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

Testing the Addition of the Immunotherapy Drug, Pembrolizumab, to the Usual Radiation Treatment for Newly Diagnosed Early Stage High Intermediate Risk Endometrial Cancer: 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:   Radiation: External Beam Radiation Therapy;   Radiation: Internal Radiation Therapy;   Biological: Pembrolizumab;   Other: Quality-of-Life Assessment;   Other: Questionnaire Administration Sponsor:   National Cancer Institute (NCI) Not yet recruiting (Source: ClinicalTrials.gov)




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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  : Not yet recruiting

First Posted  : December 30, 2019

Last Update Posted  : December 30, 2019

See Contacts and Locations

Sponsor:

National Cancer Institute (NCI)

Information provided by (Responsible Party):

National Cancer Institute (NCI)



Study DetailsTabular ViewNo Results PostedDisclaimerHow to Read a Study Record

Study Description

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Brief Summary:

This phase III trial studies pembrolizumab and usual radiation therapy to see how well it works compared with usual radiation therapy alone in treating 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 the usual radiation treatment may reduce the risk of cancer coming back.



Condition or disease Intervention/treatment Phase

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

Radiation: External Beam Radiation Therapy

Radiation: Internal Radiation Therapy

Biological: Pembrolizumab

Other: Quality-of-Life Assessment

Other: Questionnaire Administration

Phase 3



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.





Study Design

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Study Type  : Interventional  (Clinical Trial)

Estimated Enrollment  : 168 participants

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: None (Open Label)

Primary Purpose: Treatment

Official Title: A Phase III Randomized Trial of Radiation +/- MK-3475 (Pembrolizumab) for Newly Diagnosed, High Intermediate Risk Mismatch Repair Deficient (dMMR) Endometrioid Endometrial Cancer

Estimated Study Start Date  : February 7, 2020

Estimated Primary Completion Date  : February 1, 2024

Estimated Study Completion Date  : February 1, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Pembrolizumab

Genetic and Rare Diseases Information Center resources: Ovarian Cancer

U.S. FDA Resources



Arms and Interventions

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Arm Intervention/treatment

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.

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



Other: Quality-of-Life Assessment

Ancillary studies

Other Name: Quality of Life Assessment



Other: Questionnaire Administration

Ancillary studies



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 3 weeks for up to 1 year (17 cycles) in the absence of disease progression or unacceptable toxicity.

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







Outcome Measures

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Primary Outcome Measures  :

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.





Secondary Outcome Measures  :

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.





Other Outcome Measures:

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.





Eligibility Criteria

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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.





Ages Eligible for Study:  18 Years and older   (Adult, Older Adult)

Sexes Eligible for Study:  Female

Accepts Healthy Volunteers:  No

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

Contacts and Locations

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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.



Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04214067





Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator: Floor Backes NRG Oncology

More Information

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Responsible Party: National Cancer Institute (NCI)

ClinicalTrials.gov Identifier: NCT04214067     History of Changes

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 )

First Posted: December 30, 2019    Key Record Dates

Last Update Posted: December 30, 2019

Last Verified: December 2019

Individual Participant Data (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

Studies a U.S. FDA-regulated Drug Product: Yes

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

Additional relevant MeSH terms:

Adenocarcinoma

Endometrial Neoplasms

Carcinoma, Endometrioid

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Neoplasms by Site

Uterine Diseases

Genital Diseases, Female

Ovarian Neoplasms

Ovarian Diseases

Adnexal Diseases

Gonadal Disorders

Endocrine System Diseases

Pembrolizumab

Antineoplastic Agents, Immunological

Antineoplastic Agents





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