NCT03869190 - Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC) | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Stage 1 mUC Cohorts: Objective Response Rate (ORR)

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.

Time frame: Up to 61.5 months

MIBC Cohorts: Pathological Complete Response (pCR)

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.

Time frame: Up to 17.8 months

Secondary Outcomes

Stage 1 mUC Cohorts: Progression-free Survival (PFS) After Randomization

PFS after randomization was defined as the time from randomization to the first occurrence of disease progression (PD) or death from any cause, whichever occurred first in Stage 1, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. PFS for participants with no documented PD or death was censored at the day of the last tumor assessment. Kaplan-Meier (K-M) method was used to estimate the median PFS.

Time frame: 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

OS after randomization was defined as the time from randomization to death from any cause. Data for participants who had not died were censored at the last date they were known to be alive. K-M method was used to estimate the median OS.

Time frame: From randomization to death from any cause (up to 69.1 months)

Stage 1 mUC Cohorts: OS Rate at Month 12

OS rate at Month 12 was defined as percentage of participants who did not experience death from any cause at the specified timepoint. OS was defined as the time from randomization to death from any cause. K-M method was used to estimate OS rate. Percentages have been rounded off.

Time frame: At Month 12

Stage 1 mUC Cohorts: Duration of Response (DOR)

DOR was defined as the time from the first occurrence of a documented OR (CR or PR) during Stage 1 to PD or death from any cause during Stage 1, whichever occurred first, as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Additionally, any lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate the median DOR.

Time frame: 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)

DCR was defined as percentage of participants with stable disease for ≥ 18 weeks or an OR (CR or PR) during Stage 1, as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Additionally, any lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. Percentages have been rounded off.

Time frame: Up to 61.5 months

Stages 1 and 2 mUC Cohorts: Number of Participants With Adverse Events (AEs)

An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Time frame: Stage 1: Up to 62.1 months; Stage 2: Up to 18.3 months

Stage 2 mUC [Atezo + EV Cohort]: Serum Concentration of Atezolizumab at Specified Timepoints

Time frame: Predose: Day 1 of Cycles 1, 2 and 4; 30 minutes postdose: Day 1 Cycle 1

Stage 2 mUC [Atezo + EV Cohort]: Number of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab

Participants were considered to be treatment-emergent ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer unit (t.u.) greater than the baseline titer result (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here.

Time frame: Up to approximately 18.3 months

MIBC Cohorts: Landmark Recurrence-free Survival (RFS) Rate

Landmark RFS was defined as the percentage of participants who were alive without disease recurrence at specified timepoints following surgery. RFS was defined as the time from Day 1 in the first cycle after surgery to the first documented recurrence of disease or death from any cause. RFS rates at the specified landmark timepoints were estimated using the K-M method.

Time frame: At Months 12, 18, and 24

MIBC Cohorts: Landmark Event-free Survival (EFS) Rate

Landmark EFS was defined as the percentage of participants who were alive without experiencing a predefined event at specified timepoints. EFS was defined as the time from randomization to any of the following events, whichever occurred first: PD that precludes surgery, as assessed by the investigator; local or distant disease recurrence; or death from any cause. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. EFS rates at the specified landmark timepoints were estimated using the K-M method.

Time frame: At Months 12, 18, and 24

MIBC Cohorts: Landmark OS Rate

Landmark OS was defined as the percentage of participants who were alive at specified timepoints. OS was defined as the time from randomization to death from any cause. OS rates at the specified landmark timepoints were estimated using the K-M method.

Time frame: At Months 12, 18, and 24

MIBC Cohorts: Number of Participants With AEs

Time frame: Up to 17.8 months

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

Overview

Conditions

Interventions

Eligibility

Locations (33)

Outcomes

Primary Outcomes

Secondary Outcomes