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

Phase 2

Completed

• Conditions: Stage IB Uterine Corpus Cancer AJCC v7; Stage II Uterine Corpus Cancer AJCC v7; Stage IVB Uterine Corpus Cancer AJCC v7; Stage IIIC Uterine Corpus Cancer AJCC v7; Stage IVA Uterine Corpus Cancer AJCC v7; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Stage IIIB Uterine Corpus Cancer AJCC v7; Endometrial Adenocarcinoma
• Interventions: Biological: Bevacizumab; Drug: Carboplatin; Drug: Cisplatin; Radiation: Intensity-Modulated Radiation Therapy; Drug: Paclitaxel

• Registration Number: NCT01005329
• Lead Sponsor: National Cancer Institute (NCI)

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.

Study Timeline

• Study First Submitted: 2009-10-29
• Study First Submitted QC: 2009-10-29
• Study First Posted: 2009-10-30
• Study Start: 2009-11-06
• Primary Completion: 2012-06-30
• Study Completion: 2013-09-22
• Results First Submitted: 2014-01-08
• Results First Submitted QC: 2014-01-08
• Results First Posted: 2014-02-24
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-15
• Last Update Posted: 2018-03-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 34

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

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Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (IMRT, cisplatin,bevacizumab,carboplatin,paclitaxel)	Bevacizumab	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.
Treatment (IMRT, cisplatin,bevacizumab,carboplatin,paclitaxel)	Intensity-Modulated Radiation Therapy	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.
Treatment (IMRT, cisplatin,bevacizumab,carboplatin,paclitaxel)	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.
Treatment (IMRT, cisplatin,bevacizumab,carboplatin,paclitaxel)	Carboplatin	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.
Treatment (IMRT, cisplatin,bevacizumab,carboplatin,paclitaxel)	Cisplatin	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.

Trial Locations

Locations (41)

McGill University Department of Oncology; 🇨🇦 Montreal, Quebec, Canada

Alta Bates Summit Medical Center-Herrick Campus; 🇺🇸 Berkeley, California, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

John H Stroger Jr Hospital of Cook County; 🇺🇸 Chicago, Illinois, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Summa Akron City Hospital/Cooper Cancer Center; 🇺🇸 Akron, Ohio, United States

Radiation Therapy Oncology Group; 🇺🇸 Philadelphia, Pennsylvania, United States

Central Maryland Radiation Oncology in Howard County; 🇺🇸 Columbia, Maryland, United States

West Michigan Cancer Center; 🇺🇸 Kalamazoo, Michigan, United States

Saint Vincent Hospital and Health Care Center; 🇺🇸 Indianapolis, Indiana, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Kansas City NCI Community Oncology Research Program; 🇺🇸 Prairie Village, Kansas, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

John Muir Medical Center-Walnut Creek; 🇺🇸 Walnut Creek, California, United States

Penrose-Saint Francis Healthcare; 🇺🇸 Colorado Springs, Colorado, United States

Poudre Valley Hospital; 🇺🇸 Fort Collins, Colorado, United States

Baptist MD Anderson Cancer Center; 🇺🇸 Jacksonville, Florida, United States

Christiana Care Health System-Christiana Hospital; 🇺🇸 Newark, Delaware, United States

Integrated Community Oncology Network-Florida Cancer Center Beaches; 🇺🇸 Jacksonville Beach, Florida, United States

Integrated Community Oncology Network-Southside Cancer Center; 🇺🇸 Jacksonville, Florida, United States

University of Florida Health Science Center - Jacksonville; 🇺🇸 Jacksonville, Florida, United States

Baptist Medical Center South; 🇺🇸 Jacksonville, Florida, United States

21st Century Oncology-Orange Park; 🇺🇸 Orange Park, Florida, United States

Integrated Community Oncology Network-Flager Cancer Center; 🇺🇸 Saint Augustine, Florida, United States

21st Century Oncology-Palatka; 🇺🇸 Palatka, Florida, United States

Bay Medical Center; 🇺🇸 Panama City, Florida, United States

Saint Vincent Anderson Regional Hospital/Cancer Center; 🇺🇸 Anderson, Indiana, United States

Stony Brook University Medical Center; 🇺🇸 Stony Brook, New York, United States

Elliot Hospital; 🇺🇸 Manchester, New Hampshire, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Summa Barberton Hospital; 🇺🇸 Barberton, Ohio, United States

Flower Hospital; 🇺🇸 Sylvania, Ohio, United States

Paoli Memorial Hospital; 🇺🇸 Paoli, Pennsylvania, United States

Lankenau Medical Center; 🇺🇸 Wynnewood, Pennsylvania, United States

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Huntsman Cancer Institute/University of Utah; 🇺🇸 Salt Lake City, Utah, United States

London Regional Cancer Program; 🇨🇦 London, Ontario, Canada

Froedtert and the Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Wheeling Hospital/Schiffler Cancer Center; 🇺🇸 Wheeling, West Virginia, United States

Pamela Youde Nethersole Eastern Hospital; 🇭🇰 Chai Wan, Hong Kong