Clinical Trials List
Protocol NumberB9991001
NCT Number(ClinicalTrials.gov Identfier)NCT02603432
2016-07-28 - 2020-11-01
Phase III
Terminated6
ICD-10C67.9
Malignant neoplasm of bladder, unspecified
ICD-10C67
Malignant neoplasm of bladder
A Phase 3, Multicenter, Multinational, Randomized, Open-Label, Parallel-Arm Study of Avelumab (MSB0010718C) Plus Best Supportive Care Versus Best Supportive Care Alone as a Maintenance Treatment in Patients with Locally Advanced or Metastatic Urothelial Cancer Whose Disease Did Not Progress After Completion of First-Line Platinum-Containing Chemotherapy
-
Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
-
Sponsor
Pfizer Inc.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 洪啟峰 Division of Urology
- Chuan-Shu Chen Division of Urology
- 熊小澐 Division of Radiology
- Jian-Ri Li Division of Urology
- Cheng-Kuang Yang Division of Urology
- Cheng-Che Chen Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Cheng-Lung Hsu Division of Hematology & Oncology
- See-Tong Pang Division of Hematology & Oncology
- Yung-Chia Kao Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chi-Rei Yang Division of Urology
- Che-Hung Lin 無
- Wei-Ching Lin 無
- Ching-Chan Lin Division of Hematology & Oncology
- Chi-Ping Huang Division of Urology
- Po-Jen Hsiao 無
- Hsi-Chin Wu Division of Urology
- Po-Fan Hsieh 無
- Su-Peng Yeh Division of Hematology & Oncology
- 陳冠亨 Division of Urology
- Yi-Huei Chang 無
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Ying-Chun Shen Division of Hematology & Oncology
- Chia-Chi Lin Division of Hematology & Oncology
- CHING-CHU LU Division of Nuclear Medicine
- Yu-Chieh Tsai Division of Hematology & Oncology
- Yeong-Shiau Pu Division of Urology
- YEN-HENG LIN Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Ya-Ting Hsu Division of Hematology & Oncology
- Jui-Hung Tsai Division of Hematology & Oncology
- Che-Yuan Hu Division of Urology
- Wu-Chou Su Division of Hematology & Oncology
- Jiann-Hui Ou Division of Urology
- Shang-Yin Wu Division of Hematology & Oncology
- Yuh-Shyan Tsai Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Locally Advanced or Metastatic Urothelial Cancer
Objectives
Primary Objective
To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs. BSC alone
in prolonging overall survival (OS) in patients with unresectable locally advanced or
metastatic UC whose disease did not progress on or following completion of first-line
platinum-containing chemotherapy in each co-primary UC patient population: 1) patients
determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified
GMP PD-L1 IHC test, and 2) all randomized patients.
Test Drug
Avelumab (MSB0010718C)
Active Ingredient
Avelumab (MSB0010718C)
Dosage Form
solution
Dosage
20mg/ml, 10ml/vial
Endpoints
Primary Endpoint
Overall Survival (OS).
Secondary Endpoints
Progression-free survival (PFS) based on Blinded Independent Central Review
(BICR) assessment per RECIST v1.1.
Investigator-assessed Progression-Free Survival (PFS). Objective Response (OR),
Time to Tumor Response (TTR), Duration of Response (DR), and Disease Control
(DC), as assessed per RECIST v1.1 by BICR and investigator.
Safety: Adverse events (AEs) and laboratory abnormalities as graded by National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
v.4.03; vital signs (blood pressure, pulse rate).
Pharmacokinetics (PK): maximum concentrations (Cmax) and trough concentrations
(Ctrough) for avelumab.
Immunogenicity: Incidence of anti-drug antibodies (ADA; neutralizing antibody
[Nab]) against avelumab.
Biomarkers: Tumor tissue biomarkers including, but not limited to, PD-L1 expression
and tumor-infiltrating CD8+ T lymphocytes.
Patient-Reported Outcomes: patient-reported bladder cancer symptom, functioning,
global quality of life (QOL), and Time to Deterioration (TTD) using the NCCNFACT FBlSI; and health status using the EQ-5D-5L.
Exploratory Endpoints
Biomarkers: Peripheral blood and additional tumor tissue biomarkers consisting of
the levels of cells, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or proteins
that may be related to anti-tumor immune response and/or response to or disease
progression on avelumab, such as genes related to IFN- or transforming growth
factor (TGF)-.
