Bevacizumab, Radiation Therapy, and Cisplatin in Treating Patients With Previously Untreated Locally Advanced Cervical Cancer

• ClinicalTrials.gov Identifier: NCT00369122
• Recruitment Status: Completed
• First Posted: August 29, 2006
• Results First Posted: May 17, 2013
• Last Update Posted: March 20, 2018
• Sponsor: National Cancer Institute (NCI)
• Collaborator: Radiation Therapy Oncology Group
• Information provided by (Responsible Party): National Cancer Institute (NCI)

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Stage IB Cervical Cancer AJCC v6 and v7; Stage IIA Cervical Cancer AJCC v7; Stage IIB Cervical Cancer AJCC v6 and v7; Stage III Cervical Cancer AJCC v6 and v7
• Interventions: Biological: Bevacizumab; Drug: Cisplatin; Radiation: External Beam Radiation Therapy; Radiation: Internal Radiation Therapy
• Enrollment: 60

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description	Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35.
Period Title: Overall Study
Started	60
Completed	49 [1]
Not Completed	11
Reason Not Completed
Ineligible	10
No protocol treatment	1
[1] Subjects contributing data to the primary analysis are considered to have completed the study.

Baseline Characteristics

Arm/Group Title		Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description		Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35.
Overall Number of Baseline Participants		60
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	60 participants
		45.5; (20 to 80)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants
	Female	60 100.0%
	Male	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Treatment-related Serious Adverse Events (SAEs) and Adverse Events (AEs) as Assessed by CTCAE v. 3.0 Criteria Within the First 90 Days From Treatment Start.
Description	Adverse events (AEs) graded using CTCAE v3.0. Grade (Gr) refers to the severity of the AE and assigns Gr 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: 1= Mild AE, 2= Moderate AE, 3= Severe AE, 4= Life-threatening or disabling AE, 5= Death related to AE. Treatment-related SAEs defined as Grade (Gr) >= 4 vaginal bleeding, Gr >=4 thrombotic event, Gr >=3 arterial event, gastrointestinal (GI) bleeding , or bowel/bladder perforation, and any Gr 5 treatment-related AE. Treatment-related AEs defined as all SAEs, Gr 3-4 nausea, vomiting, or diarrhea persisting for >2 weeks despite medical intervention, Gr 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia defined as a temperature >38.5 degree Celsius and granulocytes < 1000/mm3, Grade 3-4 hematologic toxicity with the exception of neutropenia and leukopenia, and Grade 3-4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs.
Time Frame	From start of treatment to 90 days.

Outcome Measure Data

Analysis Population Description

Eligible patients who began study treatment.

Arm/Group Title	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description:	Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35.
Overall Number of Participants Analyzed	49
Measure Type: Number; Unit of Measure: participants
Serious Adverse Events	0
Adverse Events	15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Other Statistical Analysis		Based on a report by Laciano, et al. an SAE rate of 5% and AE rate of 35% were considered tolerable and an SAE rate >=20% and AE rate >=55% excessive. If there were >=6 pts with SAES or >=22 pts with AEs then the treatment would be rejected. This study design provides alpha of 0.05 and power of 90%.

2. Secondary Outcome

Title	Number of Subjects With Treatment-related SAEs and AEs as Assessed by CTCAE v. 3.0 Criteria at Any Time.
Description	Adverse events (AEs) graded using CTCAE v3.0. Grade (Gr) refers to the severity of the AE and assigns Gr 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: 1= Mild AE, 2= Moderate AE, 3= Severe AE, 4= Life-threatening or disabling AE, 5= Death related to AE. Treatment-related SAEs defined as Gr >= 4 vaginal bleeding, Gr >=4 thrombotic event, Gr >=3 arterial event, gastrointestinal (GI) bleeding , or bowel/bladder perforation, and any Gr 5 treatment-related AE. Treatment-related AEs defined as all SAEs, Gr 3-4 nausea, vomiting, or diarrhea persisting for >2 weeks despite medical intervention, Gr 4 neutropenia or leukopenia persisting for >7 days, febrile neutropenia defined as a temperature >38.5 degree Celsius and granulocytes < 1000/mm3, Grade 3-4 hematologic toxicity with the exception of neutropenia and leukopenia, and Grade 3-4 GI, renal, cardiac, pulmonary, hepatic, or neurologic AEs.
Time Frame	From start of treatment to last follow-up, up to 6.0 years. Analysis occurred after all patients had been on study for at least 2 years.

