Testing the Addition of the Immunotherapy Drug Pembrolizumab to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) in Stage III-IV or Recurrent Endometrial Cancer

Status: Active

Description

This phase III trial studies how well the combination of pembrolizumab, paclitaxel and carboplatin, works compared with paclitaxel and carboplatin alone in treating patients with endometrial cancer that is stage III or IV, or has come back (recurrent). 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. Paclitaxel and carboplatin are chemotherapy drugs used as part of the usual treatment approach for this type of cancer. This study aims to assess if adding immunotherapy to these drugs is better or worse than the usual approach for treatment of this cancer.

Eligibility Criteria

Inclusion Criteria

  • Measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial cancer.
  • Pathology report showing results of institutional MMR IHC testing.
  • Histologic confirmation of the original primary tumor is required (submission of pathology report(s) is required). Patients with the following histologic types are eligible: Endometrioid adenocarcinoma, serous adenocarcinoma, dedifferentiated/undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.).
  • Submission of tumor specimens for centralized MMR IHC testing is required after Step 1 and before Step 2 registration.
  • In patients with measurable disease (stage III and IVA), lesions will be defined and monitored by RECIST version (v) 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be >= 10 mm when measured by computed tomography (CT) or magnetic resonance imaging (MRI). Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI.
  • Patients may have received * NO prior chemotherapy for treatment of endometrial cancer OR * Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a component of concurrent chemotherapy and radiation therapy [with or without cisplatin]) provided adjuvant chemotherapy was completed >= 12 months prior to STEP 1 registration.
  • 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, and/or intravaginal brachytherapy. All radiation therapy must be completed at least 4 weeks prior to STEP 1 registration.
  • Patients may have received prior hormonal therapy for treatment of endometrial cancer. All hormonal therapy must be discontinued at least three weeks prior to STEP 1 registration.
  • Performance status of 0, 1 or 2.
  • Platelets >= 100,000/mcl.
  • Absolute neutrophil count (ANC) >= 1,500/mcl.
  • Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN).
  • Total serum bilirubin level =< 1.5 x upper limit of normal (ULN) (patients with known Gilbert’s disease who have bilirubin level =< 3 x ULN may be enrolled).
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN.
  • Thyroid stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid patients on thyroid replacement therapy).
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of Step 1 registration are eligible for this trial.
  • For patients of child bearing potential: negative urine or serum pregnancy test within 72 hours prior to Step 2 registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required.
  • Administration of study drugs (pembrolizumab, paclitaxel, carboplatin) may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of childbearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from up to 14 days prior to Step 2 registration (for oral contraceptives), during treatment, and for 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Patients will be considered of nonreproductive potential if they are either: * Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient); OR * Have a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to Step 2 registration; OR * Have a congenital or acquired condition that prevents childbearing.
  • 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 with 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 pembrolizumab and/or its excipients.
  • 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 Step 1 registration.
  • 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 Step 1 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.
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression, and they have been off steroids for at least 4 weeks prior to Step 1 registration and remain clinically stable.
  • 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 who have a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
  • 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.
  • 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.
  • Pregnant or lactating patients.

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 205-934-0220
Email: tmyrick@uab.edu

Alaska

Anchorage
Alaska Women's Cancer Care
Status: Active
Contact: Site Public Contact
Phone: 907-212-6871
Email: AKPAMC.OncologyResearchSupport@providence.org

California

Orange
UC Irvine Health / Chao Family Comprehensive Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 877-827-8839
Email: ucstudy@uci.edu

Connecticut

Danbury
Danbury Hospital
Status: Active
Contact: Site Public Contact
Phone: 203-739-8074
Norwalk
Norwalk Hospital
Status: Active
Contact: Site Public Contact
Phone: 203-852-2996
Email: jennifer.long@norwalkhealth.org

Georgia

Savannah
Lewis Cancer and Research Pavilion at Saint Joseph's / Candler
Status: Active
Contact: Site Public Contact
Phone: 912-819-5704
Email: underberga@sjchs.org

Idaho

Boise
Saint Luke's Mountain States Tumor Institute
Status: Active
Contact: Site Public Contact
Phone: 208-381-2774
Email: eslinget@slhs.org
Fruitland
Saint Luke's Mountain States Tumor Institute - Fruitland
Status: Active
Contact: Site Public Contact
Phone: 208-381-8059
Email: hallsc@slhs.org
Meridian
Saint Luke's Mountain States Tumor Institute - Meridian
Status: Active
Contact: Site Public Contact
Phone: 208-381-8059
Email: hallsc@slhs.org
Nampa
Saint Luke's Mountain States Tumor Institute - Nampa
Status: Active
Contact: Site Public Contact
Phone: 208-381-8059
Email: hallsc@slhs.org
Twin Falls
Saint Luke's Mountain States Tumor Institute-Twin Falls
Status: Active
Contact: Site Public Contact
Phone: 208-381-8059
Email: hallsc@slhs.org

