A Phase 1/2 Randomized, Umbrella Study to Evaluate the Efficacy and Safety of MK-2870 Plus Enfortumab Vedotin (EV) With and Without Pembrolizumab, as Treatment for Participants With Advanced Urothelial Carcinoma (KEYMAKER-U04): Substudy 04C
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 38
- 试验地点
- 25
- 主要终点
- Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE)
研究概览
简要总结
This study is a substudy being conducted under one pembrolizumab umbrella master study KEYMAKER-U04. The substudy will consist of 2 parts. Part 1 will evaluate the safety and preliminary efficacy of sacituzumab tirumotecan plus enfortumab vedotin (EV). Part 2 will be based on Part 1 results and will evaluate the efficacy, pharmacokinetics, and safety of sacituzumab tirumotecan plus EV in combination with pembrolizumab in participants with advanced urothelial carcinoma.
详细描述
The master study for this substudy is MK-3475-U04/KEYMAKER-U04. The master study will not be screening any participants and will not be registered.
As of Amendment 5, Part 2 will not be conducted. No participants will be enrolled in Part 2, and no data for Part 2 will be collected.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- All
- 接受健康志愿者
- 否
入选标准
- •The main inclusion criteria include but are not limited to the following:
- •Must have histologically documented, locally advanced/metastatic urothelial carcinoma (la/mUC).
- •Must provide an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion demonstrating UC, not previously irradiated, and adequate for biomarker evaluation. A newly obtained biopsy is strongly preferred, but not required if archival tissue is evaluable.
- •Any AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Endocrine-related AEs adequately treated with hormone replacement are eligible.
- •PART 1 ONLY: Participants must have received platinum-based chemotherapy for treatment of la/mUC.
- •PART 1 ONLY: Participants must not have received >2 lines of therapy for la/mUC. Platinum-based chemotherapy followed by avelumab maintenance is considered 2 lines of therapy.
- •PART 2 ONLY: Participants must not have received prior systemic therapy for la/mUC.
排除标准
- •The main exclusion criteria include but are not limited to the following:
- •Known additional malignancy that is progressing or has required active treatment within the past 3 years.
- •Known active central nervous system metastases and/or carcinomatous meningitis.
- •Has Grade ≥2 peripheral neuropathy.
- •Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
- •Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea).
- •Has uncontrolled, significant cardiovascular disease or cerebrovascular disease and/or serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.
- •Has active keratitis or corneal ulcerations. Superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator.
- •Has a history of uncontrolled diabetes.
- •Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- •Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
- •PART 2 ONLY: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for participants with adrenal insufficiency.
- •PART 2 ONLY: Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy.
- •Is human immunodeficiency virus (HIV)-infected and has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
- •Has active Hepatitis B or Hepatitis C virus infection.
- •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.
- •PART 2 ONLY: History of allogeneic tissue/solid organ transplant.
- •Has not adequately recovered from major surgery or has ongoing surgical complications.
研究组 & 干预措施
Sacituzumab tirumotecan plus EV
Participants will receive sacituzumab tirumotecan as an intravenous (IV) infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: Sacituzumab tirumotecan (Biological)
Sacituzumab tirumotecan plus EV
Participants will receive sacituzumab tirumotecan as an intravenous (IV) infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: Enfortumab Vedotin (Biological)
Sacituzumab tirumotecan plus EV
Participants will receive sacituzumab tirumotecan as an intravenous (IV) infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision.
干预措施: Supportive care measures (Drug)
Sacituzumab tirumotecan plus EV and pembrolizumab
Participants will receive sacituzumab tirumotecan as an IV infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Participants will also receive pembrolizumab 200 mg as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles).
干预措施: Sacituzumab tirumotecan (Biological)
Sacituzumab tirumotecan plus EV and pembrolizumab
Participants will receive sacituzumab tirumotecan as an IV infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Participants will also receive pembrolizumab 200 mg as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles).
干预措施: Enfortumab Vedotin (Biological)
Sacituzumab tirumotecan plus EV and pembrolizumab
Participants will receive sacituzumab tirumotecan as an IV infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Participants will also receive pembrolizumab 200 mg as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles).