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description:	Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35.
Overall Number of Participants Analyzed	49
Measure Type: Number; Unit of Measure: participants
Serious Adverse Events	0
Adverse Events	18

3. Secondary Outcome

Title	Disease-free Survival (Three-year Rate Reported)
Description	Failure is defined as local, regional, or distant disease, or death due to any cause. Disease-free survival time is defined as time from registration to the date of failure and disease-free survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive and disease-free are censored at the date of last contact.
Time Frame	From registration to 3 years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description:	Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35.
Overall Number of Participants Analyzed	49
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	68.7; (53.5 to 79.8)

4. Secondary Outcome

Title	Overall Survival (Three-year Rate Reported)
Description	Overall survival time is defined as time from registration to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
Time Frame	From registration to 3 years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description:	Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35.
Overall Number of Participants Analyzed	49
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	81.3; (67.2 to 89.8)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Per the protocol, toxicity data was collected via Common Terminology Criteria (CTC) 3.0 then mapped to CTCAE 4.0 for reporting on this website. Subjects experiencing more than one of a given AE are counted only once for that AE.
Arm/Group Title	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
Arm/Group Description	Patients undergo pelvic EBRT once daily, 5 days a week, for 5 weeks for a total of 45 Gy. Some patients also undergo low-dose rate brachytherapy twice, 1-3 weeks apart, beginning >= 4 weeks after initiating EBRT or high-dose rate brachytherapy 5 times, >= 48 hours apart, beginning >= 2 weeks after initiating EBRT. EBRT and chemotherapy are halted on the day of high-dose rate brachytherapy. Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, and 35. Data is reported for all patients who received study treatment, which is 59 patients.
All-Cause Mortality
	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
	Affected / at Risk (%)
Total	13/59 (22.03%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	1/59 (1.69%)
Gastrointestinal disorders
Abdominal pain * 1	1/59 (1.69%)
Diarrhea * 1	2/59 (3.39%)
Nausea * 1	1/59 (1.69%)
Proctitis * 1	1/59 (1.69%)
Rectal pain * 1	1/59 (1.69%)
Vomiting * 1	1/59 (1.69%)
General disorders
Fever * 1	1/59 (1.69%)
Immune system disorders
Allergic reaction * 1	1/59 (1.69%)
Infections and infestations
Bladder infection * 1	1/59 (1.69%)
Catheter related infection * 1	1/59 (1.69%)
Lung infection * 1	1/59 (1.69%)
Injury, poisoning and procedural complications
Vascular access complication * 1	1/59 (1.69%)
Investigations
GGT increased * 1	1/59 (1.69%)
Lymphocyte count decreased * 1	2/59 (3.39%)
Neutrophil count decreased * 1	1/59 (1.69%)
Platelet count decreased * 1	2/59 (3.39%)
White blood cell decreased * 1	1/59 (1.69%)
Metabolism and nutrition disorders
Anorexia * 1	1/59 (1.69%)
Dehydration * 1	3/59 (5.08%)
Hyperglycemia * 1	1/59 (1.69%)
Hypokalemia * 1	1/59 (1.69%)
Musculoskeletal and connective tissue disorders
