A Randomized Phase III Trial of Carboplatin, Paclitaxel, Pembrolizumab Versus Carboplatin, Paclitaxel, Bevacizumab Versus Carboplatin, Paclitaxel, Pembrolizumab, Bevacizumab in the Treatment of pMMR, TP53 Mutated Advanced or Recurrent Endometrial Cancer
Summary
This phase III trial compares the effect of bevacizumab in combination with carboplatin, paclitaxel and pembrolizumab to the usual treatments of carboplatin and paclitaxel with or without pembrolizumab in treating patients with stage III, IVA or IVB mismatch repair protein proficient (pMMR) and TP53 mutated endometrial cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has come back after a period of improvement (recurrent). Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Carboplatin is in a class of medications known as platinum-containing compounds. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Adding bevacizumab to the combination of carboplatin, paclitaxel and pembrolizumab may be more effective than the usual treatment combinations of carboplatin and paclitaxel with or without pembrolizumab in treating patients with advanced or recurrent pMMR and TP53 mutated endometrial cancer.
Detailed description
PRIMARY OBJECTIVE: I. To demonstrate that bevacizumab, an anti-VEGF antibody therapy, (or an anti-VEGF antibody biosimilar) in combination with carboplatin, paclitaxel, and pembrolizumab is superior to carboplatin, paclitaxel, and pembrolizumab (the control arm) or carboplatin, paclitaxel, and bevacizumab in prolonging progression-free survival (PFS) in patients with pMMR, TP53 mutated advanced stage (III or IV) or recurrent endometrial cancer. SECONDARY OBJECTIVES: I. To demonstrate that bevacizumab in combination with carboplatin, paclitaxel, and pembrolizumab is superior to carboplatin, paclitaxel, and pembrolizumab or carboplatin, paclitaxel, and bevacizumab in prolonging overall survival (OS) in patients with pMMR, TP53 mutated advanced stage (III or IV) or recurrent endometrial cancer. II. To examine the impact of the addition of bevacizumab in combination with carboplatin and paclitaxel or with carboplatin, paclitaxel, and pembrolizumab on PFS and OS based on type of p53 immunohistochemistry (IHC) aberrancy (over expression/cytoplasmic expression versus null \[complete absence of staining\]) and mutation type. III. To evaluate toxicity on treatment with bevacizumab when combined with carboplatin, paclitaxel, and/or pembrolizumab as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5.0. IV. To explore the anti-tumor activity in each treatment arm as assessed by objective response rate in the subset of patients with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. OUTLINE: Patients are randomized to 1 of 3 arms. ARM 1 (REFERENCE ARM): Patients receive paclitaxel intravenously (IV) over 3 hours, carboplatin IV and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for up to 6-10 cycles in the absence of disease progression or unacceptable toxicity. Starting 3 weeks after last combination phase cycle, patients may continue to receive maintenance pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for up to an additional14 cycles. Additionally, patients undergo urine and blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study. ARM 2 (EXPERIMENTAL TRIPLET ARM): Patients receive paclitaxel IV over 3 hours, carboplatin IV, and bevacizumab IV or anti-VEGF antibody biosimilar on day 1 of each cycle. Cycles repeat every 3 weeks for up to 6-10 cycles in the absence of disease progression or unacceptable toxicity. Starting 3 weeks after last combination phase cycle, patients may continue to receive maintenance bevacizumab IV on day 1 of each cycle. Treatment repeats every 3 weeks for up to an additional 28 doses. Additionally, patients undergo urine and blood sample collection and CT or MRI throughout the study. ARM 3 (EXPERIMENTAL QUADRUPLET ARM): Patients receive paclitaxel IV over 3 hours, carboplatin IV, pembrolizumab IV over 30 minutes, and bevacizumab IV or anti-VEGF antibody biosimilar on day 1 of each cycle. Cycles repeat every 3 weeks for up to 6-10 cycles in the absence of disease progression or unacceptable toxicity. Starting 3 weeks after last combination phase cycle, patients may continue to receive maintenance pembrolizumab IV over 30 minutes every 6 weeks for up to an additional 14 cycles and bevacizumab IV every 3 weeks for up to an additional 28 doses. Additionally, patients undergo urine and blood sample collection and CT or MRI throughout the study. After completion of study treatment, patients are followed every 3 months for 2 years then every 6 months for up to 3 years.
