A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 272
- 试验地点
- 65
- 主要终点
- Objective Response Rate (ORR) for mUC Cohort Stage 1
研究概览
简要总结
A Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with MIBC and in participants with locally advanced or metastatic Urothelial Carcinoma (UC) who have progressed during or following a platinum-containing regimen. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population (e.g., with regard to prior anti-cancer treatment or biomarker status). Participants in the mUC Cohort who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment regimen for Stage 2.
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
- All
- 接受健康志愿者
- 否
入选标准
- •for mUC Cohort:
- •Histologically documented, locally advanced or metastatic UC (also termed TCC or urothelial cell carcinoma of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)
- •Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status by means of central testing
- •Disease progression during or following treatment with no more than one platinum-containing regimen for inoperable, locally advanced or metastatic UC or disease recurrence
- •ECOG Performance Status of 0 or 1
- •Measurable disease (at least one target lesion) according to RECIST v1.1
- •Adequate hematologic and end-organ function
- •Negative HIV test at screening
- •Negative total hepatitis B core antibody (HBcAb) test and hepatitis C virus (HCV) antibody at screening
- •Tumor accessible for biopsy
- •For women of childbearing potential: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating eggs
- •For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
- •Inclusion Criteria for MIBC Cohorts:
- •ECOG PS of 0 or 1
- •Fit and planned-for cystectomy
- •Histologically documented MIBC (pT2-4, N0, M0), also termed TCC or urothelial cell carcinoma of the urinary bladder
- •N0 or M0 disease by CT or MRI
- •Adequate hematologic and end-organ function
- •Availability of TURBT specimen
- •Negative HIV, HBcAb, and HCV test at screening
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm
- •For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm
排除标准
- •for mUC Cohort:
- •Prior treatment with a T-cell co-stimulating therapy or a CPI including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- •Prior treatment with any of the protocol-specified study treatments including treatment with poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, nectin-4 targeting agents, signal regulatory protein alpha-targeting agents, or TIGIT-targeting agents, Trop-2 targeting agents, FAP-directed therapies, 4-1BB (CD137)-directed therapies, or topoisomerase 1 inhibitors
- •Treatment with investigational therapy within 28 days prior to initiation of study treatment
- •Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
- •Eligibility only for the control arm
- •Prior allogeneic stem cell or solid organ transplantation
- •Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment
- •Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressant medication during study treatment
- •Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- •Uncontrolled tumor-related pain
- •Uncontrolled or symptomatic hypercalcemia
- •Symptomatic, untreated, or actively progressing CNS metastases
- •History of leptomeningeal disease
- •Active or history of autoimmune disease or immune deficiency
- •History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
- •History of malignancy other than UC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
- •Active tuberculosis
- •Severe infection within 4 weeks prior to initiation of study treatment
- •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- •Significant cardiovascular disease
- •Uncontrolled hypertension
- •Grade 3 or greater hemorrhage or bleeding event within 28 days prior to initiation of study treatment
- •Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment
- •Pregnancy or breastfeeding, or intention of becoming pregnant during the study
- •Additional drug-specific exclusion criteria might apply
- •Exclusion for MIBC Cohorts:
- •Prior treatment with systemic immunostimulatory agents prior to the initiation of study treatment
- •Eligibility only for the control arm
- •Prior allogeneic stem cell or solid organ transplantation
- •Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions: Patients who received acute, low-dose, systemic immunosuppressant medications, or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor approval has been obtained. Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
- •Severe infection within 4 weeks prior to initiation of study treatment
- •Pregnancy or breastfeeding, or intention of becoming pregnant during the study
- •Also includes all the mUC exclusion criteria
- •Additional Exclusion Criteria for Atezo+Tira and Atezo (Atezolizumab) +Tira+Cis (Cisplatin)+Gem (Gemcitabine) in the MIBC Cohorts:
- •- Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening.
- •Additional Exclusion Criteria for the Cisplatin-Eligible MIBC Cohort:
- •Patients who decline neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate.
- •Impaired renal function.
研究组 & 干预措施
Atezolizumab + Magrolimab for mUC Cohort (Stage 1)
Participants will receive atezolizumab and magrolimab (Hu5F9-G4) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Magrolimab (Hu5F9-G4) (Drug)
Atezolizumab + Niraparib for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Niraparib (Nira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Niraparib (Drug)
Atezolizumab + Niraparib for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Niraparib (Nira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Enfortumab Vedotin (Drug)
Atezolizumab + Tiragolumab for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Tiragolumab (Tira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Tiragolumab (Drug)
Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 2)
Participants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Enfortumab Vedotin (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 1
Participants will receive 3 cycles of Atezolizumab, Cisplatin, and Gemcitabine pre-surgery and 14 cycles of Atezolizumab only post-surgery.
干预措施: Cisplatin (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 2
Participants will receive Atezolizumab, Tiragolumab (Tira), Cisplatin and Gemcitabine for 3 cycles pre-surgery and 14 cycles of Atezolizumab and Tiragolumab (Tira) post-surgery.
干预措施: Cisplatin (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 2
Participants will receive Atezolizumab, Tiragolumab (Tira), Cisplatin and Gemcitabine for 3 cycles pre-surgery and 14 cycles of Atezolizumab and Tiragolumab (Tira) post-surgery.
干预措施: Gemcitabine (Drug)
Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 2)
Participants will receive atezolizumab and Sacituzumab Govitecan (SG) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab for mUC Cohort (Stage 1)
Participants will receive atezolizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Magrolimab for mUC Cohort (Stage 1)
Participants will receive atezolizumab and magrolimab (Hu5F9-G4) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Tiragolumab for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Tiragolumab (Tira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Sacituzumab Govitecan (SG) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Sacituzumab Govitecan (SG) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Sacituzumab Govitecan (Drug)
Atezolizumab + Tocilizumab for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Tocilizumab (TCZ) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Tocilizumab for mUC Cohort (Stage 1)
Participants will receive atezolizumab and Tocilizumab (TCZ) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Tocilizumab (Drug)
Atezolizumab + RO7122290 for mUC Cohort (Stage 1)
Participants will receive atezolizumab and RO7122290 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 2)
Participants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Atezolizumab (Drug)
Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 2)
Participants will receive atezolizumab and Sacituzumab Govitecan (SG) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.
干预措施: Sacituzumab Govitecan (Drug)
Atezolizumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 1
Participants will receive Atezolizumab for 3 cycles pre-surgery and 14 cycles post-surgery.
干预措施: Atezolizumab (Drug)
Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 2
Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.
干预措施: Tiragolumab (Drug)
Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 2
Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.
干预措施: Atezolizumab (Drug)
Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 2
Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.
干预措施: Atezolizumab (Drug)
Atezolizumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 1
Participants will receive Atezolizumab for 3 cycles pre-surgery and 14 cycles post-surgery.
干预措施: Atezolizumab (Drug)
Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 2
Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.
干预措施: Tiragolumab (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 1
Participants will receive 3 cycles of Atezolizumab, Cisplatin, and Gemcitabine pre-surgery and 14 cycles of Atezolizumab only post-surgery.
干预措施: Atezolizumab (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 1
Participants will receive 3 cycles of Atezolizumab, Cisplatin, and Gemcitabine pre-surgery and 14 cycles of Atezolizumab only post-surgery.
干预措施: Gemcitabine (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 2
Participants will receive Atezolizumab, Tiragolumab (Tira), Cisplatin and Gemcitabine for 3 cycles pre-surgery and 14 cycles of Atezolizumab and Tiragolumab (Tira) post-surgery.
干预措施: Tiragolumab (Drug)
Cisplatin-eligible MIBC Cohort 3 Arm 2
Participants will receive Atezolizumab, Tiragolumab (Tira), Cisplatin and Gemcitabine for 3 cycles pre-surgery and 14 cycles of Atezolizumab and Tiragolumab (Tira) post-surgery.
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Objective Response Rate (ORR) for mUC Cohort Stage 1
时间窗: Baseline until disease progression or loss of clinical benefit (approximately 5-7 years)
Objective response rate, defined as the proportion of participants with a CR or PR on two consecutive occasions \>=4 weeks apart during Stage 1, as determined by the investigator according to RECIST v1.1.
pCR for Muscle Invasive Bladder Cancer (MIBC) Cohorts
时间窗: Randomization to approximately 5-7 years
pCR, defined as the proportion of participants with an absence of residual invasive cancer of the complete resected specimen.