Back pain * 1	1/59 (1.69%)
Nervous system disorders
Syncope * 1	1/59 (1.69%)
Psychiatric disorders
Depression * 1	1/59 (1.69%)
Renal and urinary disorders
Urinary tract obstruction * 1	1/59 (1.69%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage * 1	1/59 (1.69%)
Vascular disorders
Thromboembolic event * 1	1/59 (1.69%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, CTCAE (4.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Treatment (Radiation Therapy, Bevacizumab, Cisplatin)
	Affected / at Risk (%)
Total	59/59 (100.00%)
Blood and lymphatic system disorders
Anemia * 1	32/59 (54.24%)
Ear and labyrinth disorders
Hearing impaired * 1	1/59 (1.69%)
Tinnitus * 1	4/59 (6.78%)
Eye disorders
Blurred vision * 1	1/59 (1.69%)
Extraocular muscle paresis * 1	1/59 (1.69%)
Flashing lights * 1	1/59 (1.69%)
Gastrointestinal disorders
Abdominal distension * 1	1/59 (1.69%)
Abdominal pain * 1	11/59 (18.64%)
Anal fistula * 1	1/59 (1.69%)
Anal pain * 1	1/59 (1.69%)
Colitis * 1	1/59 (1.69%)
Constipation * 1	17/59 (28.81%)
Diarrhea * 1	30/59 (50.85%)
Dry mouth * 1	1/59 (1.69%)
Dyspepsia * 1	4/59 (6.78%)
Dysphagia * 1	2/59 (3.39%)
Esophagitis * 1	1/59 (1.69%)
Gastritis * 1	1/59 (1.69%)
Gastrointestinal disorders - Other * 1	2/59 (3.39%)
Hemorrhoids * 1	3/59 (5.08%)
Mucositis oral * 1	2/59 (3.39%)
Nausea * 1	32/59 (54.24%)
Proctitis * 1	4/59 (6.78%)
Rectal hemorrhage * 1	5/59 (8.47%)
Rectal pain * 1	5/59 (8.47%)
Vomiting * 1	15/59 (25.42%)
General disorders
Chills * 1	4/59 (6.78%)
Edema limbs * 1	4/59 (6.78%)
Fatigue * 1	34/59 (57.63%)
Fever * 1	4/59 (6.78%)
General disorders and administration site conditions - Other * 1	1/59 (1.69%)
Non-cardiac chest pain * 1	1/59 (1.69%)
Pain * 1	4/59 (6.78%)
Infections and infestations
Infections and infestations - Other * 1	4/59 (6.78%)
Sinusitis * 1	1/59 (1.69%)
Soft tissue infection * 1	1/59 (1.69%)
Urinary tract infection * 1	3/59 (5.08%)
Vaginal infection * 1	3/59 (5.08%)
Injury, poisoning and procedural complications
Dermatitis radiation * 1	6/59 (10.17%)
Ureteric anastomotic leak * 1	1/59 (1.69%)
Investigations
Activated partial thromboplastin time prolonged * 1	2/59 (3.39%)
Alanine aminotransferase increased * 1	8/59 (13.56%)
Alkaline phosphatase increased * 1	5/59 (8.47%)
Aspartate aminotransferase increased * 1	5/59 (8.47%)
Blood bilirubin increased * 1	1/59 (1.69%)
Cholesterol high * 1	1/59 (1.69%)
Creatinine increased * 1	5/59 (8.47%)
Investigations - Other * 1	3/59 (5.08%)
Lymphocyte count decreased * 1	17/59 (28.81%)
Neutrophil count decreased * 1	17/59 (28.81%)
Platelet count decreased * 1	26/59 (44.07%)
Weight gain * 1	3/59 (5.08%)
Weight loss * 1	8/59 (13.56%)
White blood cell decreased * 1	41/59 (69.49%)
Metabolism and nutrition disorders
Acidosis * 1	2/59 (3.39%)
Anorexia * 1	11/59 (18.64%)
Dehydration * 1	2/59 (3.39%)
Hypercalcemia * 1	7/59 (11.86%)
Hyperglycemia * 1	17/59 (28.81%)
Hyperkalemia * 1	2/59 (3.39%)
Hypernatremia * 1	1/59 (1.69%)
Hyperuricemia * 1	2/59 (3.39%)
Hypoalbuminemia * 1	13/59 (22.03%)
Hypocalcemia * 1	11/59 (18.64%)
Hypoglycemia * 1	2/59 (3.39%)
Hypokalemia * 1	17/59 (28.81%)
Hypomagnesemia * 1	23/59 (38.98%)
Hyponatremia * 1	16/59 (27.12%)
Hypophosphatemia * 1	2/59 (3.39%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	5/59 (8.47%)
Back pain * 1	6/59 (10.17%)
Bone pain * 1	1/59 (1.69%)
Joint range of motion decreased * 1	1/59 (1.69%)
Musculoskeletal and connective tissue disorder - Other * 1	1/59 (1.69%)