Arms & interventions
- BiologicalBevacizumab
Given IV
- ProcedureBiospecimen Collection
Undergo urine and blood sample collection
- DrugCarboplatin
Given IV
- ProcedureComputed Tomography
Undergo CT
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- DrugPaclitaxel
Given IV
- BiologicalPembrolizumab
Given IV
Outcome measures
Primary
Progression-free survival (PFS)
Will be defined using Response Evaluation Criteria in Solid Tumors version (v) 1.1. Will be tested using one-sided log-rank tests with α-levels stratified by factors used in the randomization. Patients will be grouped by their randomized treatment assignment for intention-to-treat (ITT) analyses, supported by patients in ITT population. Treatment hazard ratios and their 95% confidence intervals will be estimated using a Cox proportional hazards models specified with a main effect for the randomized treatment assignment and stratified using the stratification factors applied at randomization.
Time frame: From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 5 years
Secondary
Overall survival (OS)
Time frame: From study entry to time of death from any cause, assessed up to 5 years
Prognostic and predictive associations of type of TP53 mutation status with PFS
Time frame: Up to 5 years
Prognostic and predictive associations of type of TP53 mutation status with OS
Time frame: Up to 5 years
Incidence of adverse events (AEs) in treatment with bevacizumab when combined with carboplatin, paclitaxel, and pembrolizumab
Time frame: Up to 90 days after last dose of study treatment
Objective response rate
Time frame: Within 12 months of initiating therapy
Eligibility criteria
Study locations (218)
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Alaska Women's Cancer Care
Anchorage, Alaska, 99508
Cancer Center at Saint Joseph's
Phoenix, Arizona, 85004
Highlands Oncology Group - Fayetteville
Fayetteville, Arkansas, 72703
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
Highlands Oncology Group - Rogers
Rogers, Arkansas, 72758
Highlands Oncology Group
Springdale, Arkansas, 72762
Mercy Cancer Center - Carmichael
Carmichael, California, 95608
Mercy San Juan Medical Center
Carmichael, California, 95608
Mercy Cancer Center - Elk Grove
Elk Grove, California, 95758
Los Angeles General Medical Center
Los Angeles, California, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033
Stanford Cancer Institute Palo Alto
Palo Alto, California, 94304
Eisenhower Medical Center
Rancho Mirage, California, 92270
Mercy Cancer Center - Rocklin
Rocklin, California, 95765
Mercy Cancer Center - Sacramento
Sacramento, California, 95816
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
Woodland Memorial Hospital
Woodland, California, 95695
Hartford Hospital
Hartford, Connecticut, 06102
Hartford HealthCare - Manchester
Manchester, Connecticut, 06042
The Hospital of Central Connecticut
New Britain, Connecticut, 06050
Beebe South Coastal Health Campus
Millville, Delaware, 19967
Helen F Graham Cancer Center
Newark, Delaware, 19713
Medical Oncology Hematology Consultants PA
Newark, Delaware, 19713
Beebe Health Campus
Rehoboth Beach, Delaware, 19971
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Augusta University Medical Center
Augusta, Georgia, 30912
Emory Decatur Hospital
Decatur, Georgia, 30033
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, 83854
Kootenai Clinic Cancer Services - Sandpoint
Sandpoint, Idaho, 83864
Northwestern University
Chicago, Illinois, 60611
Rush MD Anderson Cancer Center
Chicago, Illinois, 60612
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526
Decatur Memorial Hospital
Decatur, Illinois, 62526
Northwestern Medicine Cancer Center Kishwaukee
