UAB - Center for Clinical and Translational Science

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)

Recruiting Locations

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.