Illinois

Chicago
Northwestern University
Status: Active
Contact: Site Public Contact
Phone: 312-695-1301
Email: cancer@northwestern.edu
University of Chicago Comprehensive Cancer Center
Status: Temporarily closed to accrual
Contact: Site Public Contact
Phone: 773-702-8222
Email: cancerclinicaltrials@bsd.uchicago.edu
University of Illinois
Status: Active
Contact: Site Public Contact
Phone: 312-355-3046
Springfield
Springfield Clinic
Status: Active
Contact: Site Public Contact
Phone: 800-444-7541

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 800-237-1225

Kentucky

Edgewood
Saint Elizabeth Medical Center South
Status: Active
Contact: Site Public Contact
Phone: 859-301-5473
Email: darla.hehman@stelizabeth.com

Maryland

Annapolis
Anne Arundel Medical Center
Status: Active
Contact: Site Public Contact
Phone: 443-481-1320
Email: kbodenhorn@aahs.org
Baltimore
Greater Baltimore Medical Center
Status: Active
Contact: Site Public Contact
Phone: 443-849-3706

Massachusetts

Winchester
Winchester Hospital
Status: Active
Contact: Site Public Contact
Phone: 412-339-5294
Email: Roster@nrgoncology.org
Worcester
UMass Memorial Medical Center - Memorial Division
Status: Active
Contact: Site Public Contact
Phone: 508-856-6265

Michigan

Ann Arbor
Saint Joseph Mercy Hospital
Status: Active
Contact: Site Public Contact
Phone: 734-712-3671
Email: stephanie.couch@stjoeshealth.org

Minnesota

Rochester
Mayo Clinic
Status: Active
Contact: Site Public Contact
Phone: 855-776-0015

Mississippi

Jackson
University of Mississippi Medical Center
Status: Active
Contact: Site Public Contact
Phone: 601-815-6700

Missouri

Kansas City
Saint Luke's Hospital of Kansas City
Status: Active
Contact: Site Public Contact
Phone: 913-948-5588
Email: aroland@kccop.org
Saint Louis
Washington University School of Medicine
Status: Active
Contact: Site Public Contact
Phone: 800-600-3606
Email: info@siteman.wustl.edu

Nebraska

Grand Island
CHI Health Saint Francis
Status: Active
Contact: Site Public Contact
Phone: 308-398-6518
Email: clinicaltrials@sfmc-gi.org
Omaha
Nebraska Methodist Hospital
Status: Active
Contact: Site Public Contact
Phone: 402-354-5144

New Jersey

New Brunswick
Rutgers Cancer Institute of New Jersey
Status: Active
Contact: Site Public Contact
Phone: 732-235-8675
Somerville
Robert Wood Johnson University Hospital Somerset
Status: Active
Contact: Site Public Contact
Phone: 908-685-2481

New Mexico

Albuquerque
University of New Mexico Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 505-925-0366
Email: LByatt@nmcca.org

New York

Bronx
Montefiore Medical Center - Moses Campus
Status: Active
Contact: Site Public Contact
Phone: 718-379-6866
Email: aaraiza@montefiore.org
Montefiore Medical Center-Einstein Campus
Status: Active
Contact: Site Public Contact
Phone: 718-379-6866
Email: aaraiza@montefiore.org
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 212-639-7592

North Carolina

Winston-Salem
Wake Forest University Health Sciences
Status: Active
Contact: Site Public Contact
Phone: 336-713-6771

Ohio

Cincinnati
Good Samaritan Hospital - Cincinnati
Status: Active
Contact: Site Public Contact
Phone: 308-398-6518
Email: clinicaltrials@sfmc-gi.org
Cleveland
MetroHealth Medical Center
Status: Active
Contact: Site Public Contact
Phone: 216-778-8526
Email: dstrater@metrohealth.org
Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 800-293-5066
Email: Jamesline@osumc.edu
Sylvania
ProMedica Flower Hospital
Status: Active
Contact: Site Public Contact
Phone: 419-824-1842

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: Active
Contact: Site Public Contact
Phone: 405-271-8777
Email: ou-clinical-trials@ouhsc.edu

Oregon

Portland
Legacy Good Samaritan Hospital and Medical Center
Status: Active
Contact: Site Public Contact
Phone: 800-220-4937
Email: cancer@lhs.org
Tualatin
Legacy Meridian Park Hospital
Status: Active
Contact: Site Public Contact
Phone: 503-413-1742

Pennsylvania

Philadelphia
Thomas Jefferson University Hospital
Status: Active
Contact: Site Public Contact
Phone: 215-955-6084
West Reading
Reading Hospital
Status: Active
Contact: Site Public Contact
Phone: 610-988-9323