DeKalb, Illinois, 60115
Northwestern Medicine Cancer Center Delnor
Geneva, Illinois, 60134
Cancer Care Center of O'Fallon
O'Fallon, Illinois, 62269
HSHS Saint Elizabeth's Hospital
O'Fallon, Illinois, 62269
Northwestern Medicine Oak Brook
Oak Brook, Illinois, 60523
Rush MD Anderson Cancer Center at Rush Oak Park
Oak Park, Illinois, 60304
Northwestern Medicine Orland Park
Orland Park, Illinois, 60462
OSF Saint Francis Medical Center
Peoria, Illinois, 61637
Southern Illinois University School of Medicine
Springfield, Illinois, 62702
Springfield Clinic
Springfield, Illinois, 62702
Springfield Memorial Hospital
Springfield, Illinois, 62781
Northwestern Medicine Cancer Center Warrenville
Warrenville, Illinois, 60555
Goshen Center for Cancer Care
Goshen, Indiana, 46526
Memorial Hospital of South Bend
South Bend, Indiana, 46601
UI Health Care Mission Cancer and Blood - Ankeny Clinic
Ankeny, Iowa, 50023
Saint Anthony Regional Hospital
Carroll, Iowa, 51401
Mercy Hospital
Cedar Rapids, Iowa, 52403
Oncology Associates at Mercy Medical Center
Cedar Rapids, Iowa, 52403
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
Clive, Iowa, 50325
Iowa Methodist Medical Center
Des Moines, Iowa, 50309
UI Health Care Mission Cancer and Blood - Des Moines Clinic
Des Moines, Iowa, 50309
Broadlawns Medical Center
Des Moines, Iowa, 50314
Mercy Medical Center - Des Moines
Des Moines, Iowa, 50314
UI Health Care Mission Cancer and Blood - Laurel Clinic
Des Moines, Iowa, 50314
UI Healthcare Mission Cancer and Blood - Fort Dodge
Fort Dodge, Iowa, 50501
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
UI Health Care Mission Cancer and Blood - Waukee Clinic
Waukee, Iowa, 50263
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
West Jefferson Medical Center
Marrero, Louisiana, 70072
East Jefferson General Hospital
Metairie, Louisiana, 70006
LSU Healthcare Network / Metairie Multi-Specialty Clinic
Metairie, Louisiana, 70006
University Medical Center New Orleans
New Orleans, Louisiana, 70112
MaineHealth Maine Medical Center- Scarborough
Scarborough, Maine, 04074
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, 48109
Bronson Battle Creek
Battle Creek, Michigan, 49017
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114
University of Michigan - Brighton Center for Specialty Care
Brighton, Michigan, 48116
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, 48188
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118
OSF Saint Francis Hospital and Medical Group
Escanaba, Michigan, 49829
Genesys Hurley Cancer Institute
Flint, Michigan, 48503
Hurley Medical Center
Flint, Michigan, 48503
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
Grand Rapids, Michigan, 49503
Trinity Health Grand Rapids Hospital
Grand Rapids, Michigan, 49503
Bronson Methodist Hospital
Kalamazoo, Michigan, 49007
West Michigan Cancer Center
Kalamazoo, Michigan, 49007
Beacon Kalamazoo Cancer Center
Kalamazoo, Michigan, 49009
Trinity Health Saint Mary Mercy Livonia Hospital
Livonia, Michigan, 48154
Trinity Health Muskegon Hospital
Muskegon, Michigan, 49444
Corewell Health Lakeland Hospitals - Niles Hospital
Niles, Michigan, 49120
Cancer and Hematology Centers of Western Michigan - Norton Shores
Norton Shores, Michigan, 49444
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan, 48341
Corewell Health Reed City Hospital
Reed City, Michigan, 49677
Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
Saint Joseph, Michigan, 49085
Corewell Health Lakeland Hospitals - Saint Joseph Hospital
Saint Joseph, Michigan, 49085
Munson Medical Center
Traverse City, Michigan, 49684
University of Michigan Health - West
Wyoming, Michigan, 49519