Stage 1 mUC Cohorts: Objective Response Rate (ORR)
时间窗: Up to 61.5 months
ORR was defined as the percentage of participants with an objective response (OR), characterized by a complete response (CR) or a partial response (PR), on 2 consecutive occasions ≥ 4 weeks apart during Stage 1, as determined by the investigator per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target and non-target lesions and normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off.
MIBC Cohorts: Pathological Complete Response (pCR)
时间窗: Up to 17.8 months
pCR was defined as the percentage of participants with an absence of residual invasive cancer of the complete resected specimen. Percentages have been rounded off.
次要结局
- Serum Concentration of Atezolizumab for mUC Cohort Stage 2(At pre-defined intervals from first administration of study drug up to approximately 5-7 years)
- Progression Free Survival (PFS) for mUC Cohort Stage 1(Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5-7 years) as determined by the investigator according to RECIST 1.1)
- Overall Survival (OS) for mUC Cohort Stage 1(Randomization to death from any cause, through the end of study (approximately 5-7 years))
- Overall Survival (at specific time-points) for mUC Cohort Stage 1(12 months)
- Duration of Response (DOR) for mUC Cohort Stage 1(Randomization until first occurrence of a documented objective response to the first recorded occurrence of disease progression or death from any cause (whichever occurs first), through end of study (approximately 5-7 years))
- Disease Control Rate (DCR) for mUC Cohort Stage 1(Baseline through end of study (approximately 5-7 years))
- Presence of ADAs to Atezolizumab for mUC Cohort Stage 2(Baseline to approximately 5-7 years)
- Landmark Recurrence-Free Survival (RFS) for MIBC Cohorts(12, 18, 24 months)
- Percentage of Participants with Adverse Events for MIBC Cohorts(Baseline to approximately 5-7 years)
- Percentage of Participants with Adverse Events for mUC Cohort Stage 1(Baseline to end of study (approximately 5-7 years))
- Serum Concentration of Sacituzumab Govitecan for mUC Cohort Stage 2(At pre-defined intervals from first administration of study drug up to approximately 5-7 years)
- Percentage of Participants with Adverse Events for mUC Cohort Stage 2(Baseline to end of study (approximately 5-7 years))
- Landmark Event-Free Survival (EFS) for MIBC Cohorts(12, 18, 24 months)
- Landmark Overall Survival (OS) for MIBC Cohorts(12, 18, 24 months)
- Serum Concentration of Enfortumab Vedotin for mUC Cohort Stage 2(At pre-defined intervals from first administration of study drug up to approximately 5-7 years)
- Stage 2 mUC [Atezo + EV Cohort]: Serum Concentration of Atezolizumab at Specified Timepoints(Predose: Day 1 of Cycles 1, 2 and 4; 30 minutes postdose: Day 1 Cycle 1)
- Stage 1 mUC Cohorts: Progression-free Survival (PFS) After Randomization(From randomization to PD or death from any cause, whichever occurred first (up to 62 months))
- Stage 1 mUC Cohorts: Overall Survival (OS) After Randomization(From randomization to death from any cause (up to 69.1 months))
- Stage 1 mUC Cohorts: OS Rate at Month 12(At Month 12)
- Stage 1 mUC Cohorts: Duration of Response (DOR)(From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to 61.5 months))
- Stage 1 mUC Cohorts: Disease Control Rate (DCR)(Up to 61.5 months)
- Stages 1 and 2 mUC Cohorts: Number of Participants With Adverse Events (AEs)(Stage 1: Up to 62.1 months; Stage 2: Up to 18.3 months)
- Stage 2 mUC [Atezo + EV Cohort]: Number of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab(Up to approximately 18.3 months)
- MIBC Cohorts: Landmark Recurrence-free Survival (RFS) Rate(At Months 12, 18, and 24)
- MIBC Cohorts: Landmark Event-free Survival (EFS) Rate(At Months 12, 18, and 24)
- MIBC Cohorts: Landmark OS Rate(At Months 12, 18, and 24)
- MIBC Cohorts: Number of Participants With AEs(Up to 17.8 months)