The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab plus gemcitabine/carboplatin or cisplatin compared with placebo plus gemcitabine/carboplatin or cisplatin on the basis of the following endpoints:- Co-primary…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
urotheel kanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Treatment with atezolizumab, both as a single-agent and in combination with
platinum-based chemotherapy offers the potential for clinical benefit in
previously untreated patients with metastatic urothelial carcinoma
See section K: Objective and protocol paragraph 1.3 and 2.1 pages 76-78.
Secondary outcome
The exploratory efficacy objectives for this study are to evaluate the efficacy
of atezolizumab given
as either monotherapy or in combination with platinum-based chemotherapy
compared with
placebo in combination with platinum-based chemotherapy on the basis of the
following endpoints:
• Disease control rate (DCR), defined as the proportion of patients with
confirmed CR or PR as best response, or stable disease maintained for >= 6
months, per RECIST v1.1
• Relationship between tumor tissue PD-L1 expression and measures of efficacy
• 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
• Disease and treatment burden as measured by the symptom (e.g., pain, fatigue)
and function scores from the QLQ C30
An additional exploratory objective is to characterize patients who are able to
continue treatment past progression by RECIST v1.1 as permitted per protocol
and to describe clinical outcomes by treatment arm using modified RECIST, such
as ORR, DOR, DCR, and PFS
The PK objective for this study is to characterize the pharmacokinetics of
atezolizumab when administered as monotherapy or in combination with
platinum-based chemotherapy in patients who are treatment-naive:
• PK parameters for atezolizumab include maximum serum concentration (Cmax) and
minimum serum concentration (Cmin) when appropriate, as data allow.
The immunogenicity objective for this study is to evaluate the immune response
to atezolizumab as monotherapy and in combination with platinum-based
chemotherapy on the basis of the following endpoint:
• Incidence of anti-therapeutic antibodies (ATAs) during the study relative to
the prevalence of ATAs at baseline
The exploratory immunogenicity objective for this study is to evaluate
potential effects of detectable ATAs on the basis of the following endpoint:
• Correlation between ATA status and efficacy, safety, and PK endpoints
Health Economics Objective:
Health status will be measured using the EuroQol 5-Dimension, 5-Level version
(EQ-5D-5L; EuroQol Group 1990) questionnaire to be included in health economic
modeling. As such, data from the EQ-5D-5L will not be reported in the Clinical
Study Report (CSR).
See also section K: Objective and protocol paragraph 2.1 pages 79-80.
Background summary
Urothelial carcinoma (UC, also termed transitional cell carcinoma [TCC],
urothelial bladder cancer or urothelial cell carcinoma [UCC] of the urinary
tract) is the most common cancer of the urinary system worldwide with
urothelial carcinoma of the bladder being the predominant histologic type and
location. The overall 5-year survival rate for metastatic urothelial carcinoma
is approximately 5.4%
Approximately 5% of patients present with metastatic disease at diagnosis.
Despite the low frequency of de novo disease, approximately half of the
patients with locally advanced urothelial carcinoma progress to metastatic
disease within two years of cystectomy.
Platinum-based combination chemotherapy is the preferred regimen in the
first-line setting, and single agent chemotherapy is typically reserved for the
second-line setting.
There is a significant medical need for efficacious and more tolerable
regimens. Overall survival for this patient population is low.
No targeted agents, such as Atezolizumab, currently have a role in the
treatment of urothelial carcinoma.
See also protocol Chapter 1 page 71-78.
Study objective
The primary efficacy objective for this study is to evaluate the efficacy of
atezolizumab plus gemcitabine/carboplatin or cisplatin compared with placebo
plus gemcitabine/carboplatin or cisplatin on the basis of the following
endpoints:
- Co-primary endpoints of progression-free survival (PFS) and overall survival
(OS) for arms A and C
- Primary endpoint of overall survival for arm B
The secondary efficacy objectives for this study are to evaluate the efficacy
of atezolizumab monotherapy and in combination with platinum based therapy
compared with placebo plus platinum based therapy on the basis of the following
endpoints:
Objective response rate (ORR).
Duration of response (DOR).
PFS assessed by Independent Review Facility (IRF).
OS rate at 1 year.
PFS rate at 1 year
Time to deterioration in global health status as measured by the European
Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life
Questionnaire Core 30 (QLQ C30).
Time to deterioration in physical function as measured by the EORTC QLQ-C30
Safety objective:
evaluate the safety and tolerability of atezolizumab given as either
monotherapy or in combination with platinum-based chemotherapy compared with
placebo plus platinum-based chemotherapy on the basis of the following: •
Incidence, nature, and severity of adverse events graded according to National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
v4.0 • Changes in vital signs, and clinical laboratory results,
Next to this the there is a Pharmacokinetic, Immunogenicity, Exploratory
Efficacy and Health Economics Objective
See also protocol Chapter 2 page 78-80.
Study design
Tumor specimens from eligible patients will be prospectively tested for PD-L1
immunohistochemistry (IHC) expression by a central laboratory prior to
randomization. The IHC scores will have two categories (tumor-infiltrating
immune cell [IC] 0/1, IC2/3). Both patients and investigators will be blind to
the PD-L1 expression status but the Sponsor will be able to view aggregate
PD-L1 expression data. The study will enroll all eligible patients whose
tissue is evaluable for expression testing, regardless of PD-L1 expression
status.
