Clinical Trial: NCT03869190 - My Cancer Genome

NCT03869190

Description:

A Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with cisplatin-ineligible 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.

Related Conditions:

Transitional Cell Carcinoma

Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT03869190

Trial Eligibility

Document

Title

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

Clinical Trial IDs

ORG STUDY ID: WO39613
NCT ID: NCT03869190

Conditions

Urothelial Carcinoma
Bladder Cancer

Interventions

Drug	Synonyms	Arms
Atezolizumab		Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1)
Enfortumab Vedotin		Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1)
Niraparib		Atezolizumab + Niraparib for mUC Cohort (Stage 1)
Hu5F9-G4		Atezolizumab + Hu5F9-G4 for mUC Cohort (Stage 1)
Tiragolumab		Atezolizumab + Tiragolumab for MIBC Cohort 1 PD-L1+
Sacituzumab Govitecan		Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 1)
Tocilizumab		Atezolizumab + Tocilizumab for mUC Cohort (Stage 1)
RO7122290		Atezolizumab + RO7122290 for MIBC Cohort 2 PD-L1-
RO7121661		RO7121661 for mUC Cohort (Stage 1)

Purpose

Trial Arms

Name	Type	Description	Interventions
Atezolizumab for mUC Cohort (Stage 1)	Active Comparator	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.	Atezolizumab
Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1)	Experimental	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.	Atezolizumab Enfortumab Vedotin
Atezolizumab + Niraparib for mUC Cohort (Stage 1)	Experimental	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.	Atezolizumab Niraparib
Atezolizumab + Hu5F9-G4 for mUC Cohort (Stage 1)	Experimental	Participants will receive atezolizumab and 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.	Atezolizumab Hu5F9-G4
Atezolizumab + Tiragolumab for mUC Cohort (Stage 1)	Experimental	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.	Atezolizumab Tiragolumab
Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 1)	Experimental	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.	Atezolizumab Sacituzumab Govitecan
Atezolizumab + Tocilizumab for mUC Cohort (Stage 1)	Experimental	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.	Atezolizumab Tocilizumab
Atezolizumab + RO7122290 for mUC Cohort (Stage 1)	Experimental	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.	Atezolizumab RO7122290
RO7121661 for mUC Cohort (Stage 1)	Experimental	Participants will receive 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.	RO7121661
Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 2)	Experimental	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.	Atezolizumab Enfortumab Vedotin
Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 2)	Experimental	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.	Atezolizumab Sacituzumab Govitecan
Atezolizumab for MIBC Cohort 1 PD-L1+	Active Comparator	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.	Atezolizumab
Atezolizumab + Tiragolumab for MIBC Cohort 1 PD-L1+	Experimental	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.	Atezolizumab Tiragolumab
Atezolizumab + RO7122290 for MIBC Cohort PD-L1+	Experimental	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.	Atezolizumab RO7122290
Atezolizumab for MIBC Cohort 2 PD-L1-	Active Comparator	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.	Atezolizumab
Atezolizumab + Tiragolumab for MIBC Cohort 2 PD-L1-	Experimental	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.	Atezolizumab Tiragolumab
Atezolizumab + RO7122290 for MIBC Cohort 2 PD-L1-	Experimental	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.	Atezolizumab RO7122290

Eligibility 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

          -  Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant
             cisplatin-based therapy is not appropriate

          -  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

          -  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:

          -  Patients will be excluded from the Atezo + Tira arm within the MIBC Cohorts if they
             meet any of the additional criteria for that arm.

          -  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

        Additional Exclusion Criteria for Atezo+Tira in the MIBC Cohorts:

        - Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV
        infection at screening

        Additional Exclusion Criteria for Atezo+RO7122290 Arm in the MIBC Cohorts:

        - Clinically significant cardiovascular or cerebrovascular disease within 6 months prior to
        Day 1 of study drug administration will be excluded.

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Objective Response Rate (ORR) for mUC Cohort Stage 1
Time Frame:	Baseline until disease progression or loss of clinical benefit (approximately 4 years)
Safety Issue:
Description:	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.

Secondary Outcome Measures

Measure:	Progression Free Survival (PFS) for mUC Cohort Stage 1
Time Frame:	Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 4 years) as determined by the investigator according to RECIST 1.1
Safety Issue:
Description:	PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1.

Measure:	Overall Survival (OS) for mUC Cohort Stage 1
Time Frame:	Randomization to death from any cause, through the end of study (approximately 4 years)
Safety Issue:
Description:	OS after randomization,defined as the time from randomization to death from any cause.

Measure:	Overall Survival (at specific time-points) for mUC Cohort Stage 1
Time Frame:	12 months
Safety Issue:
Description:	OS rate at specific timepoints, defined as the proportion of patients who have not experienced death from any cause at that timepoint.

Measure:	Duration of Response (DOR) for mUC Cohort Stage 1
Time Frame:	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 4 years)
Safety Issue:
Description:	DOR, defined as the time from the first occurrence of a documented objective response during Stage 1 to disease progression or death from anycause (whichever occurs first), as determined by the investigator according to RECIST v1.1.

Measure:	Disease Control Rate (DCR) for mUC Cohort Stage 1
Time Frame:	Baseline through end of study (approximately 4 years)
Safety Issue:
Description:	Disease control, defined as stable disease >= 18 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1.

Measure:	Percentage of Participants with Adverse Events for mUC Cohort Stage 1
Time Frame:	Baseline to end of study (approximately 4 years)
Safety Issue:
Description:

Measure:	Serum Concentration of Atezolizumab for mUC Cohort Stage 2
Time Frame:	At pre-defined intervals from first administration of study drug up to approximately 4 years
Safety Issue:
Description:

Measure:	Serum Concentration of Enfortumab Vedotin for mUC Cohort Stage 2
Time Frame:	At pre-defined intervals from first administration of study drug up to approximately 4 years
Safety Issue:
Description:

Measure:	Serum Concentration of Sacituzumab Govitecan for mUC Cohort Stage 2
Time Frame:	At pre-defined intervals from first administration of study drug up to approximately 4 years
Safety Issue:
Description:

Measure:	Presence of ADAs to Atezolizumab for mUC Cohort Stage 2
Time Frame:	Baseline to approximately 4 years
Safety Issue:
Description:	For drugs for which ADA formation is measured: presence of ADAs during the study relative to the presence of ADAs at baseline.

Measure:	Percentage of Participants with Adverse Events for mUC Cohort Stage 2
Time Frame:	Baseline to end of study (approximately 4 years)
Safety Issue:
Description:

Measure:	Landmark Recurrence-Free Survival (RFS) for MIBC Cohorts
Time Frame:	12, 18, 24 months
Safety Issue:
Description:	Landmark RFS, defined as RFS at specific timepoints.

Measure:	Landmark Event-Free Survival (EFS) for MIBC Cohorts
Time Frame:	12, 18, 24 months
Safety Issue:
Description:	Landmark EFS, defined as EFS at specific timepoints.

Measure:	Landmark Overall Survival (OS) for MIBC Cohorts
Time Frame:	12, 18, 24 months
Safety Issue:
Description:	Landmark OS, defined as OS at specific timepoints.

Measure:	Percentage of Participants with Adverse Events for MIBC Cohorts
Time Frame:	Baseline to approximately 4 years
Safety Issue:
Description:

Details

Phase:	Phase 1/Phase 2
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	Hoffmann-La Roche

Last Updated

August 18, 2021

Clinical Trials /

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