Myalgia * 1	2/59 (3.39%)
Neck pain * 1	1/59 (1.69%)
Pain in extremity * 1	1/59 (1.69%)
Nervous system disorders
Dizziness * 1	5/59 (8.47%)
Dysgeusia * 1	5/59 (8.47%)
Facial nerve disorder * 1	1/59 (1.69%)
Headache * 1	12/59 (20.34%)
Nervous system disorders - Other * 1	3/59 (5.08%)
Peripheral motor neuropathy * 1	1/59 (1.69%)
Peripheral sensory neuropathy * 1	5/59 (8.47%)
Psychiatric disorders
Agitation * 1	1/59 (1.69%)
Anxiety * 1	8/59 (13.56%)
Depression * 1	8/59 (13.56%)
Insomnia * 1	8/59 (13.56%)
Renal and urinary disorders
Bladder spasm * 1	1/59 (1.69%)
Chronic kidney disease * 1	1/59 (1.69%)
Cystitis noninfective * 1	5/59 (8.47%)
Hemoglobinuria * 1	2/59 (3.39%)
Proteinuria * 1	1/59 (1.69%)
Renal and urinary disorders - Other * 1	3/59 (5.08%)
Urinary frequency * 1	8/59 (13.56%)
Urinary incontinence * 1	3/59 (5.08%)
Urinary retention * 1	1/59 (1.69%)
Urinary tract obstruction * 1	1/59 (1.69%)
Urinary tract pain * 1	4/59 (6.78%)
Reproductive system and breast disorders
Irregular menstruation * 1	4/59 (6.78%)
Lactation disorder * 1	1/59 (1.69%)
Pelvic pain * 1	11/59 (18.64%)
Perineal pain * 1	3/59 (5.08%)
Reproductive system and breast disorders - Other * 1	1/59 (1.69%)
Uterine hemorrhage * 1	1/59 (1.69%)
Uterine obstruction * 1	1/59 (1.69%)
Uterine pain * 1	2/59 (3.39%)
Vaginal discharge * 1	11/59 (18.64%)
Vaginal dryness * 1	1/59 (1.69%)
Vaginal fistula * 1	1/59 (1.69%)
Vaginal hemorrhage * 1	25/59 (42.37%)
Vaginal inflammation * 1	5/59 (8.47%)
Vaginal obstruction * 1	6/59 (10.17%)
Vaginal pain * 1	4/59 (6.78%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage * 1	1/59 (1.69%)
Cough * 1	3/59 (5.08%)
Dyspnea * 1	5/59 (8.47%)
Epistaxis * 1	3/59 (5.08%)
Voice alteration * 1	5/59 (8.47%)
Skin and subcutaneous tissue disorders
Alopecia * 1	2/59 (3.39%)
Dry skin * 1	2/59 (3.39%)
Hyperhidrosis * 1	2/59 (3.39%)
Pruritus * 1	2/59 (3.39%)
Rash acneiform * 1	1/59 (1.69%)
Rash maculo-papular * 1	5/59 (8.47%)
Skin and subcutaneous tissue disorders - Other * 1	2/59 (3.39%)
Skin hypopigmentation * 1	1/59 (1.69%)
Skin induration * 1	2/59 (3.39%)
Skin ulceration * 1	1/59 (1.69%)
Telangiectasia * 1	2/59 (3.39%)
Vascular disorders
Flushing * 1	1/59 (1.69%)
Hot flashes * 1	14/59 (23.73%)
Hypertension * 1	6/59 (10.17%)
Hypotension * 1	5/59 (8.47%)
Vascular disorders - Other * 1	2/59 (3.39%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, CTCAE (4.0)

Limitations and Caveats

Ineligible patients are included in the adverse event reporting on ClinicalTrials.gov, but not in endpoint results, nor in any publications, per the protocol.

More Information

Certain Agreements

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

There IS 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.

Results Point of Contact

• Name/Title: Wendy Seiferheld
• Organization: Radiation Therapy Oncology Group (RTOG)
• EMail: wseiferheld@acr.org

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00369122
• Obsolete Identifiers: NCT01530633
• Other Study ID Numbers: NCI-2009-00722; NCI-2009-00722 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000493005; RTOG 0417 ( Other Identifier: Radiation Therapy Oncology Group ); RTOG-0417 ( Other Identifier: CTEP ); U10CA021661 ( U.S. NIH Grant/Contract )
• First Submitted: August 24, 2006
• First Posted: August 29, 2006
• Results First Submitted: March 5, 2013
• Results First Posted: May 17, 2013
• Last Update Posted: March 20, 2018