Clinical Trials /

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

NCT04214067

Description:

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.

Related Conditions:
  • Endometrial Endometrioid Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • 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 +/- MK-3475 (Pembrolizumab) for Newly Diagnosed Early Stage High Intermediate Risk Mismatch Repair Deficient (dMMR) Endometrioid Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-08602
  • SECONDARY ID: NCI-2019-08602
  • SECONDARY ID: NRG-GY020
  • SECONDARY ID: NRG-GY020
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04214067

Conditions

  • 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

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm II (EBRT, brachytherapy, pembrolizumab)

Purpose

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 MK-3475 (pembrolizumab) versus radiation alone.

      SECONDARY OBJECTIVES:

      I. To describe the safety and tolerability of concurrent MK-3475 (pembrolizumab) 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 MK-3475 (pembrolizumab) 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 MK-3475 (pembrolizumab) 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 3 weeks for up to 1 year (17 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (EBRT, brachytherapy)Active ComparatorPatients 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.
    Arm II (EBRT, brachytherapy, pembrolizumab)ExperimentalPatients 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 3 weeks for up to 1 year (17 cycles) in the absence of disease progression or unacceptable toxicity.
    • Pembrolizumab

    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
    
              -  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
                 or have participated in a study of an investigational agent and received
                 cancer-directed study therapy 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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:3 year recurrence-free survival
    Time Frame:Time from study entry (randomization) to the time of cancer recurrence, assessed at 3 years
    Safety Issue:
    Description:Will be estimated using the Kaplan Meier method and treatment comparisons will be made using a stratified log-rank test.

    Secondary Outcome Measures

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

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    March 3, 2020