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

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.

Study Overview

• Status: Completed
• Conditions: Stage IA Uterine Corpus Cancer AJCC v7; Stage IB Uterine Corpus Cancer AJCC v7; Stage II Uterine Corpus Cancer AJCC v7; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Adenocarcinoma; 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; Endometrial Adenosquamous Carcinoma
• Intervention / Treatment: Drug: Carboplatin; Drug: Cisplatin; Drug: Paclitaxel; Radiation: Intensity-Modulated Radiation Therapy; Biological: Bevacizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

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: CDDP; Cis-diamminedichloridoplatinum; Cismaplat; Cisplatinum; Neoplatin; Platinol; Abiplatin; Blastolem; Briplatin; Cis-diammine-dichloroplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Peyrone's Chloride; Peyrone's Salt; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Biological: Bevacizumab; Given IV; Other Names: Avastin; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; Bevacizumab Biosimilar BEVZ92; Bevacizumab Biosimilar BI 695502; Bevacizumab Biosimilar CBT 124; Bevacizumab Biosimilar FKB238; 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; BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From start of treatment to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-related, Grade 3+, Non-hematologic Adverse Events Occuring Within 1 Year 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. Adverse events reported as definitely, probably, or possibly related to study treatment.	From start of treatment to one year
Treatment-related Grade 3+ Adverse Events	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.	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.
Overall Survival (Two-year Rate Reported)	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.	From registration to two years
Disease-free Survival (Two-year Rate Reported)	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.	From registration to two years
Pelvic Failure Rate (Two-year Rate Reported)	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.	From registration to two years
Distant Failure (Two-year Rate Reported)	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.	From registration to two years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Radiation Therapy Oncology Group
• Investigators: Principal Investigator: Akila Viswanathan, Radiation Therapy Oncology Group

Publications and helpful links

General Publications

• Viswanathan AN, Moughan J, Miller BE, Xiao Y, Jhingran A, Portelance L, Bosch WR, Matulonis UA, Horowitz NS, Mannel RS, Souhami L, Erickson BA, Winter KA, Small W Jr, Gaffney DK. NRG Oncology/RTOG 0921: A phase 2 study of postoperative intensity-modulated radiotherapy with concurrent cisplatin and bevacizumab followed by carboplatin and paclitaxel for patients with endometrial cancer. Cancer. 2015 Jul 1;121(13):2156-63. doi: 10.1002/cncr.29337. Epub 2015 Apr 6.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2009
• Primary Completion (Actual): June 30, 2012
• Study Completion (Actual): September 22, 2013

Study Registration Dates

• First Submitted: October 29, 2009
• First Submitted That Met QC Criteria: October 29, 2009
• First Posted (Estimate): October 30, 2009

Study Record Updates

• Last Update Posted (Actual): March 15, 2018
• Last Update Submitted That Met QC Criteria: February 15, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Neoplasms, Complex and Mixed; Cystadenocarcinoma; Neoplasms, Cystic, Mucinous, and Serous; Adenocarcinoma; Endometrial Neoplasms; Cystadenocarcinoma, Serous; Adenocarcinoma, Clear Cell; Carcinoma, Adenosquamous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Paclitaxel; Antibodies; Cisplatin; Immunoglobulins; Bevacizumab; Albumin-Bound Paclitaxel; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Immunoglobulin G; Endothelial Growth Factors
• Other Study ID Numbers: NCI-2011-01982 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA021661 (U.S. NIH Grant/Contract); CDR0000657979; RTOG-0921 (Other Identifier: CTEP); RTOG 0921 (Other Identifier: Radiation Therapy Oncology Group)