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.
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 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
813
Given IV
Undergo CT scan
Given IV
Given IV
Given IV
Ancillary studies
Ancillary studies
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Alaska Women's Cancer Care
Anchorage, Alaska, United States
CTCA at Western Regional Medical Center
Goodyear, Arizona, United States
NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro
Jonesboro, Arkansas, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Progression-free Survival (PFS)
Progression free survival (PFS) Note: For arm 2 (dMMR Cohort), the point estimate and the upper limit of the confidence interval are not able to be estimated due to insufficient events.
Time frame: Duration of time from study entry to time of progression per RECIST criteria or death due to any cause, whichever occurs first. The interquartile range for follow-up was (6.37 months, 30.62 months). The maximum for follow-up was 37.85 months.
Adverse Events With Grade 3 (or Higher)
Assessed by Common Terminology Criteria for Adverse Events (CTCAE V5.0). The endpoint is the count of participants with an adverse event of grade 3 (or higher) by treatment group.
Time frame: For the adverse event time frame, the interquartile range was (0.79 months, 3.42 months); the maximum was 28.39 months.
Objective Tumor Response
Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.1.
Time frame: For the time frame for tumor response, the interquartile range was (2.27 months, 8.66 months) and the maximum was 36.37 months.
Duration of Objective Response
The time difference between the dates of first response and first progression; patients who do not progress are considered censored. Note: for Arm 2 (dMMR Cohort), the upper limit of the confidence interval is not able to be estimated due to an insufficient number of events.
Time frame: For the duration of objective response, the interquartile range is (4.24 months, 7.92 months); the maximum is 28.68 months.
Overall Survival (OS)
Overall Survival (OS). This endpoint will be assessed by Kaplan-Meier.
Time frame: Time from study entry to time of death or the date of last contact, assessed up to 5 years
Quality of Life (QoL) in pMMR Patients Only
QoL are collected in pMMR patients only and measured with the Function Assessment of Cancer Therapy -Endometrial Trial Outcome Index (FACT En-TOI). The FACT-En TOI scores range 0 - 120 with a larger score suggesting better or favorable state of QOL.
Time frame: 0-54 weeks from start of treatment
Concordance Between Institutional Mismatch Repair (MMR) Immunohistochemistry (IHC) Testing and Centralized MMR IHC
Concordance between institutional MMR IHC testing and centralized MMR IHC. The concordance of institutional MMR IHC testing and centralized MMR IHC will be characterized by agreement statistics including the kappa statistic (e.g. Cohen's kappa coefficient).
Time frame: IHC testing values (for both central and institutional) were collected at baseline.
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