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan, 48197
Essentia Health Saint Joseph's Medical Center
Brainerd, Minnesota, 56401
Mercy Hospital
Coon Rapids, Minnesota, 55433
Essentia Health - Deer River Clinic
Deer River, Minnesota, 56636
Essentia Health Cancer Center
Duluth, Minnesota, 55805
Fairview Southdale Hospital
Edina, Minnesota, 55435
Essentia Health Hibbing Clinic
Hibbing, Minnesota, 55746
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Essentia Health Sandstone
Sandstone, Minnesota, 55072
Essentia Health Virginia Clinic
Virginia, Minnesota, 55792
Minnesota Oncology Hematology PA-Woodbury
Woodbury, Minnesota, 55125
Mercy Hospital Springfield
Springfield, Missouri, 65804
CoxHealth South Hospital
Springfield, Missouri, 65807
Community Hospital of Anaconda
Anaconda, Montana, 59711
Billings Clinic Cancer Center
Billings, Montana, 59101
Bozeman Health Deaconess Hospital
Bozeman, Montana, 59715
Benefis Sletten Cancer Institute
Great Falls, Montana, 59405
Logan Health Medical Center
Kalispell, Montana, 59901
Community Medical Center
Missoula, Montana, 59804
Nebraska Medicine-Bellevue
Bellevue, Nebraska, 68123
Fred and Pamela Buffett Cancer Center - Kearney
Kearney, Nebraska, 68845
Nebraska Methodist Hospital
Omaha, Nebraska, 68114
Nebraska Medicine-Village Pointe
Omaha, Nebraska, 68118
University of Nebraska Medical Center
Omaha, Nebraska, 68198
Women's Cancer Center of Nevada
Las Vegas, Nevada, 89106
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, 07920
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, 07748
Memorial Sloan Kettering Bergen
Montvale, New Jersey, 07645
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Rutgers New Jersey Medical School
Newark, New Jersey, 07101
The Valley Hospital - Luckow Pavilion
Paramus, New Jersey, 07652
Valley Health System Ridgewood Campus
Ridgewood, New Jersey, 07450
Sidney Kimmel Cancer Center Washington Township
Sewell, New Jersey, 08080
University of New Mexico Cancer Center
Albuquerque, New Mexico, 87106
Northwell Health Imbert Cancer Center
Bay Shore, New York, 11706
Memorial Sloan Kettering Commack
Commack, New York, 11725
Northwell Health Physician Partners at Flushing
Flushing, New York, 11354
Northwell Health Cancer Institute at Huntington
Greenlawn, New York, 11740
Memorial Sloan Kettering Westchester
Harrison, New York, 10604
Northwell Health/Center for Advanced Medicine
Lake Success, New York, 11042
Manhattan Eye Ear and Throat Hospital
New York, New York, 10065
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Lenox Hill Hospital
New York, New York, 10075
Queens Cancer Center
Rego Park, New York, 11374
University of Rochester
Rochester, New York, 14642
Phelps Memorial Hospital Center
Sleepy Hollow, New York, 10591
Staten Island University Hospital
Staten Island, New York, 10305
Stony Brook University Medical Center
Stony Brook, New York, 11794
Montefiore Medical Center-Einstein Campus
The Bronx, New York, 10461
Montefiore Medical Center-Weiler Hospital
The Bronx, New York, 10461
Montefiore Medical Center - Moses Campus
The Bronx, New York, 10467
Memorial Sloan Kettering Nassau
Uniondale, New York, 11553
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Southeastern Medical Oncology Center-Clinton
Clinton, North Carolina, 28328
Duke University Medical Center
Durham, North Carolina, 27710
Southeastern Medical Oncology Center-Goldsboro
Goldsboro, North Carolina, 27534
Southeastern Medical Oncology Center-Jacksonville
Jacksonville, North Carolina, 28546
Duke Women's Cancer Care Raleigh
Raleigh, North Carolina, 27607
Essentia Health Cancer Center-South University Clinic
Fargo, North Dakota, 58103
