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

Study Overview
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Brief Summary
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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 after a period of improvement (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
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PRIMARY OBJECTIVE: I. To evaluate the efficacy of pembrolizumab (MK-3475) 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) immunohistochemistry (IHC) 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 IHC status in patients who enter the study with measurable disease. IV. To evaluate the effect of pembrolizumab (MK-3475) 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 (MK-3475) 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 (MK-3475) 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 (MK-3475) in combination with paclitaxel and carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and recurrent endometrial cancer by Programmed Death Ligand 1 (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 of each cycle, paclitaxel IV over 3 hours on day 1 of each cycle, and carboplatin IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with stable disease (SD) or partial response (PR) who still have measurable disease may continue treatment for up to a total 10 cycles (if deemed necessary by the treating physician) in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive placebo IV over 30 minutes on day 1 of each cycle. Treatment repeats every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable toxicity. On February 6, 2023, all patient treatment assignments were unblinded. Patients randomized to Arm I will not receive additional placebo infusions. ARM II: COMBINATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle, paclitaxel IV over 3 hours on day 1 of each cycle, and carboplatin IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease may continue treatment for up to a total of 10 cycles (if deemed necessary by the treating physician) in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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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

Conditions
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Endometrial Clear Cell Adenocarcinoma, Endometrial Dedifferentiated Carcinoma, 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 Dedifferentiated Carcinoma, 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 IV Uterine Corpus Cancer AJCC v8

Intervention / Treatment
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* Drug: Carboplatin
* Procedure: Computed Tomography
* Drug: Paclitaxel
* Biological: Pembrolizumab
* Other: Placebo Administration
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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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, 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 2 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, intravaginal brachytherapy and/or palliative radiation therapy. All radiation therapy must be completed at least 4 weeks prior to STEP 2 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 2 registration. Interval or cytoreductive surgery, after start of treatment on this trial, and prior to documentation of disease progression, is NOT permitted. Age >= 18 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. If TSH is not within normal range despite no symptoms of thyroid dysfunction, normal Free T4 level is required. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of Step 2 registration are eligible for this trial. For patients of child bearing potential: negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. Administration of study drugs (pembrolizumab [MK-3475], 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 at least 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 (MK-3475) and/or its excipients; and/or a severe hypersensitivity reaction to paclitaxel and/or carboplatin 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 2 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 2 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 2 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (placebo, paclitaxel, carboplatin)<br>COMBINATION PHASE: Patients receive placebo IV over 30 minutes on day 1 of each cycle, paclitaxel IV over 3 hours on day 1 of each cycle, and carboplatin IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease may continue treatment for up to a total of 10 cycles (if deemed necessary by the treating physician) in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive placebo IV over 30 minutes on day 1 of each cycle. Treatment repeats every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study. On February 6, 2023, all patient treatment assignments were unblinded. Patients randomized to Arm 1 will not receive additional placebo infusions. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Placebo Administration<br>* Given IV<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (pembrolizumab, paclitaxel, carboplatin)<br>COMBINATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle, paclitaxel IV over 3 hours on day 1 of each cycle, and carboplatin IV over 30 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease may continue treatment for up to a total of 10 cycles (if deemed necessary by the treating physician) in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Will be tested with a stratified log-rank statistic. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | 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. | 5 years | 
| Objective tumor response | Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1. | 5 years | 
| Duration of objective response | The time difference between the dates of first response and first progression; patients who do not progress are considered censored. | 5 years | 
| Overall survival (OS) |  | Time from study entry to time of death or the date of last contact, assessed up to 5 years | 
| Quality of life (QoL) and patient-reported outcomes (PROs) | 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. | 5 years | 
| Incidence of pembrolizumab treatment and self-reported neurotoxicity | Assessed with FACT/GOG-Ntx. | 5 years | 
| Concordance between Institutional Mismatch repair (MMR) immunohistochemistry (IHC) testing and centralized MMR IHC | Concordance between institutional MMR IHC testing and centralized MMR IHC. The patient's MMR IHC 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 IHC 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). | 5 years | 
| Effect of pembrolizumab on PFS and OS by Program Death Ligand 1 (PD-L1) IHC | Will assess the effect of pembrolizumab on PFS and OS by PD-L1 (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 IHC status will be assessed with odds ratios. A test may be conducted with a Fisher's Exact Test, and confidence intervals will be provided. | 5 years | 
| Association between PD-L1 IHC and MMR status | Measures of association between PD-L1 IHC (CPS) and MMR IHC 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). | 5 years |