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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04214067
Recruitment Status : Recruiting
First Posted : December 30, 2019
Last Update Posted : January 25, 2021
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE December 27, 2019
First Posted Date  ICMJE December 30, 2019
Last Update Posted Date January 25, 2021
Actual Study Start Date  ICMJE February 7, 2020
Estimated Primary Completion Date February 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 27, 2019)
168
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2024
Estimated Primary Completion Date February 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States,   Puerto Rico
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04214067
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Floor Backes NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP