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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01005329

Enrollment

Registered

2009-10-30

Start date

2009-11-06

Completion date

2013-09-22

Last updated

2018-03-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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 IIIA Uterine Corpus Cancer AJCC v7, Stage IIIB Uterine Corpus Cancer AJCC v7, Stage IIIC Uterine Corpus Cancer AJCC v7, Stage II Uterine Corpus Cancer AJCC v7, Stage IVA Uterine Corpus Cancer AJCC v7, Stage IVB Uterine Corpus Cancer AJCC v7

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.

Detailed description

PRIMARY OBJECTIVE: I. 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: I. To evaluate treatment-related adverse events occurring within 1 year from the start of treatment. II. 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.

Interventions

BIOLOGICALBevacizumab

Given IV

DRUGCarboplatin

Given IV

DRUGCisplatin

Given IV

RADIATIONIntensity-Modulated Radiation Therapy

Undergo IMRT

DRUGPaclitaxel

Given IV

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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.
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.
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.
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.

Countries

Canada, Hong Kong, United States

Participant flow

Participants by arm

Arm	Count
Chemoradiation (IMRT), Chemotherapy 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.	30
Total	30

Arm

Count

Chemoradiation (IMRT), Chemotherapy

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.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Ineligible or received no protocol trt.	4

Baseline characteristics

Characteristic	Chemoradiation (IMRT), Chemotherapy
Age, Continuous	59 years
Sex: Female, Male Female	30 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	30 / 30
serious Total, serious adverse events	8 / 30

Outcome results

Primary

Percentage of Participants With Treatment-related, Grade 3+, Non-hematologic Adverse Events Occuring Within 90 Days After Treatment Start

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