Testing the Addition of an Antiangiogenic Drug (Bevacizumab) to Chemotherapy (Carboplatin and Paclitaxel) Combined With Immunotherapy (Pembrolizumab) for pMMR, TP53 Mutated Endometrial Cancer
Purpose
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.
Conditions
- Advanced Endometrial Carcinoma
- Recurrent Endometrial Carcinoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- Female
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- Documentation of disease:
- Stage III and stage IVA endometrial cancers (with measurable disease),
- Stage IVB endometrial cancer (with or without measurable disease), or
- Recurrent endometrial cancer (with or without measurable disease)
- In patients with measurable disease, lesions will be defined and monitored by RECIST
1.1. Measurable disease (RECIST 1.1) is defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded).
Each lesion must be ≥ 10 mm when measured by CT or MRI. Lymph nodes must be ≥ 15 mm
in short axis when measured by CT or MRI
- Histologic confirmation of the original primary tumor is required (submission of
pathology report[s] is required). Patients with the following histologic types are
eligible: endometrioid, serous, dedifferentiated/undifferentiated, clear cell, mixed
epithelial, carcinosarcoma, adenocarcinoma not otherwise specified (N.O.S.)
- Patients must have:
- Tumoral mismatch repair proficient (pMMR) disease as assessed by
immunohistochemistry (IHC) AND
- P53 IHC with aberrant staining pattern (aberrant p53 expression is consistent
with mutant TP53). TP53 mutation by next-generation sequencing will also be
accepted
- A pathology report demonstrating results of institutional MMR IHC and p53 IHC and/or
TP53 by next-generation sequencing
- Patients may have received:
- NO prior chemotherapy for treatment of endometrial cancer OR
- Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a
component of concurrent chemotherapy and radiation therapy [with or without
cisplatin]) provided adjuvant chemotherapy was completed ≥ 12 months prior to
registration
- Patients may have received prior radiation therapy for treatment of endometrial
cancer. Prior radiation therapy may have included pelvic radiation therapy, extended
field pelvic/para-aortic radiation therapy, intravaginal brachytherapy, and/or
palliative radiation therapy. All radiation therapy must be completed at least 4
weeks prior to registration. For patients with recent radiation, they must have
RECIST-evaluable disease outside of the radiation field and have recovered their
marrow function
- Patients may have received prior hormonal (endocrine) therapy. All hormonal
(endocrine) therapy must have been completed at least 1 week prior to registration
- NO prior pembrolizumab (or other anti-PD1, anti-PDL1 or anti-CTLA4 therapy) or
bevacizumab (or other antiangiogenic therapy)
- Interval or cytoreductive surgery, after start of treatment on this trial, and prior
to documentation of disease progression, is NOT permitted
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of disease
progression. Patients with brain metastases must have follow up imaging
demonstrating no evidence of disease progression and that the disease is stable off
of steroids
- Age ≥ 18
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- Not pregnant and not nursing
- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
- Platelets ≥ 100,000 cells/mm^3
- Hemoglobin ≥ 8 g/dl
- Creatinine clearance (CrCl) of ≥ 30 mL/min by the Cockcroft-Gault formula
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with
known Gilbert's disease who have bilirubin level ≤ 3 x institutional ULN may be
enrolled)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x
institutional ULN
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class II or better
- No active infection requiring parenteral antibiotics
- No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not
diverted), gastrointestinal perforation, gastrointestinal (GI) obstruction, and/or
need for drainage nasogastric or gastrostomy tube
- No clinically significant bleeding within 28 days prior to registration
- No uncontrolled hypertension, defined as systolic ≥ 160 mm Hg or diastolic ≥ 100 mm
Hg
- No major surgery within 28 days of initiation of bevacizumab
- No active autoimmune disease or history of autoimmune disease that might recur,
which may affect vital organ function or require immune suppressive treatment
including corticosteroids. This includes, but is not limited to, patients with a
history of immune related neurologic disease, multiple sclerosis, autoimmune
(demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic
autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue
diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence
or exacerbation of disease
- Patients with vitiligo, endocrine deficiencies including type I diabetes
mellitus, thyroiditis managed with replacement hormones including physiologic
corticosteroids are eligible
- Topical or inhaled steroids are allowed
- Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome
and psoriasis controlled with topical medication and patients with positive
serology, such as antinuclear antibodies (ANA), and anti-thyroid antibodies
should be evaluated with the presence of target organ involvement and potential
need for systemic treatment but should otherwise be eligible
- No history of (non-infectious) pneumonitis that required steroids, or current
pneumonitis
- No history of stem cell or solid organ transplant
- No history of allergic reaction to the study agent(s) or compounds of similar
chemical or biologic composition to the study agent(s) (or any of its excipients)
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm 1 (paclitaxel, carboplatin, pembrolizumab) |
Patients receive paclitaxel 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 additional 14 cycles. Additionally, patients undergo urine and blood sample collection and CT or MRI throughout the study. |
|
|
Experimental Arm 2 (paclitaxel, carboplatin, bevacizumab) |
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. |
|
|
Experimental Arm 3 (paclitaxel, carboplatin, pembrolizumab, bevacizumab) |
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. |
|
Recruiting Locations
Birmingham, Alabama 35233
Carmichael, California 95608
Carmichael, California 95608
Elk Grove, California 95758
Rocklin, California 95765
Sacramento, California 95816
Sacramento, California 95817
Site Public Contact
916-734-3089
Woodland, California 95695
Newark, Delaware 19713
Newark, Delaware 19713
Coeur d'Alene, Idaho 83814
Post Falls, Idaho 83854
Sandpoint, Idaho 83864
Decatur, Illinois 62526
Decatur, Illinois 62526
Peoria, Illinois 61637
Springfield, Illinois 62702
Site Public Contact
217-545-7929
Springfield, Illinois 62702
Site Public Contact
800-444-7541
Springfield, Illinois 62781
Goshen, Indiana 46526
South Bend, Indiana 46601
Site Public Contact
800-284-7370
Cedar Rapids, Iowa 52403
Site Public Contact
319-365-4673
Cedar Rapids, Iowa 52403
Site Public Contact
319-363-2690
Marrero, Louisiana 70072
Metairie, Louisiana 70006
Metairie, Louisiana 70006
New Orleans, Louisiana 70112
Baltimore, Maryland 21287
Boston, Massachusetts 02215
Site Public Contact
877-442-3324
Brighton, Michigan 48114
Canton, Michigan 48188
Chelsea, Michigan 48118
Escanaba, Michigan 49829
Flint, Michigan 48503
Flint, Michigan 48503
Livonia, Michigan 48154
Pontiac, Michigan 48341
Ypsilanti, Michigan 48197
Brainerd, Minnesota 56401
Deer River, Minnesota 56636
Duluth, Minnesota 55805
Hibbing, Minnesota 55746
Site Public Contact
218-786-3308
Sandstone, Minnesota 55072
Virginia, Minnesota 55792
Springfield, Missouri 65804
Site Public Contact
417-269-4520
Springfield, Missouri 65807
Site Public Contact
417-269-4520
Anaconda, Montana 59711
Billings, Montana 59101
Bozeman, Montana 59715
Great Falls, Montana 59405
Missoula, Montana 59804
Basking Ridge, New Jersey 07920
Site Public Contact
212-639-7592
Middletown, New Jersey 07748
Site Public Contact
212-639-7592
Montvale, New Jersey 07645
Site Public Contact
212-639-7592
New Brunswick, New Jersey 08903
Site Public Contact
732-235-7356
Newark, New Jersey 07101
Site Public Contact
732-235-7356
Paramus, New Jersey 07652
Ridgewood, New Jersey 07450
Sewell, New Jersey 08080
Commack, New York 11725
Site Public Contact
212-639-7592
Harrison, New York 10604
Site Public Contact
212-639-7592
New York, New York 10065
Site Public Contact
212-639-7592
Stony Brook, New York 11794
Site Public Contact
800-862-2215
The Bronx, New York 10461
The Bronx, New York 10461
The Bronx, New York 10467
Uniondale, New York 11553
Site Public Contact
212-639-7592
Chapel Hill, North Carolina 27599
Clinton, North Carolina 28328
Goldsboro, North Carolina 27534
Jacksonville, North Carolina 28546
Fargo, North Dakota 58103
Sylvania, Ohio 43560
Oklahoma City, Oklahoma 73104
Portland, Oregon 97210
Portland, Oregon 97213
Portland, Oregon 97225
Tualatin, Oregon 97062
Site Public Contact
503-413-1742
Erie, Pennsylvania 16505
Greensburg, Pennsylvania 15601
Site Public Contact
724-838-1900
Mechanicsburg, Pennsylvania 17050
Philadelphia, Pennsylvania 19107
Philadelphia, Pennsylvania 19114
Pittsburgh, Pennsylvania 15213
Site Public Contact
412-647-2811
Pittsburgh, Pennsylvania 15237
Site Public Contact
412-367-6454
Washington, Pennsylvania 15301
Willow Grove, Pennsylvania 19090
Providence, Rhode Island 02905
Site Public Contact
401-274-1122
Charlottesville, Virginia 22908
Richmond, Virginia 23298
Edmonds, Washington 98026
Issaquah, Washington 98029
Seattle, Washington 98122
Vancouver, Washington 98686
Site Public Contact
503-413-2150
Bridgeport, West Virginia 26330
Charleston, West Virginia 25304
Site Public Contact
304-388-9944
Martinsburg, West Virginia 25401
Morgantown, West Virginia 26506
Parkersburg, West Virginia 26101
Ashland, Wisconsin 54806
Green Bay, Wisconsin 54301
Green Bay, Wisconsin 54303
Oconto Falls, Wisconsin 54154
Sheboygan, Wisconsin 53081
Sheboygan, Wisconsin 53081
Spooner, Wisconsin 54801
Sturgeon Bay, Wisconsin 54235-1495
Superior, Wisconsin 54880
Site Public Contact
701-364-6272
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
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.