OhioHealth O'Bleness Hospital
Athens, Ohio, 45701
UHHS-Chagrin Highlands Medical Center
Beachwood, Ohio, 44122
Geauga Hospital
Chardon, Ohio, 44024
Case Western Reserve University
Cleveland, Ohio, 44106
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Columbus Oncology and Hematology Associates Inc
Columbus, Ohio, 43214
Riverside Methodist Hospital
Columbus, Ohio, 43214
Grant Medical Center
Columbus, Ohio, 43215
Doctors Hospital
Columbus, Ohio, 43228
Delaware Health Center-Grady Cancer Center
Delaware, Ohio, 43015
Grady Memorial Hospital
Delaware, Ohio, 43015
Columbus Oncology and Hematology Associates
Dublin, Ohio, 43016
Dublin Methodist Hospital
Dublin, Ohio, 43016
OhioHealth Mansfield Hospital
Mansfield, Ohio, 44903
OhioHealth Marion General Hospital
Marion, Ohio, 43302
UH Seidman Cancer Center at Lake Health Mentor Campus
Mentor, Ohio, 44060
University Hospitals Parma Medical Center
Parma, Ohio, 44129
OhioHealth Pickerington Methodist Hospital
Pickerington, Ohio, 43147
ProMedica Flower Hospital
Sylvania, Ohio, 43560
OhioHealth Westerville Medical Campus/Westerville Cancer Center
Westerville, Ohio, 43082
UH Seidman Cancer Center at Saint John Medical Center
Westlake, Ohio, 44145
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Legacy Good Samaritan Hospital and Medical Center
Portland, Oregon, 97210
Providence Portland Medical Center
Portland, Oregon, 97213
Providence Saint Vincent Medical Center
Portland, Oregon, 97225
Legacy Meridian Park Hospital
Tualatin, Oregon, 97062
UPMC Hillman Cancer Center Erie
Erie, Pennsylvania, 16505
UPMC Cancer Centers - Arnold Palmer Pavilion
Greensburg, Pennsylvania, 15601
UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion
Mechanicsburg, Pennsylvania, 17050
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
Jefferson Torresdale Hospital
Philadelphia, Pennsylvania, 19114
UPMC-Magee Womens Hospital
Pittsburgh, Pennsylvania, 15213
UPMC-Passavant Hospital
Pittsburgh, Pennsylvania, 15237
UPMC Cancer Center-Washington
Washington, Pennsylvania, 15301
Asplundh Cancer Pavilion
Willow Grove, Pennsylvania, 19090
Women and Infants Hospital
Providence, Rhode Island, 02905
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
University of Utah Sugarhouse Health Center
Salt Lake City, Utah, 84106
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
South Jordan Health Center
South Jordan, Utah, 84009
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
Swedish Cancer Institute-Edmonds
Edmonds, Washington, 98026
Swedish Cancer Institute-Issaquah
Issaquah, Washington, 98029
Swedish Medical Center-First Hill
Seattle, Washington, 98122
Legacy Salmon Creek Hospital
Vancouver, Washington, 98686
United Hospital Center
Bridgeport, West Virginia, 26330
West Virginia University Charleston Division
Charleston, West Virginia, 25304
WVUH-Berkely Medical Center
Martinsburg, West Virginia, 25401
West Virginia University Healthcare
Morgantown, West Virginia, 26506
Camden Clark Medical Center
Parkersburg, West Virginia, 26101
Duluth Clinic Ashland
Ashland, Wisconsin, 54806
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, 54301
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin, 54303
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, 54601
Saint Vincent Hospital Cancer Center at Oconto Falls
Oconto Falls, Wisconsin, 54154
Saint Vincent Hospital Cancer Center at Sheboygan
Sheboygan, Wisconsin, 53081
Sheboygan Physicians Group
Sheboygan, Wisconsin, 53081
Essentia Health-Spooner Clinic
Spooner, Wisconsin, 54801
Saint Vincent Hospital Cancer Center at Sturgeon Bay
Sturgeon Bay, Wisconsin, 54235-1495
Essentia Health Saint Mary's Hospital - Superior
Superior, Wisconsin, 54880