Efficacy: Immune-related (ir)PFS; irOR, irTTR, irDR, and irDC per immune-related
RECIST (irRECIST).
Overall Survival (OS).
Secondary Endpoints
Progression-free survival (PFS) based on Blinded Independent Central Review
(BICR) assessment per RECIST v1.1.
Investigator-assessed Progression-Free Survival (PFS). Objective Response (OR),
Time to Tumor Response (TTR), Duration of Response (DR), and Disease Control
(DC), as assessed per RECIST v1.1 by BICR and investigator.
Safety: Adverse events (AEs) and laboratory abnormalities as graded by National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
v.4.03; vital signs (blood pressure, pulse rate).
Pharmacokinetics (PK): maximum concentrations (Cmax) and trough concentrations
(Ctrough) for avelumab.
Immunogenicity: Incidence of anti-drug antibodies (ADA; neutralizing antibody
[Nab]) against avelumab.
Biomarkers: Tumor tissue biomarkers including, but not limited to, PD-L1 expression
and tumor-infiltrating CD8+ T lymphocytes.
Patient-Reported Outcomes: patient-reported bladder cancer symptom, functioning,
global quality of life (QOL), and Time to Deterioration (TTD) using the NCCNFACT FBlSI; and health status using the EQ-5D-5L.
Exploratory Endpoints
Biomarkers: Peripheral blood and additional tumor tissue biomarkers consisting of
the levels of cells, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or proteins
that may be related to anti-tumor immune response and/or response to or disease
progression on avelumab, such as genes related to IFN- or transforming growth
factor (TGF)-.
Efficacy: Immune-related (ir)PFS; irOR, irTTR, irDR, and irDC per immune-related
RECIST (irRECIST).
Inclution Criteria
Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1. Diagnosis:
a. Histologically confirmed, unresectable locally advanced or metastatic transitional
cell carcinoma of the urothelium.
b. Documented Stage IV disease (T4b, N0, M0; any T, N1–N3, M0; any T, any N,
M1) at the start of first-line chemotherapy.
c. Measurable disease prior to the start of first-line chemotherapy by RECIST v1.1.
2. Prior first-line chemotherapy must have consisted of at least 4 cycles and no more
than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other
chemotherapy regimens are allowed in this study.
3. Patients without progressive disease as per RECIST v1.1 guidelines (ie, with an
ongoing CR, PR, or SD) following completion of 4 to 6 cycles of first-line
chemotherapy.
a. Eligibility based on this criterion will be determined by an independent expedited
central review of pre-chemotherapy and post-chemotherapy radiological
assessments (CT/MRI scans); see Study Overview, Section 3.1.
4. Tumor samples:
a. Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue
block (slides not acceptable) from the most recent primary or metastatic tumor
biopsy or resection obtained prior to treatment with first line chemotherapy but
within one year of randomization, with no intervening systemic anti-cancer
therapy. If a suitable tissue sample is not otherwise available, then an FFPE tissue
block from a de novo biopsy (core needle or excisional) must have been obtained
for research purposes prior to randomization in this study.
b. Provision of an archival FFPE tumor tissue block from primary tumor resection
specimen (if not provided per above). If an FFPE tissue block cannot be
provided, 15 unstained slides (10 minimum) will be acceptable.
5. Evidence of a signed and dated informed consent document indicating that the patient
(or a legally acceptable representative, as allowed by local guideline/practice) has
been informed of all pertinent aspects of the study.
6. Patients who are willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other study procedures.
7. Age 18 years (20 years in Japan).
8. Estimated life expectancy of at least 3 months.
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or
1 (Appendix 1).
10. Adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) 1,500/mm3
or 1.5 x 109
/L;
b. Platelets 100,000/mm3
or 100 x 109
/L;
c. Hemoglobin 9 g/dL (may have been transfused).
11. Adequate renal function, defined as estimated creatinine clearance 30 mL/min as
calculated using the Cockcroft-Gault equation (Appendix 5).
12. Adequate liver function, including:
a. Total serum bilirubin 1.5 x upper limit of normal (ULN);
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
2.5 x ULN.
13. Serum pregnancy test (for females of childbearing potential) negative at screening.
14. Male patients able to father children and female patients of childbearing potential and
at risk for pregnancy must agree to use 2 highly effective methods of contraception
(Section 4.3.1) throughout the study and for at least 60 days after the last dose of
assigned treatment.
