouth	1/30 (3.3%)
Dyspepsia	7/30 (23.3%)
Dysphagia	2/30 (6.7%)
Esophageal pain	1/30 (3.3%)
Fecal incontinence	2/30 (6.7%)
Flatulence	2/30 (6.7%)
Gastroesophageal reflux disease	2/30 (6.7%)
Gastrointestinal disorders - Other, specify	2/30 (6.7%)
Gastrointestinal pain	1/30 (3.3%)
Hemorrhoids	3/30 (10%)
Mucositis oral	5/30 (16.7%)
Nausea	19/30 (63.3%)
Proctitis	3/30 (10%)
Rectal hemorrhage	4/30 (13.3%)
Rectal pain	3/30 (10%)
Salivary duct inflammation	1/30 (3.3%)
Vomiting	11/30 (36.7%)
General disorders
Chills	3/30 (10%)
Edema face	2/30 (6.7%)
Edema limbs	8/30 (26.7%)
Fatigue	26/30 (86.7%)
Fever	1/30 (3.3%)
Flu like symptoms	1/30 (3.3%)
Gait disturbance	1/30 (3.3%)
General disorders and administration site conditions - Other, specify	3/30 (10%)
Localized edema	1/30 (3.3%)
Pain	5/30 (16.7%)
Infections and infestations
Bladder infection	2/30 (6.7%)
Infections and infestations - Other, specify	2/30 (6.7%)
Lung infection	1/30 (3.3%)
Skin infection	1/30 (3.3%)
Tooth infection	1/30 (3.3%)
Upper respiratory infection	1/30 (3.3%)
Urethral infection	1/30 (3.3%)
Urinary tract infection	4/30 (13.3%)
Vaginal infection	1/30 (3.3%)
Wound infection	1/30 (3.3%)
Injury, poisoning and procedural complications
Ankle fracture	1/30 (3.3%)
Dermatitis radiation	5/30 (16.7%)
Radiation recall reaction (dermatologic)	1/30 (3.3%)
Investigations
Alanine aminotransferase increased	6/30 (20%)
Alkaline phosphatase increased	3/30 (10%)
Aspartate aminotransferase increased	6/30 (20%)
Blood bilirubin increased	1/30 (3.3%)
Cholesterol high	1/30 (3.3%)
Creatinine increased	5/30 (16.7%)
GGT increased	2/30 (6.7%)
Hemoglobin increased	1/30 (3.3%)
Investigations - Other, specify	6/30 (20%)
Lymphocyte count decreased	19/30 (63.3%)
Lymphocyte count increased	2/30 (6.7%)
Neutrophil count decreased	17/30 (56.7%)
Platelet count decreased	16/30 (53.3%)
Weight gain	2/30 (6.7%)
Weight loss	6/30 (20%)
White blood cell decreased	23/30 (76.7%)
Metabolism and nutrition disorders
Anorexia	11/30 (36.7%)
Dehydration	4/30 (13.3%)
Hypercalcemia	3/30 (10%)
Hyperglycemia	19/30 (63.3%)
Hypertriglyceridemia	1/30 (3.3%)
Hyperuricemia	3/30 (10%)
Hypoalbuminemia	7/30 (23.3%)
Hypocalcemia	5/30 (16.7%)
Hypoglycemia	1/30 (3.3%)
Hypokalemia	6/30 (20%)
Hypomagnesemia	15/30 (50%)
Hyponatremia	6/30 (20%)
Hypophosphatemia	2/30 (6.7%)
Metabolism and nutrition disorders - Other, specify	2/30 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/30 (10%)
Arthritis	1/30 (3.3%)
Back pain	7/30 (23.3%)
Bone pain	2/30 (6.7%)
Buttock pain	1/30 (3.3%)
Flank pain	1/30 (3.3%)
Generalized muscle weakness	3/30 (10%)
Muscle weakness lower limb	1/30 (3.3%)
Musculoskeletal and connective tissue disorder - Other, specify	4/30 (13.3%)
Myalgia	6/30 (20%)
Neck pain	1/30 (3.3%)
Pain in extremity	7/30 (23.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/30 (3.3%)
Tumor pain	1/30 (3.3%)
Nervous system disorders
Cognitive disturbance	1/30 (3.3%)
Concentration impairment	1/30 (3.3%)
Dizziness	6/30 (20%)
Dysgeusia	3/30 (10%)
Extrapyramidal disorder	1/30 (3.3%)
Headache	12/30 (40%)
Neuralgia	1/30 (3.3%)
Paresthesia	5/30 (16.7%)
Peripheral motor neuropathy	4/30 (13.3%)
Peripheral sensory neuropathy	14/30 (46.7%)
Syncope	2/30 (6.7%)
Psychiatric disorders
Agitation	1/30 (3.3%)
Anxiety	7/30 (23.3%)
Depression	7/30 (23.3%)
Insomnia	5/30 (16.7%)
Renal and urinary disorders
Acute kidney injury	1/30 (3.3%)
Bladder spasm	1/30 (3.3%)
Cystitis noninfective	3/30 (10%)
Hematuria	2/30 (6.7%)
Renal and urinary disorders - Other, specify	5/30 (16.7%)
Urinary frequency	8/30 (26.7%)
Urinary incontinence	5/30 (16.7%)
Urinary retention	1/30 (3.3%)
Urinary tract pain	8/30 (26.7%)
Urinary urgency	5/30 (16.7%)
Reproductive system and breast disorders
Breast pain	2/30 (6.7%)
Dyspareunia	1/30 (3.3%)
Pelvic pain	1/30 (3.3%)
Vaginal discharge	6/30 (20%)
Vaginal dryness	7/30 (23.3%)
Vaginal hemorrhage	4/30 (13.3%)
Vaginal inflammation	3/30 (10%)
Vaginal pain	3/30 (10%)
Vaginal stricture	3/30 (10%)
Vaginismus	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/30 (3.3%)
Cough	7/30 (23.3%)
Dyspnea	8/30 (26.7%)
Epistaxis	4/30 (13.3%)
Hoarseness	1/30 (3.3%)
Nasal congestion	1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/30 (3.3%)
Sinus disorder	1/30 (3.3%)
Sore throat	1/30 (3.3%)
Skin and subcutaneous tissue disorders
Alopecia	17/30 (56.7%)
Erythema multiforme	3/30 (10%)
Pain of skin	1/30 (3.3%)
Pruritus	4/30 (13.3%)
Rash acneiform	3/30 (10%)
Rash maculo-papular	4/30 (13.3%)
Scalp pain	1/30 (3.3%)
Skin and subcutaneous tissue disorders - Other, specify	3/30 (10%)
Skin induration	1/30 (3.3%)
Telangiectasia	3/30 (10%)
Vascular disorders
Hot flashes	8/30 (26.7%)
Hypertension	9/30 (30%)
Hypotension	1/30 (3.3%)
Lymphedema	1/30 (3.3%)
Lymphocele	1/30 (3.3%)
Thromboembolic event	1/30 (3.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.