Testing the Addition of the Immunotherapy Drug, Pembrolizumab, to the Usual Radiation Treatment for Newly Diagnosed Early Stage High Intermediate Risk Endometrial Cancer

• ClinicalTrials.gov Identifier: NCT04214067
• Recruitment Status: Recruiting
• First Posted: December 30, 2019
• Last Update Posted: January 25, 2021
• Sponsor: National Cancer Institute (NCI)
• Collaborator: NRG Oncology
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: December 27, 2019
• First Posted Date: December 30, 2019
• Last Update Posted Date: January 25, 2021
• Actual Study Start Date: February 7, 2020
• Estimated Primary Completion Date: February 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2020)

3 year recurrence-free survival [ Time Frame: Time from study entry (randomization) to the time of cancer recurrence, assessed at 3 years ]

Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.

Original Primary Outcome Measures (submitted: December 27, 2019)

Recurrence-free survival [ Time Frame: Time from study entry (randomization) to the time of cancer recurrence, assessed at 3 years ]

Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.

Current Secondary Outcome Measures (submitted: January 29, 2020)

• Incidence of adverse events [ Time Frame: 12 months ]
  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).
• Recurrence patterns [ Time Frame: 5 years ]
  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.
• 5 year recurrence free survival [ Time Frame: Time from study entry (randomization) to the time of cancer recurrence, assessed at 5 years ]
  Proportions will be compared by treatment using Fisher's exact test. This analysis may be delayed until the data are mature.
• Overall survival [ Time Frame: Duration of time from study entry to time of death or the date of last contact, assessed up to 5 years ]
  Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.
• Patients reported outcomes [ Time Frame: Up to 2 years after starting treatment ]
  Will be assessed by questionnaire.

Original Secondary Outcome Measures (submitted: December 27, 2019)

• Incidence of adverse events [ Time Frame: 12 months ]
  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).
• Recurrence patterns [ Time Frame: 5 years ]
  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.
• Recurrence free survival [ Time Frame: Time from study entry (randomization) to the time of cancer recurrence, assessed at 5 years ]
  Proportions will be compared by treatment using Fisher's exact test. This analysis may be delayed until the data are mature.
• Overall survival [ Time Frame: Duration of time from study entry to time of death or the date of last contact, assessed up to 5 years ]
  Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.
• Patients reported outcomes [ Time Frame: Up to 2 years after starting treatment ]
  Will be assessed by questionnaire.

Current Other Pre-specified Outcome Measures (submitted: January 29, 2020)

• Potential transformations of the severity of adverse events [ Time Frame: 12 months ]
  An example of potential transformation of the severity of adverse events is whether or not the patient experienced >= grade 3 events. It will be assessed by CTCAE and treatment regimen.
• Biomarker analysis [ Time Frame: Baseline ]
  Will assess baseline genetic characteristics (e.g. mutations) and microenvironment parameters, treatment, and interactions between treatment and biomarkers in a Cox regression.
• Functional Assessment of Cancer Therapy (FACT)-Immune Checkpoint Modulator (ICM) subscale [ Time Frame: Up to 2 years after starting treatment ]
  Treatment differences in the FACT-ICM subscale and self-reported bother from side effects will be explored using a linear mixed model for repeated measures, adjusted for the baseline score.

Original Other Pre-specified Outcome Measures (submitted: December 27, 2019)

• Potential transformations of the severity of adverse events (e.g. whether or not the patient experienced >= grade 3 events) [ Time Frame: 12 months ]
  Will be assessed by CTCAE and treatment regimen.
• Biomarker analysis [ Time Frame: Baseline ]
  Will assess baseline genetic characteristics (e.g. mutations) and microenvironment parameters, treatment, and interactions between treatment and biomarkers in a Cox regression.
• Functional Assessment of Cancer Therapy (FACT)-Immune Checkpoint Modulator (ICM) subscale [ Time Frame: Up to 2 years after starting treatment ]
  Treatment differences in the FACT-ICM subscale and self-reported bother from side effects will be explored using a linear mixed model for repeated measures, adjusted for the baseline score.

Descriptive Information

• Brief Title: Testing the Addition of the Immunotherapy Drug, Pembrolizumab, to the Usual Radiation Treatment for Newly Diagnosed Early Stage High Intermediate Risk Endometrial Cancer
• Official Title: A Phase III Randomized Trial of Radiation +/- Pembrolizumab (MK-3475) for Newly Diagnosed Early Stage High Intermediate Risk Mismatch Repair Deficient (dMMR) Endometrioid Endometrial Cancer
• Brief Summary: 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.

Detailed Description

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.

EXPLORATORY 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.