This study will enroll approximately 1215 patients at approximately 200 sites
Patients will be randomized in a 1:1:1 ratio to receive one of the following:
• Arm A (experimental arm): blinded atezolizumab in combination with
gemcitabine/carboplatin or gemcitabine/cisplatin
• Arm B (experimental arm): open-label atezolizumab monotherapy
• Arm C (control arm): blinded placebo in combination with
gemcitabine/carboplatin or gemcitabine/cisplatin
Investigators will determine whether their patient is eligible or ineligible to
receive cisplatin-based chemotherapy. Those patients considered eligible to
receive cisplatin and who are randomized to Arm A or Arm C will receive
gemcitabine/cisplatin. Those patients determined as cisplatin ineligible (see
Inclusion Criteria) and who are randomized to Arm A or Arm C will receive
gemcitabine/carboplatin. The Sponsor anticipates a 60:40 ratio of
cisplatin-eligible to cisplatin-ineligible patients for Arms A-C, based on
treatment patterns and data from real world data studies.
Randomization will be stratified by the following factors:
• PD-L1 status (IC0/1 vs. IC2/3)
• Investigator*s choice of chemotherapy (gemcitabine/carboplatin vs.
gemcitabine/cisplatin)
• Bajorin model risk factor score/liver metastasis (0 vs. 1 vs. 2 or liver
metastasis)
Patients will undergo scheduled tumor assessment at baseline and every 9 weeks
thereafter for 54 weeks after randomization. After 54 weeks, patients will
undergo tumor assessment every 12 weeks until disease progression per RECIST
v1.1, death, study termination by the Sponsor, or withdrawal of consent,
whichever occurs first. Patients must discontinue treatment at the first
occurrence of radiographic progression, per RECIST v1.1, with the certain
exceptions, see protocol page 83.
See also protocol Chapter 3 page 80-87 (rationale for study design on pages
86-87) .
Intervention
Patients will be randomized in a 1:1:1 ratio to receive one of the following:
• Arm A (experimental arm): blinded atezolizumab in combination with
gemcitabine/carboplatin or gemcitabine/cisplatin: via IV infusion
• Arm B (experimental arm): open-label atezolizumab monotherapy: via IV
infusion
• Arm C (control arm): blinded placebo in combination with
gemcitabine/carboplatin or gemcitabine/cisplatin: via IV infusion
Next to this there is bloodsampling and biopties are being taken.
See protocol Chapter 4.5 pages 111- 119.
Study burden and risks
As described in the patient information sheet there are risks and burden
associated with participation as the chemotherapeutic agents as well as
Atezolizumab might cause side effects as well as the treatment of these
patients in general (e.g. blood sampling, radiographic assessments, biopties).
Atezolizumab has been/ is being investigated in phase 1, 2 and 3 studies.
Response is being seen and the Treatment combination with chemotherapy have
been generally well tolerated as seen in an ongoing phase 1B study.
Atezolizumab (TECENTRIQ* ) is approved in the United States for use in patients
with locally advanced or metastatic urothelial carcinoma who have disease
progression during or following platinum-based chemotherapy, or whose disease
has worsened within 12 months of receiving platinum-based chemotherapy before
surgery (neoadjuvant) or after surgery (adjuvant).
See protocol page 74.
See protocol paragraph 1.2 pages 73-76.
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Woerden 3446 GR
NL
Beneluxlaan 2a Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
• Signed Informed Consent Form
• Age * 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of * 2
• Able to comply with the study protocol, in the investigator*s judgment
• Histologically documented, locally advanced (T4b, any N; or any T, N 2*3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed Transitional cell carcinoma (TCC), also called urothelial cell carcinoma (UCC) of the urinary tract; including renal pelvis, ureters, urinary bladder, and 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 be evaluable for tumor PD-L1 expression prior to study enrollment; patients who have fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with the Medical Monitor.
• No prior chemotherapy for inoperable locally advanced or mUC
• Patients eligible for platinum based therapy. To define a patient as ineligible (*unfit*) for cisplatin-based therapy the following criteria (based on Galsky et al. 2011) can be used:
• Measurable disease, as defined by RECIST v1.1
• Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 28 days prior to the first study treatment:
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of * 1% per year during the treatment period and for at least 6 months after the last dose of cisplatin, carboplatin or gemcitabine or for 5 months after the last dose of atezolizumab
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below:;The inclusion criteria are described more into detail in the protocol page 94-97.
Exclusion criteria
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Specific Exclusions
• Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:
• Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrollment
• Active or untreated CNS metastases as determined by computed tomography or magnetic resonance imaging evaluation during screening and prior radiographic assessments
• Leptomeningeal disease
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled tumor-related pain
• Uncontrolled hypercalcemia defined as any one or more of the following criteria:
• Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1;General Medical Exclusions
• Life expectancy of * 12 weeks
• Pregnant or lactating, or intending to become pregnant during the study
• Serum albumin * 2.5 g/dL ;Exclusion Criteria Related to Atezolizumab
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener*s granulomatosis, Sjögren*s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• Patients with prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina
• Known left ventricular ejection fraction (LVEF) * 40%
• Positive test for HIV
• Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
• Active tuberculosis
• Severe infections within 4 weeks prior to randomization including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Therapeutic oral or IV antibiotics within 2 weeks prior to randomization
• Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Prior treatment with CD137 agonists, anti*CTLA-4, anti*programmed death-1 (PD-1), or anti*PD-L1 therapeutic antibody or pathway targeting agents
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 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 (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti*tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1 or anticipated requirement for systemic immunosuppressive medications during the study;The exclusion criteria are described more into detail in the protocol page 97-101.
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 | EUCTR201600025035-NL |
| ClinicalTrials.gov | NCT02807636 |
| CCMO | NL60663.056.17 |