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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

NCT03914612

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.

Related Conditions:
  • Endometrial Adenocarcinoma
  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Endometrioid Adenocarcinoma
  • Endometrial Mixed Adenocarcinoma
  • Endometrial Serous Adenocarcinoma
  • Endometrial Undifferentiated Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-02186
  • SECONDARY ID: NCI-2019-02186
  • SECONDARY ID: NRG-GY018
  • SECONDARY ID: NRG-GY018
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03914612

Conditions

  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Endometrioid Adenocarcinoma
  • Endometrial Mixed Cell 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

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (placebo, paclitaxel, carboplatin)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (placebo, paclitaxel, carboplatin)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm II (pembrolizumab, paclitaxel, carboplatin)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      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 the objective response rate (ORR) as assessed by Response Evaluation Criteria
      in Solid Tumors (RECIST) 1.1 in patients who enter the study with measurable disease.

      III. To evaluate the duration of response (DOR) in patients who enter the study with
      measurable disease.

      IV. To evaluate the effect of pembrolizumab on OS in patients with proficient mismatch repair
      (pMMR) or deficient mismatch repair (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-Endometrial (FACT-En) Trial Outcome Index (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 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 Arms

NameTypeDescriptionInterventions
Arm I (placebo, paclitaxel, carboplatin)Active ComparatorCOMBINATION 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.
  • Carboplatin
  • Paclitaxel
Arm II (pembrolizumab, paclitaxel, carboplatin)ExperimentalCOMBINATION 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.
  • Carboplatin
  • Paclitaxel
  • Pembrolizumab

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, 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Will be tested with a stratified log-rank statistic.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:5 years
Safety Issue:
Description: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.
Measure:Objective tumor response
Time Frame:5 years
Safety Issue:
Description:Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1.
Measure:Duration of objective response
Time Frame:5 years
Safety Issue:
Description:The time difference between the dates of first response and first progression; patients who do not progress are considered censored.
Measure:Overall survival (OS)
Time Frame:Time from study entry to time of death or the date of last contact, assessed up to 5 years
Safety Issue:
Description:
Measure:Quality of life (QoL) and patient-reported outcomes (PROs)
Time Frame:5 years
Safety Issue:
Description: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.
Measure:Incidence of pembrolizumab treatment and self-reported neurotoxicity
Time Frame:5 years
Safety Issue:
Description:Assessed with FACT/GOG-Ntx.
Measure:Concordance between Institutional Mismatch repair (MMR) immunohistochemistry (IHC) testing and centralized MMR IHC
Time Frame:5 years
Safety Issue:
Description: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).
Measure:Effect of pembrolizumab on PFS and OS by PD-L1 IHC
Time Frame:5 years
Safety Issue:
Description: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.
Measure:Association between Program Death Ligand 1 (PD-L1) IHC and MMR status
Time Frame:5 years
Safety Issue:
Description: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).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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