Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC)

Roche

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Bladder Cancer; Urothelial Carcinoma

Treatments: Drug: Enfortumab Vedotin; Drug: Tiragolumab; Drug: Cisplatin; Drug: Gemcitabine; Drug: Atezolizumab; Drug: Niraparib; Drug: Sacituzumab Govitecan; Drug: Tocilizumab; Drug: Magrolimab (Hu5F9-G4)

Study type: Interventional

Funder types: Industry; Other

Identifiers

NCT03869190

WO39613

Details and patient eligibility

About

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.

Enrollment: 272 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria 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

Exclusion Criteria 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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272 participants in 16 patient groups

Atezolizumab for mUC Cohort (Stage 1)

Active Comparator group

Description:

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.

Treatment:

Drug: Atezolizumab

Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Drug: Enfortumab Vedotin

Atezolizumab + Niraparib for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Niraparib

Drug: Atezolizumab

Atezolizumab + Magrolimab for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Magrolimab (Hu5F9-G4)

Drug: Atezolizumab

Atezolizumab + Tiragolumab for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Drug: Tiragolumab

Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Sacituzumab Govitecan

Drug: Atezolizumab

Atezolizumab + Tocilizumab for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Tocilizumab

Drug: Atezolizumab

Atezolizumab + RO7122290 for mUC Cohort (Stage 1)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 2)

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Drug: Enfortumab Vedotin

Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 2)

Experimental group

Description:

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.

Treatment:

Drug: Sacituzumab Govitecan

Drug: Atezolizumab

Atezolizumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 1

Active Comparator group

Description:

Participants will receive Atezolizumab for 3 cycles pre-surgery and 14 cycles post-surgery.

Treatment:

Drug: Atezolizumab

Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 2

Experimental group

Description:

Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.

Treatment:

Drug: Atezolizumab

Drug: Tiragolumab

Atezolizumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 1

Active Comparator group

Description:

Participants will receive Atezolizumab for 3 cycles pre-surgery and 14 cycles post-surgery.

Treatment:

Drug: Atezolizumab

Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 2

Experimental group

Description:

Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.

Treatment:

Drug: Atezolizumab

Drug: Tiragolumab

Cisplatin-eligible MIBC Cohort 3 Arm 1

Active Comparator group

Description:

Participants will receive 3 cycles of Atezolizumab, Cisplatin, and Gemcitabine pre-surgery and 14 cycles of Atezolizumab only post-surgery.

Treatment:

Drug: Atezolizumab

Drug: Gemcitabine

Drug: Cisplatin

Cisplatin-eligible MIBC Cohort 3 Arm 2

Experimental group

Description:

Participants will receive Atezolizumab, Tiragolumab (Tira), Cisplatin and Gemcitabine for 3 cycles pre-surgery and 14 cycles of Atezolizumab and Tiragolumab (Tira) post-surgery.

Treatment:

Drug: Atezolizumab

Drug: Gemcitabine

Drug: Cisplatin

Drug: Tiragolumab