Rhode Island

Providence
Women and Infants Hospital
Status: Active
Contact: Site Public Contact
Phone: 401-274-1122

South Carolina

Charleston
Medical University of South Carolina
Status: Active
Contact: Site Public Contact
Phone: 843-792-9321
Email: hcc-clinical-trials@musc.edu
Greenville
Saint Francis Cancer Center
Status: Active
Contact: Site Public Contact
Phone: 864-603-6213
Email: meissa_beckman@bshsi.org
Saint Francis Hospital
Status: Active
Contact: Site Public Contact
Phone: 864-603-6213
Email: meissa_beckman@bshsi.org

South Dakota

Sioux Falls
Avera Cancer Institute
Status: Active
Contact: Site Public Contact
Phone: 888-634-7268
Email: oncregulatory@avera.org

Texas

Houston
Methodist Willowbrook Hospital
Status: Active
Contact: Site Public Contact
Phone: 412-339-5294
Email: Roster@nrgoncology.org
The Methodist Hospital System
Status: Active
Contact: Site Public Contact
Phone: 713-790-2700
Sugar Land
Houston Methodist Sugar Land Hospital
Status: Active
Contact: Site Public Contact
Phone: 281-242-2873

Washington

Seattle
Swedish Medical Center-First Hill
Status: Active
Contact: Site Public Contact
Phone: 206-215-3086
Email: PCRC-NCORP@Swedish.org
Vancouver
Legacy Salmon Creek Hospital
Status: Active
Contact: Site Public Contact
Phone: 503-413-2150

West Virginia

Charleston
West Virginia University Charleston Division
Status: Active
Contact: Site Public Contact
Phone: 304-388-9944
Morgantown
Monongalia Hospital
Status: Active
Contact: Site Public Contact
Phone: 304-598-6560
West Virginia University Healthcare
Status: Active
Contact: Site Public Contact
Phone: 304-293-7374
Email: cancertrialsinfo@hsc.wvu.edu

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of pembrolizumab in combination with paclitaxel and carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and recurrent endometrial cancer.

SECONDARY OBJECTIVES:

I. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) for each treatment arm.

II. To evaluate blinded independent central review (BICR) assessed or investigator assessed objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by treatment arm and by mismatch repair (MMR) status in patients who enter the study with measurable disease.

III. To evaluate BICR assessed or investigator assessed duration of response (DOR) by treatment arm and by MMR status in patients who enter the study with measurable disease.

IV. To evaluate the effect of pembrolizumab on overall survival (OS) in patients with mismatch repair protein proficient (pMMR) or mismatch repair deficiency (dMMR).

V. To determine whether the addition of pembrolizumab to standard combination chemotherapy is associated with improved patient reported physical function as measured with the Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function scale (short form), quality of life as measured with the Functional Assessment of Cancer Therapy (FACT) - Endometrial Trial Outcome Index (En TOI) and worsened fatigue as measured with the PROMIS-Fatigue scale (short form) in the pMMR patients.

VI. To determine concordance between institutional MMR immunohistochemistry (IHC) testing and centralized MMR IHC.

EXPLORATORY OBJECTIVES:

I. To explore the correlation between patient-reported physical function as measured with the PROMIS-physical function scale (short form) and quality of life as measure with the FACT-En TOI.

II. To explore whether the addition of pembrolizumab to standard combination chemotherapy is associated with self-reported neurotoxicity as measured with the FACT/Gynecologic Oncology Group Neurotoxicity (GOG-Ntx) subscale (short) and the extent to which patients differ on their self-reported bother from side effects of cancer therapy in the pMMR patients.

III. To evaluate the efficacy of pembrolizumab in combination with paclitaxel and carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and recurrent endometrial cancer by PD-L1 IHC (positive versus [vs] negative).

IV. To assess the association between PD-L1 IHC (positive vs negative) and mismatch repair status (pMMR and dMMR).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:

COMBINATION PHASE: Patients receive placebo intravenously (IV) over 30 minutes on day 1, paclitaxel IV over 3 hours on day 1, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients with stable disease (SD) or partial response (PR) who still have measurable disease receive placebo IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 29 cycles in the absence of disease progression or unacceptable toxicity.

ARM II:

COMBINATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1, paclitaxel IV over 3 hours on day 1, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients with SD or PR who still have measurable disease receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 29 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 Phase & Type

Trial Phase

Phase III

Trial Type

Treatment

Lead Organization

Lead Organization
NRG Oncology

Principal Investigator
Ramez Nassef Eskander

Trial IDs

Primary ID NRG-GY018
Secondary IDs NCI-2019-02186
Clinicaltrials.gov ID NCT03914612