A Phase 3 Randomized, Open-label, Active-comparator Controlled Clinical Study of Pembrolizumab Versus Platinum Doublet Chemotherapy in Participants With Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma in the First-line Setting (KEYNOTE-C93/GOG-3064/ENGOT-en15)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 280
- 试验地点
- 354
- 主要终点
- Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
研究概览
简要总结
The purpose of this study is to assess the safety and efficacy of treatment with pembrolizumab (MK-3475) compared to a combination of carboplatin and paclitaxel in women with mismatch repair deficient (dMMR) advanced or recurrent endometrial carcinoma who have not previously been treated with prior systemic chemotherapy.
The primary study hypotheses are that pembrolizumab is superior to the combination of carboplatin and paclitaxel with respect to Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) and Overall Survival (OS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Has a histologically confirmed diagnosis of inoperable, Stage III or IV or recurrent Endometrial Carcinoma (EC) or carcinosarcoma (mixed Mullerian tumor) that is centrally confirmed as dMMR.
- •Has radiographically evaluable disease, either measurable or non-measurable per RECIST 1.1, as assessed by the investigator. Note: primary Stage IVB that has undergone surgical resection is allowed regardless of presence of measurable or evaluable disease.
- •Has received no prior systemic therapy for EC except for the following:
- •May have received 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of curative-intent resection if the recurrence occurred ≥6 months after the last dose of chemotherapy.
- •May have received prior radiation with or without radiosensitizing chemotherapy if >2 weeks before the start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
- •May have received prior hormonal therapy for treatment of EC, provided that it was discontinued ≥1 week prior to randomization.
- •Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization.
- •Is not pregnant or breastfeeding and agrees to not donate eggs and use a highly effective contraceptive method for 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy if a woman of childbearing potential (WOCBP).
- •Has a negative highly sensitive pregnancy test (urine or serum) within 24 hours for urine or 72 hours for serum before the first dose of study intervention if a WOCBP.
- •Provides an archival tumor tissue sample or newly obtained (core, incisional, or excisional) biopsy of a tumor lesion not previously irradiated for verification of dMMR status and histology.
- •If Hepatitis B surface antigen (HBsAg) positive, has received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load prior to randomization.
- •If has a history of Hepatitis C virus (HCV) infection, has undetectable HCV viral load at screening.
排除标准
- •Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas and neuroendocrine tumors are not allowed.
- •Has EC of any histology that is proficient mismatch repair (pMMR).
- •Is a candidate for curative-intent surgery or curative-intent radiotherapy.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], Tumor necrosis factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor superfamily member 9 [CD137]).
- •Has received prior systemic anticancer therapy including investigational agents for any advanced or metastatic EC. (Note: Prior chemotherapy administered as adjuvant therapy, neoadjuvant therapy, and/or concurrently with radiation is permitted.
- •Has had a major operation and has not recovered adequately from the procedure and/or any complications from the operation before starting study intervention.
- •Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
- •Is currently participating in or has participated in a study of an investigational agent for EC, has participated in a study of an investigational agent for non-EC within 4 weeks before the first dose of study intervention, or has used an investigational device within 4 weeks before the first dose of study intervention.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
- •Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) that have undergone potentially curative therapy are not excluded.
- •Has known active CNS metastases and/or carcinomatous meningitis.
- •Has a known intolerance to any study intervention and/or any of its excipients.
- •Has an active autoimmune disease that has required systemic treatment in past 2 years.
- •Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- •Has an active infection, requiring systemic therapy.
- •Has a known history of human immunodeficiency virus (HIV) infection.
- •Has had an allogenic tissue/solid organ transplant.
研究组 & 干预措施
Pembrolizumab
Participants receive pembrolizumab 400 mg via IV infusion on Day 1 of each 6-week cycle (Q6W) for up to 18 cycles (up to approximately 2 years).
