Urothelial Carcinoma
Conditions
Brief summary
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
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.
Interventions
DRUGMOXR0916
MOXR0916, 300 milligram (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle.
DRUGAtezolizumab
Atezolizumab, 1200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The study design has been amended in that the study blinding will not be maintained.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to approximately 45 months | 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. |
| Overall Survival (OS) | Up to approximately 45 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Pain Progression, Pain Palliation, and Fatigue Progression as Measured by Participant-Reported Severity According to the M. D. Anderson Symptom Inventory (MDASI) | Up to approximately 45 months | 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. |
| Percentage of Participants Reporting Symptom Interference With Daily Living at the Time of Progression According to the MDASI | Up to approximately 45 months | 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. |
| Percentage of Participants With Adverse Event (AEs) | Up to approximately 45 months | An adverse event is any untoward medical occurrence, regardless of causal attribution. |
| Area Under the Plasma Drug Concentration-time Curve (AUC) of MOXR0916 and Atezolizumab | 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 | AUC represents the body's exposure to an administered drug. |
| Objective Response (OR) According to RECIST v1.1 | Up to approximately 45 months | 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. |
| Minimum Plasma Concentration (Cmin) of MOXR0916 and Atezolizumab | 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 | Cmin refers to the minimum (trough) serum concentration of a drug in a specified compartment or test area of the body. |
| Clearance of MOXR0916 and Atezolizumab | 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 a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to MOXR0916 and Atezolizumab | Cycles 1 - 4 and 8, 12, and 16 (each cycle is 21 days), Day 1: predose | ATAs may be produced by the body in response to an administered drug. |
| Maximum Plasma Concentration (Cmax) of MOXR0916 and Atezolizumab | 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 | 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. |
| Duration of Objective Response (DOR) According to RECIST v1.1 | Up to approximately 45 months | 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. |
Countries
Belgium, Canada, South Korea, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MOXR0916 Plus Atezolizumab Participants were administered MOXR0916, 300 milligram (mg) and atezolizumab, 1200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle. | 4 |
| Atezolizumab Participants were administered atezolizumab, 1200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle. | 1 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death due to Disease Progression | 1 | 0 |
| Overall Study | Safety Follow-Up Completed | 2 | 0 |
| Overall Study | Study Terminated By Sponsor | 1 | 1 |
Baseline characteristics
| Characteristic | MOXR0916 Plus Atezolizumab | Atezolizumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 0 / 1 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
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.
Time frame: Up to approximately 45 months
Population: Due to early termination, no formal analyses were performed for OS.
Primary
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.
Time frame: Up to approximately 45 months
Population: Due to early termination, no formal analyses were performed for PFS.
Secondary
Area Under the Plasma Drug Concentration-time Curve (AUC) of MOXR0916 and Atezolizumab
AUC represents the body's exposure to an administered drug.
Time frame: 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
Population: Due to early termination, no formal analyses were performed for any of the pharmacokinetic measures.
Secondary
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.
Time frame: 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
Population: Due to early termination, no formal analyses were performed for any of the pharmacokinetic measures.
Secondary
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.
Time frame: Up to approximately 45 months
Population: Due to early termination, no formal analyses were performed for DOR.
Secondary
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.
Time frame: 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
Population: Due to early termination, no formal analyses were performed for any of the pharmacokinetic measures.
Secondary
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.
Time frame: 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
Population: Due to early termination, no formal analyses were performed for any of the pharmacokinetic measures.
Secondary
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.
Time frame: Up to approximately 45 months
Population: Due to early termination, no formal analyses were performed for OR.
Secondary
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.
Time frame: Up to approximately 45 months
Population: Due to early termination, no formal analyses were performed for percentage of participants reporting symptom interference with daily living at the time of progression according to the MDASI
Secondary
Percentage of Participants With Adverse Event (AEs)
An adverse event is any untoward medical occurrence, regardless of causal attribution.
Time frame: Up to approximately 45 months
Population: The safety population was defined as all participants who have received at least one dose of study medication. Data were collected but are not being summarized due to privacy concerns with the low number of patients analyzed.
Secondary
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.
Time frame: Cycles 1 - 4 and 8, 12, and 16 (each cycle is 21 days), Day 1: predose
Population: Due to early termination, no formal analyses were performed for percentage of participants with ATAs to MOXR0916 and Atezolizumab.
Secondary
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.
Time frame: Up to approximately 45 months
Population: Due to early termination, no formal analyses were performed for time to pain progression, pain palliation and fatigue progression.