Patient eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the
study:
1. Diagnosis:
a. Histologically confirmed, unresectable locally advanced or metastatic transitional
cell carcinoma of the urothelium.
b. Documented Stage IV disease (T4b, N0, M0; any T, N1–N3, M0; any T, any N,
M1) at the start of first-line chemotherapy.
c. Measurable disease prior to the start of first-line chemotherapy by RECIST v1.1.
2. Prior first-line chemotherapy must have consisted of at least 4 cycles and no more
than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other
chemotherapy regimens are allowed in this study.
3. Patients without progressive disease as per RECIST v1.1 guidelines (ie, with an
ongoing CR, PR, or SD) following completion of 4 to 6 cycles of first-line
chemotherapy.
a. Eligibility based on this criterion will be determined by an independent expedited
central review of pre-chemotherapy and post-chemotherapy radiological
assessments (CT/MRI scans); see Study Overview, Section 3.1.
4. Tumor samples:
a. Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue
block (slides not acceptable) from the most recent primary or metastatic tumor
biopsy or resection obtained prior to treatment with first line chemotherapy but
within one year of randomization, with no intervening systemic anti-cancer
therapy. If a suitable tissue sample is not otherwise available, then an FFPE tissue
block from a de novo biopsy (core needle or excisional) must have been obtained
for research purposes prior to randomization in this study.
b. Provision of an archival FFPE tumor tissue block from primary tumor resection
specimen (if not provided per above). If an FFPE tissue block cannot be
provided, 15 unstained slides (10 minimum) will be acceptable.
5. Evidence of a signed and dated informed consent document indicating that the patient
(or a legally acceptable representative, as allowed by local guideline/practice) has
been informed of all pertinent aspects of the study.
6. Patients who are willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other study procedures.
7. Age 18 years (20 years in Japan).
8. Estimated life expectancy of at least 3 months.
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or
1 (Appendix 1).
10. Adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) 1,500/mm3
or 1.5 x 109
/L;
b. Platelets 100,000/mm3
or 100 x 109
/L;
c. Hemoglobin 9 g/dL (may have been transfused).
11. Adequate renal function, defined as estimated creatinine clearance 30 mL/min as
calculated using the Cockcroft-Gault equation (Appendix 5).
12. Adequate liver function, including:
a. Total serum bilirubin 1.5 x upper limit of normal (ULN);
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
2.5 x ULN.
13. Serum pregnancy test (for females of childbearing potential) negative at screening.
14. Male patients able to father children and female patients of childbearing potential and
at risk for pregnancy must agree to use 2 highly effective methods of contraception
(Section 4.3.1) throughout the study and for at least 60 days after the last dose of
assigned treatment.
Exclusion Criteria
Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients whose disease progressed by RECIST v1.1 on or after first-line
chemotherapy for urothelial cancer.
2. Prior adjuvant or neoadjuvant therapy within 12 months of randomization.
3. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
4. Major surgery 4 weeks or major radiation therapy 2 weeks prior to randomization.
Prior palliative radiotherapy (10 fractions) to metastatic lesion(s) is permitted,
provided it has been completed at least 48 hours prior to patient randomization.
5. Patients with known symptomatic central nervous system (CNS) metastases requiring
steroids. Patients with previously diagnosed CNS metastases are eligible if they have
completed their treatment and have recovered from the acute effects of radiation
therapy or surgery prior to randomization, have discontinued corticosteroid treatment
for these metastases for at least 4 weeks, and are neurologically stable.
6. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however,
sensory neuropathy Grade 2 is acceptable.
7. Diagnosis of any other malignancy within 5 years prior to randomization, except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the
breast or of the cervix, or low-grade (Gleason 6) prostate cancer on surveillance
without any plans for treatment intervention (eg, surgery, radiation, or castration).
8. Participation in other studies involving investigational drug(s) within 4 weeks prior to
randomization. Observational studies are permitted.
9. Active autoimmune disease that might deteriorate when receiving an
immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid disease not requiring immunosuppressive treatment are eligible.
10. Any of the following in the previous 6 months: myocardial infarction, severe/unstable
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure,
cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or
symptomatic pulmonary embolism.
11. Active infection requiring systemic therapy.
12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any
history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma
symptom control per the Global Initiative for Asthma 2015).62
13. Known prior or suspected hypersensitivity to study drugs or any component in their
formulations.
