Clinical Trials /

Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer

NCT02899793

Description:

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).

Related Conditions:
  • Endometrial Adenocarcinoma
  • Endometrial Carcinoma
  • Endometrial Serous Adenocarcinoma
  • Endometrial Undifferentiated Carcinoma
  • Uterine Corpus Carcinosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Ultramutated and Hypermutated Endometrial Cancer
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 1605017712
  • NCT ID: NCT02899793

Conditions

  • Recurrent Endometrial Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475Pembrolizumab

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
PembrolizumabExperimentalPembrolizumab 200 mg, Q3W, IV Infusion, Day 1 of each 3 week cycle
  • Pembrolizumab

Eligibility 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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency of objective tumor response as assessed by RECIST 1.1
Time Frame:24 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Duration of progression-free survival (PFS)
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:24 months
Safety Issue:
Description:Overall survival is defined as the duration of time from study entry to time of death or the date of last contact.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Yale University

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