This phase III trial compares whether the addition of pembrolizumab to radiation therapy is more effective than radiation therapy alone in reducing the risk of cancer coming back (recurrence) in patients with newly diagnosed stage I-II endometrial cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. The addition of pembrolizumab to radiation treatment may be more effective than radiation treatment alone in reducing cancer recurrence.
PRIMARY OBJECTIVE: I. To compare the 3-year recurrence-free survival of women with high intermediate risk (HIR) stage I/II mismatch repair deficient (dMMR) endometrioid endometrial cancer treated with radiation and pembrolizumab (MK-3475) versus radiation alone. SECONDARY OBJECTIVES: I. To describe the safety and tolerability of concurrent pembrolizumab (MK-3475) and radiation compared to radiation alone in patients with MMR deficient high intermediate risk endometrial cancer (HIR EC). II. To describe the recurrence patterns in each group. III. To measure recurrence free survival at 5 years in each group. IV. To estimate disease specific overall survival in each group. V. To determine whether the addition of pembrolizumab (MK-3475) to radiation, compared with radiation alone is associated with decreased quality of life at 6- and 24-weeks, as measured with the Functional Assessment of Cancer Therapy (FACT)-Endometrial (En) Trial Outcome Index (TOI), increased gastrointestinal (GI) symptoms as measured with the GI subscale, and increased fatigue as measured with the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue scale (short form). VI. To validate the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM) subscale, which assesses in cancer patients on immunotherapy. VII. To evaluate the ability of ctDNA to predict outcomes in the experimental and control groups. CORRELATIVE/TERTIARY OBJECTIVES: I. To explore the baseline tumor genetic and microenvironment parameters predictive of clinical benefit or resistance to immunotherapy. II. To determine whether the addition of pembrolizumab (MK-3475) to radiation, compared with radiation alone, is associated with decreased quality of life as measured with the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM subscale) and more self-reported bother from side effects as measured with a single item GP5 "I am bothered by side effects," a question from the FACT-En TOI. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo pelvic external beam radiation therapy (EBRT) daily for 5-6 weeks and vaginal brachytherapy completed within 7 days after completion of EBRT in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo EBRT and brachytherapy as in Arm I. Within 7 days prior to the start of radiation therapy, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment with pembrolizumab repeats every 6 weeks for up to 1 year (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients in both arms also undergo collection of blood samples and computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, or x-ray imaging throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
164
Undergo collection of blood
Undergo vaginal brachytherapy
Undergo CT
Undergo EBRT
Undergo MRI
Given IV
Ancillary studies
Ancillary studies
Undergo x-rays
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Community Cancer Institute
Clovis, California, United States
University Oncology Associates
Clovis, California, United States
John Muir Medical Center-Concord
Concord, California, United States
UC San Diego Moores Cancer Center
La Jolla, California, United States
3 year recurrence-free survival
Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.
Time frame: Time from study entry (randomization) to the time of cancer recurrence, assessed at 3 years
Incidence of adverse events
Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) by treatment regimen. Will be evaluated descriptively using frequencies and percentages and will be reported using tables. Differences between treatment arms will be assessed through absolute deviations and contingency table analyses. All patients who receive treatment, will be evaluated for toxicity. Toxicities by type and maximum grade over the course of treatment and follow up will be summarized and by date of occurrence (acute toxicity and late adverse effects).
Time frame: 12 months
Recurrence patterns
The cumulative incidences of vaginal recurrence, pelvic recurrence, retroperitoneal, and distant recurrence from endometrial cancer will be estimated within treatment regimen. Treatments will be compared graphically using Kaplan-Meier estimates of the survival function.
Time frame: 5 years
5 year recurrence free survival
Proportions will be compared by treatment using Fisher's exact test. This analysis may be delayed until the data are mature.
Time frame: Time from study entry (randomization) to the time of cancer recurrence, assessed at 5 years
Overall survival
Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.
Time frame: Duration of time from study entry to time of death or the date of last contact, assessed up to 5 years
Patient-reported outcomes
Will be assessed by questionnaire.
Time frame: Up to 2 years after starting treatment
Impact of circulating tumor deoxyribonucleic acid (ctDNA) on treatment outcomes
Will examine the association between ctDNA and 2- year (or 3-year) progression free survival in a 2-stages of analysis.
Time frame: Up to 5 years
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Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
UCSF Medical Center-Mission Bay
San Francisco, California, United States
John Muir Medical Center-Walnut Creek
Walnut Creek, California, United States
...and 270 more locations