干预措施: pembrolizumab (Biological)
Carboplatin+paclitaxel
Participants receive a combination of paclitaxel 175 mg/m^2 on Day 1 of each 3-week cycle (Q3W) and carboplatin AUC 5 or 6 on Day 1 Q3W for 6 cycles (up to approximately 4 months). Participants who experience a severe hypersensitivity reaction to paclitaxel or an adverse event (AE) requiring discontinuation of paclitaxel may receive docetaxel 75 mg/m^2 in place of paclitaxel on Day 1 Q3W after Sponsor consultation. Participants who experience a severe hypersensitivity reaction to carboplatin or an AE requiring discontinuation of carboplatin may receive cisplatin 75 mg/m^2 in place of carboplatin on Day 1 Q3W after Sponsor consultation.
干预措施: carboplatin (Drug)
Carboplatin+paclitaxel
Participants receive a combination of paclitaxel 175 mg/m^2 on Day 1 of each 3-week cycle (Q3W) and carboplatin AUC 5 or 6 on Day 1 Q3W for 6 cycles (up to approximately 4 months). Participants who experience a severe hypersensitivity reaction to paclitaxel or an adverse event (AE) requiring discontinuation of paclitaxel may receive docetaxel 75 mg/m^2 in place of paclitaxel on Day 1 Q3W after Sponsor consultation. Participants who experience a severe hypersensitivity reaction to carboplatin or an AE requiring discontinuation of carboplatin may receive cisplatin 75 mg/m^2 in place of carboplatin on Day 1 Q3W after Sponsor consultation.
干预措施: paclitaxel (Drug)
Carboplatin+paclitaxel
Participants receive a combination of paclitaxel 175 mg/m^2 on Day 1 of each 3-week cycle (Q3W) and carboplatin AUC 5 or 6 on Day 1 Q3W for 6 cycles (up to approximately 4 months). Participants who experience a severe hypersensitivity reaction to paclitaxel or an adverse event (AE) requiring discontinuation of paclitaxel may receive docetaxel 75 mg/m^2 in place of paclitaxel on Day 1 Q3W after Sponsor consultation. Participants who experience a severe hypersensitivity reaction to carboplatin or an AE requiring discontinuation of carboplatin may receive cisplatin 75 mg/m^2 in place of carboplatin on Day 1 Q3W after Sponsor consultation.
干预措施: docetaxel (Drug)
Carboplatin+paclitaxel
Participants receive a combination of paclitaxel 175 mg/m^2 on Day 1 of each 3-week cycle (Q3W) and carboplatin AUC 5 or 6 on Day 1 Q3W for 6 cycles (up to approximately 4 months). Participants who experience a severe hypersensitivity reaction to paclitaxel or an adverse event (AE) requiring discontinuation of paclitaxel may receive docetaxel 75 mg/m^2 in place of paclitaxel on Day 1 Q3W after Sponsor consultation. Participants who experience a severe hypersensitivity reaction to carboplatin or an AE requiring discontinuation of carboplatin may receive cisplatin 75 mg/m^2 in place of carboplatin on Day 1 Q3W after Sponsor consultation.
干预措施: cisplatin (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
时间窗: Up to approximately 45 months
PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by BICR will be reported for participants.
Overall Survival
时间窗: Up to approximately 59 months
OS is defined as the time from randomization to death due to any cause. The OS will be reported for all participants.
次要结局
- Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)(Up to approximately 45 months)
- Number of Participants Who Experience at Least One Adverse Event (AE)(Up to approximately 27 months)
- Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)(Up to approximately 45 months)
- Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator(Up to approximately 45 months)
- Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)(Up to approximately 45 months)
- Progression-Free Survival 2 (PFS2) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator(Up to approximately 45 months)
- Change From Baseline in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Combined Score(Baseline and up to approximately 25 months)
- Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)(Up to approximately 24 months)
- Change From Baseline in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) (Item 29) And Quality of Life (QoL) (Item 30) Combined Score(Baseline and up to approximately 25 months)