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

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ClinicalTrials.gov Identifier: NCT03914612
Recruitment Status : Not yet recruiting
First Posted : April 15, 2019
Last Update Posted : May 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Endometrial Clear Cell Adenocarcinoma Endometrial Endometrioid Adenocarcinoma Endometrial Mixed Adenocarcinoma Endometrial Serous Adenocarcinoma Endometrial Undifferentiated Carcinoma Recurrent Endometrial Adenocarcinoma Recurrent Endometrial Carcinoma Recurrent Endometrial Clear Cell Adenocarcinoma Recurrent Endometrial Endometrioid Adenocarcinoma Recurrent Endometrial Mixed Cell Adenocarcinoma Recurrent Endometrial Serous Adenocarcinoma Recurrent Endometrial Undifferentiated Carcinoma Stage III Uterine Corpus Cancer AJCC v8 Stage IIIA Uterine Corpus Cancer AJCC v8 Stage IIIB Uterine Corpus Cancer AJCC v8 Stage IIIC Uterine Corpus Cancer AJCC v8 Stage IIIC1 Uterine Corpus Cancer AJCC v8 Stage IIIC2 Uterine Corpus Cancer AJCC v8 Stage IV Uterine Corpus Cancer AJCC v8 Stage IVA Uterine Corpus Cancer AJCC v8 Stage IVB Uterine Corpus Cancer AJCC v8 Drug: Carboplatin Drug: Paclitaxel Biological: Pembrolizumab Other: Placebo Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 810 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Placebo-Controlled Study of Pembrolizumab (MK-3475, NSC #776864) in Addition to Paclitaxel and Carboplatin for Measurable Stage III or IVA, Stage IVB or Recurrent Endometrial Cancer
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2023


Arm Intervention/treatment
Active Comparator: Arm I (placebo, paclitaxel, carboplatin)

COMBINATION PHASE: Patients receive placebo 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 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.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Other: Placebo
Given IV
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Experimental: Arm II (pembrolizumab, paclitaxel, carboplatin)

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.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

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




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Duration of time from study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 5 years ]
    Will be tested with a stratified log-rank statistic.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 5 years ]
    Assessed by Common Terminology Criteria for Adverse Events (CTCAE). Toxicities will be screened for differences between treatments by using an exact method or a Chi-Square test. For a given adverse event, each patient will be graded according to the worse grade experienced while on therapy (and within 30 days of treatment). These toxicities will then be divided into two or three categories such as mild, moderate, and severe or mild to moderate versus severe. The rates of severe toxicities may be characterized by risk ratios or odds ratios with confidence intervals (unadjusted for multiplicity). The number of toxicities examined is usually fairly large, so these analyses will be considered exploratory and may be inspected in light of other studies.

  2. Objective tumor response [ Time Frame: 5 years ]
    Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1.

  3. Duration of objective response [ Time Frame: 5 years ]
    The time difference between the dates of first response and first progression; patients who do not progress are considered censored.

  4. Overall survival (OS) [ Time Frame: Time from study entry to time of death or the date of last contact, assessed up to 5 years ]
  5. Quality of life (QoL) and patient-reported outcomes (PROs) [ Time Frame: 5 years ]
    Measured by the Function Assessment of Cancer Therapy (FACT)-Endometrial Trial Outcome Index (En-TOI), the FACT/Gynecologic Oncology Group (GOG)-Neurotoxicity (Ntx) subscale (short), Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue (short form),the PROMIS-physical function (short form) and a single-item measuring bother from side effects of cancer therapy. A linear mixed model for repeated measures will be used to estimate and compare the mean differences between the treatment groups. Model covariates will include the patients' randomly assigned study treatment, age at enrollment onto the study, pre-treatment quality of life/patient reported outcome score, assessment time and treatment-by-time interaction. The stratification factors will be the same factors included in the clinical primary analysis. Hochberg's step-up multiple testing procedure (Hochberg, 1988) will be used to adjust p-values for each assessment time points estimated from the fitted model.

  6. Incidence of pembrolizumab treatment and self-reported neurotoxicity [ Time Frame: 5 years ]
    Assessed with FACT/GOG-Ntx.

  7. Concordance between Institutional Mismatch repair (MMR) immunohistochemistry (IHC) testing and centralized MMR IHC [ Time Frame: 5 years ]
    Concordance between institutional MMR IHC testing and centralized MMR IHC. The patient's MMR status will be assessed for prognostic value by conducting stratified log-rank tests or Cox Proportional Hazards (PH) modeling when assessing the impact on PFS or OS. When assessing the impact on the probability of response, a logistic regression model will be considered and include other pertinent variables that may influence response. A Cox PH model will be used to assess predictive value of MMR status for regimen efficacy through an interaction term. A similar type of analysis may be attempted with response using logistic regression. The concordance of institutional MMR IHC testing and centralized MMR IHC will be characterized by agreement statistics such as kappa statistics (e.g. Cohen's kappa coefficient).

  8. Effect of pembrolizumab on PFS and OS by PD-L1 IHC [ Time Frame: 5 years ]
    Will assess the effect of pembrolizumab on PFS and OS by PD-L1 IHC (combined positive score [CPS]) within proficient MMR (pMMR) and deficient MMR (dMMR) populations. The effectiveness of pembrolizumab will be compared by PD-L1 status (CPS). A formal test will be conducted by examining the interaction term between pembrolizumab treatment (yes or no) with PD-L1 status. The association between PD-L1 CPS status and MMR status will be assessed with odds ratios. A test may be conducted with a Fisher's Exact Test, and confidence intervals will be provided.

  9. Association between Program Death Ligand 1 (PD-L1) IHC and MMR status [ Time Frame: 5 years ]
    Measures of association between PD-L1 IHC (CPS) and MMR status. The concordance of institutional MMR IHC testing and centralized MMR IHC will be characterized by agreement statistics such as kappa statistics (e.g. Cohen's kappa coefficient).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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, 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 either

    • 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 and 2.
  • Platelets >= 100,000/mcl.
  • Absolute neutrophil count (ANC) >= 1,500/mcl.
  • Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2.

    • GFR (estimated creatinine clearance or CLcr) will be estimated using the Cockcroft and Gault equation for females followed by conversion to a value normalized to 1.73 m^2 with the patient's body surface area (BSA).
  • 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.
  • 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 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.
  • 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, 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.

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): NCT03914612


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ramez N Eskander NRG Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03914612     History of Changes
Other Study ID Numbers: NCI-2019-02186
NCI-2019-02186 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GY018 ( Other Identifier: NRG Oncology )
NRG-GY018 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: April 15, 2019    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: April 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

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

Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma
Adenocarcinoma
Endometrial Neoplasms
Uterine Neoplasms
Carcinoma, Endometrioid
Cystadenocarcinoma, Serous
Adenocarcinoma, Clear Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Genital Diseases, Female
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Pembrolizumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents