For the primary and secondary efficacy objectives, analyses will be performed in patients in different patient subpopulations according to programmed death*ligand 1 (PD-L1) expression in tumor tissue as evaluated by immunohistochemistry (IHC). The…
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lokaal gevorderd of gemetastaseerde urotheliale blaaskanker
Research involving
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Intervention
Outcome measures
Primary outcome
The primary efficacy outcome measures are as follows:
• IRF-assessed objective response according to RECIST v1.1
• Investigator-assessed objective response according to modified RECIST (this
is applicable only to Cohort 2)
An objective response is defined as a confirmed PR or CR. Modified RECIST
outcomes, which incorporate the measurement of new lesions, are described in
detail in Appendix 3. The ORR is defined as the proportion
Secondary outcome
The secondary efficacy outcome measures are as follows:
•DOR, defined as the time from the first occurrence of a documented PR or CR
(whicheveroccurs first) to the time of first radiographic progression as
determined by an IRF perRECIST v1.1 or death due to any cause on study
•Investigator-assessed ORR per RECIST v1.1 is defined as the proportion of
patients whoseoverall response is either confirmed PR or CR assessed by the
investigator according toRECIST v1.1
•DOR will also be measured as the time from the first occurrence of a
documented PR or CR (whichever occurs first) to the time of first radiographic
progression as assessed byinvestigator per RECIST v1.1 or death due to any
cause on study
•DOR per modified RECIST, defined as the time from the first occurrence of a
documentedPR or CR (whichever occurs first) to the time of first confirmed
radiographic progression asassessed by investigator per modified RECIST or
death due to any cause on study, this isapplicable only to Cohort 2
•PFS per the IRF is defined as the time from the first dose of atezolizumab to
the time of firstradiographic progression as determined by IRF per RECIST v1.1
or death from any causeon study
•PFS per investigator is defined as the time from the first dose of
atezolizumab to the time offirst radiographic progression as determined by
investigator per RECIST v1.1 or death fromany cause on study
•PFS per modified RECIST (applicable only to Cohort 2) is defined as the time
fromrandomization to disease progression as determined by the investigator per
modifiedRECIST or death from any cause, whichever comes first. A patient is
considered to havedisease progression by modified RECIST if either of the
following conditions are met:
a)Modified RECIST criteria for progression were met at a tumor assessment and
nosubsequent tumor assessment was performed
b)Modified RECIST criteria for progression were met at a tumor assessment and
atthe subsequent tumor assessment the criteria for confirmed progression
bymodified RECIST were also met
For patients who meet criterion a), the date of progression is the date of the
tumor assessment that met the criteria for modified RECIST. For patients who
meet criterion b), the date of progression is the date of the tumor assessment
at which the modified RECIST criteria for progression were first met. Patients
who do not meet either of the above criteria are not considered to have had
disease progression by modified RECIST.
•OS, defined as the time from the first dose of atezolizumab to the time of
death from anycause on study
•Landmark outcome: 1-year OS
Background summary
Atezolizumab is a human Ig G1 monoclonal antibody consisting of two heavy
chains (448 amino acids) and two light chains (214 amino acids) and is produced
in Chinese hamster ovary cells. Atezolizumab was engineered to eliminate
Fc-effector function via a single amino acid substitution (asparagine to
alanine) at position 298 on the heavy atezolizumab*F. Hoffmann-La Roche Ltd
Protocol GO29293, Version 3 (EU Countries Only) 38 chain, which results in a
non-glycosylated antibody that has minimal binding to Fc receptors and prevents
Fc-effector function at expected concentrations in humans. Atezolizumab targets
human programmed death*ligand 1 (PD-L1) and inhibits its interaction with its
receptors, programmed death*1 (PD-1) and B7.1 (CD80, B7-1). Both of these
interactions are reported to provide inhibitory signals to T cells.
Atezolizumab is being investigated as a potential therapy against solid tumors
and hematologic malignancies in humans.
Study objective
For the primary and secondary efficacy objectives, analyses will be performed
in patients in different patient subpopulations according to programmed
death*ligand 1 (PD-L1) expression in tumor tissue as evaluated by
immunohistochemistry (IHC). The IHC assay will be used to evaluate PD-L1
expression on tumor-infiltrating immune cells (ICs) and will have three scoring
categories (IC0, IC1, and IC2/3).
Primary Objectives
The primary objective for this study is to evaluate the efficacy of
atezolizumab in patients with locally advanced or metastatic urothelial bladder
cancer (UBC), as measured by:
• Independent Review Facility (IRF)*assessed objective response rate (ORR)
according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST
v1.1)
• Investigator-assessed ORR according to modified RECIST (this is applicable
only to Cohort 2)
The efficacy analysis for each cohort will follow a hierarchical fixed-sequence
procedure.
Secondary Objectives
The secondary objectives for this study are as follows:
• To evaluate progression-free survival (PFS) and duration of response (DOR)
according to RECIST v1.1 as assessed by an IRF
• To evaluate PFS and DOR according to modified RECIST as assessed by the
investigator (this is applicable only to Cohort 2)
• To evaluate ORR, DOR, and PFS according to RECIST v1.1 as assessed by the
investigator
• To evaluate overall survival (OS) and 1-year OS
• To evaluate the safety and tolerability of atezolizumab
• To characterize the pharmacokinetics of atezolizumab
• To evaluate the incidence and titers of anti-therapeutic antibodies (ATAs)
against atezolizumab and to explore the potential relationship of the
immunogenicity response with pharmacokinetics, safety, and efficacy
Exploratory Objectives
The exploratory objectives for this study are as follows:
• To further evaluate anti-tumor activity by IHC categories
• To evaluate the relationship between tumor biomarkers (including but not
limited to PD-L1, programmed death*1 [PD-1], and others), as defined by IHC and
efficacy
• To assess predictive, prognostic, and pharmacodynamic exploratory biomarkers
in archival and/or fresh tumor tissue and blood and their association with
disease status and/or response to study treatment
• To evaluate the utility of biopsy at the time of apparent disease progression
to distinguish apparent increases in tumor volume related to the
immunomodulatory activity of atezolizumab (i.e., pseudoprogression/tumor immune
infiltration) from true disease progression
• To evaluate investigator-assessed time in response (TIR) per RECIST v1.1
• To evaluate investigator-assessed TIR per modified RECIST
• To evaluate investigator-assessed disease control rate (DCR)
Study design
This is a Phase II, global, multicenter, single-arm trial designed to evaluate
the efficacy and safety of atezolizumab in patients with locally advanced or
metastatic UBC.
For more detailed information, please see section 3.1 of the study protocol.
Intervention
Eligible patients will be placed in Cohort 1 or 2, depending on their medical
history.
A fixed dose of 1200 mg IV atezolizumab will be administered on Day 1 of each
21-day cycle.
During treatment, patients in Cohort 2 will be permitted to continue
atezolizumab treatment after RECIST v1.1 criteria for progressive disease are
met and if they meet all of the following criteria:
• Evidence of clinical benefit as assessed by the investigator
• Absence of symptoms and signs indicating unequivocal progression of disease
(including worsening of laboratory values [e.g., new or worsening
hypercalcemia])
• No decline in ECOG performance status that can be attributed to disease
progression
• Absence of tumor progression at critical anatomical sites (e.g.,
leptomeningeal disease) that cannot be managed by protocol-allowed medical
interventions
Cohort 2 patients treated with atezolizumab for whom radiographic disease
progression is confirmed at a subsequent tumor assessment may be considered for
continued study treatment at the discretion of the investigator if they
continue to meet the criteria above.
For more information, see also section 3.1 of the study protocol.
Study burden and risks
For more information, please see the answer on question number E9.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
• Histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2*3) or metastatic (M1, Stage IV) TCC (also termed urothelial cell carcinoma) of the urothelium (including renal pelvis, ureters, urinary bladder, urethra)
• Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to have sufficient viable tumor content prior to study enrollment; tumor specimens will be evaluated for PD-L1 expression; patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with Medical Monitor.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Patients with ECOG 2 are allowed in Cohort 1.
• Measurable disease, as defined by RECIST v1.1 Previously irradiated lesions should not be counted as target lesions.;Cohort 1-Specific Inclusion Criteria
• No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UBC
• Ineligible (*unfit*) for cisplatin-based chemotherapy as defined by any one of the following criteria:
- Impaired renal function (glomerular filtration rate [GFR] > 30 but < 60 mL/min). GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)
- A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies
- Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including tingling)
- ECOG performance score of 2;Cohort 2-Specific Inclusion Criteria
• Disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC], CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence
Exclusion criteria
Cancer Specific Exclusion Criteria
• Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment
• Active or untreated central nervous system (CNS) metastases as determined by CT or MRI evaluation during screening and prior radiographic assessments
• Leptomeningeal disease;Medication-Related Exclusion Criteria:
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
• Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-005486-39-NL |
| ClinicalTrials.gov | NCT02108652 |
| CCMO | NL48550.031.14 |