干预措施: Pembrolizumab (Biological)
Sacituzumab tirumotecan plus EV and pembrolizumab
Participants will receive sacituzumab tirumotecan as an IV infusion and EV as an IV infusion on Days 1 and 8 of every 3-week cycle until disease progression, intolerable toxicity, or investigator decision. Participants will also receive pembrolizumab 200 mg as an IV infusion on Day 1 of every 3-week cycle for up to ~2 years (35 cycles).
干预措施: Supportive care measures (Drug)
结局指标
主要结局
Part 1: Percentage of Participants Who Experienced At Least One Adverse Event (AE)
时间窗: Up to ~3 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 1 will be reported.
Part 2: Percentage of Participants with DLT
时间窗: Up to 21 days
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the NCI CTCAE 5.0. The number of participants who experience a DLT in Part 2 will be reported.
Part 2: Percentage of Participants Who Discontinued Study Treatment Due to an AE
时间窗: Up to ~2 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study treatment due to an AE in Part 2 will be reported.
Part 1: Percentage of Participants with Dose-limiting toxicities (DLT)
时间窗: Up to 21 days
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). The number of participants who experience a DLT in Part 1 will be reported.
Part 1: Percentage of Participants Who Discontinued Study Treatment Due to an AE
时间窗: Up to ~2 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinue study treatment due to an AE in Part 1 will be reported.
Part 2: Objective Response Rate (ORR)
时间窗: Up to ~3 years
ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) (disappearance of all target lesions) or partial response (PR) (at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator. ORR will be reported for participants in Part 2.
Part 2: Percentage of Participants Who Experienced At Least One AE
时间窗: Up to ~3 years
An AE is defined as any untoward medical occurrence in a participant administered study drug, which does not necessarily have to have a causal relationship with the study drug. The number of participants experiencing an AE in Part 2 will be reported.
次要结局
- Part 1: Cmax of Free Payload for Sacituzumab Tirumotecan(Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 1: Cmax of Enfortumab Vedotin-ADC(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8)
- Part 1: Incidence of ADA to Enfortumab Vedotin(Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8)
- Part 1: Maximum Serum Concentration (Cmax) of Sacituzumab Tirumotecan-Antibody-Drug Conjugate (ADC)(Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 1: Ctrough of Free Payload for Sacituzumab Tirumotecan(Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 1: Ctrough of Free Payload for Enfortumab Vedotin(Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8)
- Part 1: Incidence of Antidrug Antibodies (ADA) to Sacituzumab Tirumotecan(Day 1 of Cycles 1 (each cycle is 21 days), 2, 3, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Cmax of Free Payload for Sacituzumab Tirumotecan(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 1: ORR(Up to ~3 years)
- Part 1: Serum Trough Concentration (Ctrough) of Sacituzumab Tirumotecan-ADC(Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, Day 1 of Cycles 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Cmax of Sacituzumab Tirumotecan-ADC(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Cmax of Free Payload for Pembrolizumab(Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Duration of Response (DOR)(Up to ~3 years)
- Part 1: Ctrough of Enfortumab Vedotin-ADC(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8)
- Part 1: Cmax of Free Payload for Enfortumab Vedotin(Days 1, 8, 15 of Cycle 1 (each cycle is 21 days), Day 1 of Cycle 2, Days 1 and 8 of Cycle 3, and Day 1 of Cycles 4 and 8)
- Part 2: Ctrough of Sacituzumab Tirumotecan-ADC(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Cmax of Enfortumab Vedotin-ADC(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8)
- Part 2: Ctrough of Enfortumab Vedotin-ADC(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8)
- Part 2: Ctrough of Pembrolizumab-ADC(Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Ctrough of Free Payload for Sacituzumab Tirumotecan(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Ctrough of Free Payload for Pembrolizumab(Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Incidence of ADA to Enfortumab Vedotin(Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8)
- Part 2: Cmax of Free Payload for Enfortumab Vedotin(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8)
- Part 2: Ctrough of Free Payload for Enfortumab Vedotin(Days 1 and 8 of Cycle 1 (each cycle is 21 days), Day 1 of Cycles 2, 4 and 8)
- Part 2: Cmax of Pembrolizumab-ADC(Days 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Incidence of ADA to Pembrolizumab(Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)
- Part 2: Incidence of ADA to Sacituzumab Tirumotecan(Day 1 of Cycles 1 (each cycle is 21 days), 2, 4 and 8 and every 4 cycles thereafter up to Cycle 35, at end of treatment, and at 30 days post last dose)