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Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer

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ClinicalTrials.gov Identifier: NCT02899793
Recruitment Status : Recruiting
First Posted : September 14, 2016
Last Update Posted : September 13, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Yale University

Brief Summary:
Primary Objectives: To assess the antitumor activity (proportion of objective response by RECIST 1.1 criteria) of pembrolizumab with objective tumor response in patients with persistent, recurrent or metastatic endometrial cancer harboring an ultra-mutated or hyper-mutated (MMR gene-defective) phenotype identified by next generation sequencing (NGS) and comprehensive genomic profiling (CGP). To determine the nature and degree of toxicity of pembrolizumab as assessed by CTCAE in patients with persistent, recurrent or metastatic endometrial carcinoma. Secondary Objective(s): To estimate the duration of progression-free survival (PFS) and overall survival (OS).

Condition or disease Intervention/treatment Phase
Recurrent Endometrial Cancer Drug: Pembrolizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Evaluation of Pembrolizumab, a Humanized Antibody Against PD-1, in the Treatment of Persistent or Recurrent Hypermutated/Ultramutated Endometrial Cancer Identified by Next Generation Sequencing (NGS) and Comprehensive Genomic Profiling (CGP)
Study Start Date : September 2016
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab
Pembrolizumab 200 mg, Q3W, IV Infusion, Day 1 of each 3 week cycle
Drug: Pembrolizumab
Pembrolizumab 200 mg (fixed dose) IV every 3 weeks (+/- 3 days) until progression or adverse effects prohibit therapy
Other Name: MK-3475




Primary Outcome Measures :
  1. Frequency of objective tumor response as assessed by RECIST 1.1 [ Time Frame: 24 months ]
    RECIST (Response Evaluation Criteria In Solid Tumors) is a set of published rules that define when cancer patients improve ("respond"), stay the same ("stable") or worsen ("progression") during treatments.

  2. Frequency and severity of adverse events as assessed by CTCAE v4 [ Time Frame: 24 months ]
    Common Terminology Criteria for Adverse Events (CTCAE) are a set of criteria for the standardized classification of adverse effects of drugs used in cancer therapy.


Secondary Outcome Measures :
  1. Duration of progression-free survival (PFS) [ Time Frame: 24 months ]
    Progression-free survival is defined as the duration of time from study entry to time of progression, death, or the date of last contact, whichever occurs first.

  2. Overall survival (OS) [ Time Frame: 24 months ]
    Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have histologically confirmed endometrial cancer that is recurrent or progressive following at least one prior chemotherapy regimen.
  2. Patients with the following histologic epithelial cell types are eligible: Endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, mixed epithelial carcinoma, carcinosarcoma, and adenocarcinoma not otherwise specified (N.O.S.).
  3. Tumors must demonstrate ultramutation (POLE-mutation) and/or hyper-mutation (due to MMR gene defect) in a representative primary or metastatic tumor site by next generation sequencing (NGS) and Comprehensive Genomic Profiling (CGP) testing.
  4. All patients must have measurable disease by RECIST 1.1.
  5. Patients must have a ECOG performance status of 0 or 1.
  6. Women of childbearing potential must have a negative urine and serum pregnancy test within 72 hours prior to receiving first dose and must be willing to use contraceptive through 120 days of last dose of Pembrolizumab.
  7. Patients must have recovered from effects of recent surgery, radiotherapy, or chemotherapy.
  8. Patients may have received prior radiation therapy for treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, intravaginal brachytherapy and/or palliative radiation therapy. All radiation therapy must be completed at least 4 weeks prior to the first date of study therapy.
  9. Patients may have received prior hormonal therapy for treatment of endometrial carcinoma. All hormonal therapy must be discontinued at least one week prior to the first date of study therapy.
  10. Patients may have received prior therapy (including chemotherapy, biologic/targeted therapy and immunotherapy) for treatment of endometrial cancer. All therapy must be discontinued at least 3 weeks prior to the first date of study therapy. Any investigational agent must be discontinued at least 30 days prior to the first date of study therapy.
  11. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen.
  12. Patients are allowed to receive, but not required to receive, up to 4 additional lines of therapy.
  13. At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy) There is no delay in treatment for minor procedures (e.g., tumor FNA or core biopsy, venous access device placement).
  14. Have demonstrated adequate organ function. All screen labs should be performed within 14 days of treatment initiation
  15. Patients must have signed an approved informed consent and authorization permitting release of personal health information.
  16. Patients must be 18 years or older

Exclusion Criteria:

  1. Patients who have had prior therapy with nivolumab, pembrolizumab or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune check point pathways.
  2. History of severe hypersensitivity reaction to any monoclonal antibody.
  3. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure and unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  4. Patients who are pregnant or nursing. The effects of pembrolizumab on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. WOCBP should use an adequate method to avoid pregnancy for 23 weeks after the last dose of investigational drug. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IV/L or equivalent units of HCG) within 24 hours prior to the start ofpembrolizumab. Women must not be breastfeeding.
  5. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile or have undergone definitive radiation) do not require contraception.
  6. Patients with known brain metastases or leptomeningeal metastases are excluded unless the following conditions are met: Metastases have been treated and there is no evidence of progression by CT scan or magnetic resonance imaging (MRI) prior to the first dose of pembrolizumab administration). There must also be no requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalents) for at least 1 week prior to study drug administration.
  7. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection (e.g., HCV RNA [qualitative] is detected).
  8. 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, should be excluded. These include but are 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 SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IRB), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patient with vitiligo, endocrine deficiencies including 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.

    NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).

  9. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
  10. Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, abdominal/pelvic fistula, gastrointestinal perforation, GI obstruction and/or who require parenteral hydration and/or nutrition..
  11. Has a known history of active TB (Bacillus Tuberculosis)
  12. Hypersensitivity to pembrolizumab or any of its excipients.
  13. Prior invasive malignancy (except non-melanomatous skin cancer such as basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer) unless disease free for a minimum of 3 years.
  14. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  15. Has an active infection requiring systemic therapy.
  16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  18. Has not recovered from adverse events to <Grade 1 or prior treatment level due to a previously administered agent. Subjects with Grade <2 neuropathy or alopecia of any grade are an exception to this criterion and may qualify for the study.
  19. Has a known additional malignancy that progressed or required active treatment within the last five years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  20. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  21. Patients should not have used investigational agents or device within 4 weeks prior to first dose.
  22. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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): NCT02899793


Contacts
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Contact: Alessandro D. Santin, M.D. 203-737-4450 alessandro.santin@yale.edu
Contact: Lisa D. Baker, R.N. 203-785-6398 lisa.baker@yale.edu

Locations
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United States, Connecticut
Yale New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Alessandro D. Santin, M.D.    203-737-4450    alessandro.santin@yale.edu   
Contact: Lisa Baker, R.N.    203-785-6398    lisa.baker@yale.edu   
Sponsors and Collaborators
Yale University
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Alessandro D. Santin, M.D Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT02899793     History of Changes
Other Study ID Numbers: 1605017712
First Posted: September 14, 2016    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
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Pembrolizumab
Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Diseases
Genital Diseases, Female
Antineoplastic Agents, Immunological
Antineoplastic Agents