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Endometrial Endometrioid Adenocarcinoma
• Stage I Uterine Corpus Cancer AJCC v8
• Stage IA Uterine Corpus Cancer AJCC v8
• Stage IB Uterine Corpus Cancer AJCC v8
• Stage II Uterine Corpus Cancer AJCC v8

Intervention

• Radiation: External Beam Radiation Therapy
  Undergo EBRT
  Other Names:

  • Definitive Radiation Therapy
  • EBRT
  • External Beam Radiation
  • External Beam Radiotherapy
  • External Beam RT
  • external radiation
  • External Radiation Therapy
  • external-beam radiation
  • Radiation, External Beam
• Radiation: Internal Radiation Therapy
  Undergo vaginal brachytherapy
  Other Names:

  • Brachytherapy
  • Brachytherapy, NOS
  • Internal Radiation
  • Internal Radiation Brachytherapy
  • Radiation Brachytherapy
  • Radiation, Internal
• Biological: Pembrolizumab
  Given IV
  Other Names:

  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

• Active Comparator: Arm I (EBRT, brachytherapy)
  Patients undergo pelvic 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.
  Interventions:

  • Radiation: External Beam Radiation Therapy
  • Radiation: Internal Radiation Therapy
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Arm II (EBRT, brachytherapy, pembrolizumab)
  Patients undergo EBRT and brachytherapy as in Arm I. Within 7 days prior to the start of radiation therapy, patients also receive pembrolizumab 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.
  Interventions:

  • Radiation: External Beam Radiation Therapy
  • Radiation: Internal Radiation Therapy
  • Biological: Pembrolizumab
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 27, 2019): 168
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 1, 2024
• Estimated Primary Completion Date: February 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have:

  • Stage I endometrioid endometrial cancer and a combination of age and risk factors as listed below:

    • Age >= 70 and >= 1 risk factor
    • Age 50 - < 70 and 2 risks factors

    • Age < 50 and 3 risk factors

      • Risk factors:

        • Myometrial invasion >= 50%
        • Lymphovascular space invasion
        • Grade 2 or 3 OR

  • Stage II endometrioid endometrial cancer

    • Note: Patients with isolated tumor cells in sentinel lymph nodes are eligible (considered N0i) as long as there is no evidence of micro- or macro-metastases in any lymph nodes
• Computed tomography (CT) or magnetic resonance imaging (MRI) abdomen or pelvis and either chest X-ray or CT chest demonstrating no evidence of disease outside of the uterus. Imaging can be performed pre-operatively or post-operatively. CT with contrast is the preferred modality. PET/CT is NOT to be used for any disease assessment or reassessment unless there is documentation that PET/CT is of diagnostic quality equal to CT with contrast
• Patients must have deficient mismatch repair as demonstrated by lack of expression of at least one mismatch repair protein by immunohistochemistry (IHC) and/or evidence of microsatellite instability (MSI) high. The institutional pathology report documenting MMR deficiency must be submitted
• Patients must have undergone surgical staging with at least hysterectomy, removal of cervix, bilateral (if both are present) salpingo-oophorectomy, and either sentinel lymph node assessment or complete pelvic +/- aortic lymphadenectomy. Secondary staging is allowed to determine stage. Patients with isolated tumor cells in sentinel lymph nodes are eligible (considered N0i) as long as there is no evidence of micro- or macro-metastases in any lymph nodes
• Patients must have received no prior therapy for endometrial cancer, including hormonal therapy, chemotherapy, targeted therapy, immunotherapy or radiation therapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Platelets >= 100,000/mcl (within 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)
• Creatinine =< 1.5 x laboratory upper limit of normal (ULN) (within 14 days prior to registration)
• Bilirubin =< 1.5 x ULN (within 14 days prior to registration) (patients with known Gilbert's disease who have bilirubin level =< 3 x ULN may be enrolled)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to registration)
• Patients must be registered between 1 and 8 weeks after initial (staging) surgery performed for the combined purpose of diagnosis and staging
• Human immunodeficiency virus (HIV) testing is not required by protocol unless clinically indicated. Known HIV positive patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients who are currently participating and receiving cancer-directed study therapy for endometrial cancer or have participated in a study of an investigational agent and received cancer-directed study therapy for endometrial cancer within 4 weeks prior to registration
• Patients who have received prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody or other similar agents
• Patients who have a history of a severe hypersensitivity reaction to monoclonal antibody or MK-3475 (pembrolizumab) and/or its excipients
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic 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. 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), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Patients with a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis

• Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to registration:

  • Patients who have received steroids as CT scan contrast premedication may be enrolled
  • The use of inhaled or topical corticosteroids is allowed
  • The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
  • The use of physiologic doses of corticosteroids may be approved after consultation with the study chair (e.g. 10 mg of prednisone used for replacement therapy for adrenal insufficiency)
• Patients who are lactating
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; and cirrhosis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection (except for uncomplicated urinary tract infection), interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who have received any of the prohibited medications

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States, Puerto Rico

Administrative Information

• NCT Number: NCT04214067
• Other Study ID Numbers: NCI-2019-08602; NCI-2019-08602 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NRG-GY020 ( Other Identifier: NRG Oncology ); NRG-GY020 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
• URL: https://grants.nih.gov/policy/sharing.htm

• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: NRG Oncology

Investigators

• Principal Investigator: Floor Backes; NRG Oncology

• PRS Account: National Cancer Institute (NCI)
• Verification Date: November 2020