A Study of MOXR0916 in Combination With Atezolizumab Versus Atezolizumab Alone in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Therapy

Study Overview
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Brief Summary
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This is a Phase II, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of MOXR0916 in combination with atezolizumab versus placebo and atezolizumab in participants with locally advanced or metastatic urothelial carcinoma (UC) who have not received prior systemic therapy in the locally advanced/metastatic setting and who are ineligible to receive cisplatin-based therapy.

Detailed Description
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The study design has been amended after the decision to prematurely stop patient accrual due to enrollment challenges. As only 5 participants were enrolled, the study blinding will not be maintained, and placebo infusions will not be administered. Patients assigned to the MOXR0916 arm may continue study treatment with the combination of atezolizumab and MOXR0916 or with atezolizumab alone based on a discussion of benefit and risk with the treating investigator.

Official Title
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A Phase II, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study of MOXR0916 in Combination With Atezolizumab Versus Atezolizumab Alone in Patients With Untreated Locally Advanced or Metastatic Urothelial Carcinoma Who Are Ineligible for Cisplatin-Based Therapy

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: MOXR0916
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status of <= 2 Life expectancy >= 12 weeks Histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma (UC) Availability of a representative formalin-fixed paraffin-embedded tumor specimen No prior systemic therapy for inoperable locally advanced or metastatic UC Ineligible for cisplatin-based chemotherapy as defined by any one of the following criteria: Impaired renal function (glomerular filtration rate [GFR] > 30 but < 60 milliliter/minute [mL/min]); National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0 Grade >= 2 audiometric hearing loss (of 25 Decibel at two contiguous frequencies or more severe); NCI CTCAE v 4.0 Grade >= 2 peripheral neuropathy; ECOG Performance Status of 2 Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 Adequate hematologic and end-organ function Exclusion Criteria: Significant cardiovascular disease Known clinically significant liver disease Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment Prior treatment with CD137 or OX40 agonists, anti-cytotoxic T-lymphocyte-associated protein (CTLA4), anti-programmed death-1 (PD-1), anti- programmed death-ligand 1 (PD-L1), anti-CD-27, anti- glucocorticoid-induced tumor necrosis factor receptor (GITR) therapeutic antibody or pathway-targeting agents Untreated central nervous system (CNS) metastases or active (progressing or requiring corticosteroids for symptomatic control) CNS metastases Any history of leptomeningeal disease Malignancies other than UC within 5 years prior to Cycle 1, Day 1 History of autoimmune disease History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography scan Active hepatitis B and C virus infection Positive HIV test at screening Active tuberculosis Prior allogeneic stem cell or solid organ transplantation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MOXR0916 plus Atezolizumab<br> | Drug: MOXR0916<br>* MOXR0916, 300 milligram (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle.<br>Drug: Atezolizumab<br>* Atezolizumab, 1200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle.<br>|
| Active Comparator: Atezolizumab<br> | Drug: Atezolizumab<br>* Atezolizumab, 1200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first. Per RECIST v1.1, progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline); and an absolute increase of >= 5 millimeter (mm) in the sum of diameters. | Up to approximately 45 months | 
| Overall Survival (OS) | Kaplan Meier estimate of median OS was defined as the time at which half of the participants had died, regardless of the cause of death. | Up to approximately 45 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) According to RECIST v1.1 | OR is defined as a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. | Up to approximately 45 months | 
| Duration of Objective Response (DOR) According to RECIST v1.1 | DOR is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1. Objective response is defined as a complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. | Up to approximately 45 months | 
| Time to Pain Progression, Pain Palliation, and Fatigue Progression as Measured by Participant-Reported Severity According to the M. D. Anderson Symptom Inventory (MDASI) | The MDASI is a cancer-related, self-reported questionnaire consisting of 19 items assessing symptom severity and interference with different aspects of a participant's life. The MDASI items are rated from 0 to 10, with 0 indicating that the symptom is either not present or does not interfere with the participant's activities and 10 indicating that the symptom is as bad as you can imagine or interfered completely with the participant's life. | Up to approximately 45 months | 
| Percentage of Participants Reporting Symptom Interference With Daily Living at the Time of Progression According to the MDASI | The MDASI is a cancer-related, self-reported questionnaire consisting of 19 items assessing symptom severity and interference with different aspects of a participant's life. The MDASI items are rated from 0 to 10, with 0 indicating that the symptom is either not present or does not interfere with the participant's activities and 10 indicating that the symptom is as bad as you can imagine or interfered completely with the participant's life. | Up to approximately 45 months | 
| Percentage of Participants With Adverse Event (AEs) | An adverse event is any untoward medical occurrence, regardless of causal attribution. | Up to approximately 45 months | 
| Area Under the Plasma Drug Concentration-time Curve (AUC) of MOXR0916 and Atezolizumab | AUC represents the body's exposure to an administered drug. | Cycle 1 (each cycle is 21 days), Day 1: predose and 30 min. after atezolizumab infusion; Cycle 1, on Days 8 and 15. Cycles 2 4, Day 1: predose and 30 min. after atezolizumab infusion. Cycles 8, 12, and 16: predose | 
| Maximum Plasma Concentration (Cmax) of MOXR0916 and Atezolizumab | Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose. | Cycle 1 (each cycle is 21 days), Day 1: predose and 30 min. after atezolizumab infusion; Cycle 1, on Days 8 and 15. Cycles 2 4, Day 1: predose and 30 min. after atezolizumab infusion. Cycles 8, 12, and 16: predose | 
| Minimum Plasma Concentration (Cmin) of MOXR0916 and Atezolizumab | Cmin refers to the minimum (trough) serum concentration of a drug in a specified compartment or test area of the body. | Cycle 1 (each cycle is 21 days), Day 1: predose and 30 min. after atezolizumab infusion; Cycle 1, on Days 8 and 15. Cycles 2 4, Day 1: predose and 30 min. after atezolizumab infusion. Cycles 8, 12, and 16: predose | 
| Clearance of MOXR0916 and Atezolizumab | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Cycle 1 (each cycle is 21 days), Day 1: predose and 30 min. after atezolizumab infusion; Cycle 1, on Days 8 and 15. Cycles 2 4, Day 1: predose and 30 min. after atezolizumab infusion. Cycles 8, 12, and 16: predose | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to MOXR0916 and Atezolizumab | ATAs may be produced by the body in response to an administered drug. | Cycles 1 - 4 and 8, 12, and 16 (each cycle is 21 days), Day 1: predose |