14. Current or prior use of immunosuppressive medication within 7 days prior to
randomization, EXCEPT the following:
a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular
injection);
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or
equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).
15. Diagnosis of prior immunodeficiency or organ transplant requiring
immunosuppressive therapy.
16. Positive test for human immunodeficiency virus (HIV) infection or known acquired
immunodeficiency syndrome (AIDS).
17. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or
chronic infection.
18. Vaccination within 4 weeks of the first dose of study treatment and while on trial is
prohibited except for administration of inactivate vaccines (for example, inactivated
influenza vaccines).
19. Patients who are investigational site staff members directly involved in the conduct of
the study and their family members, site staff members otherwise supervised by the
investigator, or patients who are Pfizer employees directly involved in the conduct of
the study.
20. Pregnant female patients; breastfeeding female patients; male patients able to father
children, and female patients of childbearing potential who are unwilling or unable to
use 2 highly effective methods of contraception as outlined in the protocol for the
duration of the study and for at least 60 days after the last dose of investigational
product.
21. Other severe acute or chronic medical conditions including but not limited to colitis,
inflammatory bowel disease, pneumonitis, and pulmonary fibrosis; psychiatric
condition including recent (within the past year) or active suicidal ideation or
behavior; or laboratory abnormality that may increase the risk associated with study
participation or study treatment administration or may interfere with the interpretation
of study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients whose disease progressed by RECIST v1.1 on or after first-line
chemotherapy for urothelial cancer.
2. Prior adjuvant or neoadjuvant therapy within 12 months of randomization.
3. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
4. Major surgery 4 weeks or major radiation therapy 2 weeks prior to randomization.
Prior palliative radiotherapy (10 fractions) to metastatic lesion(s) is permitted,
provided it has been completed at least 48 hours prior to patient randomization.
5. Patients with known symptomatic central nervous system (CNS) metastases requiring
steroids. Patients with previously diagnosed CNS metastases are eligible if they have
completed their treatment and have recovered from the acute effects of radiation
therapy or surgery prior to randomization, have discontinued corticosteroid treatment
for these metastases for at least 4 weeks, and are neurologically stable.
6. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however,
sensory neuropathy Grade 2 is acceptable.
7. Diagnosis of any other malignancy within 5 years prior to randomization, except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the
breast or of the cervix, or low-grade (Gleason 6) prostate cancer on surveillance
without any plans for treatment intervention (eg, surgery, radiation, or castration).
8. Participation in other studies involving investigational drug(s) within 4 weeks prior to
randomization. Observational studies are permitted.
9. Active autoimmune disease that might deteriorate when receiving an
immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid disease not requiring immunosuppressive treatment are eligible.
10. Any of the following in the previous 6 months: myocardial infarction, severe/unstable
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure,
cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or
symptomatic pulmonary embolism.
11. Active infection requiring systemic therapy.
12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any
history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma
symptom control per the Global Initiative for Asthma 2015).62
13. Known prior or suspected hypersensitivity to study drugs or any component in their
formulations.
14. Current or prior use of immunosuppressive medication within 7 days prior to
randomization, EXCEPT the following:
a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular
injection);
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or
equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).
15. Diagnosis of prior immunodeficiency or organ transplant requiring
immunosuppressive therapy.
16. Positive test for human immunodeficiency virus (HIV) infection or known acquired
immunodeficiency syndrome (AIDS).
17. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or
chronic infection.
18. Vaccination within 4 weeks of the first dose of study treatment and while on trial is
prohibited except for administration of inactivate vaccines (for example, inactivated
influenza vaccines).
19. Patients who are investigational site staff members directly involved in the conduct of
the study and their family members, site staff members otherwise supervised by the
investigator, or patients who are Pfizer employees directly involved in the conduct of
the study.
20. Pregnant female patients; breastfeeding female patients; male patients able to father
children, and female patients of childbearing potential who are unwilling or unable to
use 2 highly effective methods of contraception as outlined in the protocol for the
duration of the study and for at least 60 days after the last dose of investigational
product.
21. Other severe acute or chronic medical conditions including but not limited to colitis,
inflammatory bowel disease, pneumonitis, and pulmonary fibrosis; psychiatric
condition including recent (within the past year) or active suicidal ideation or
behavior; or laboratory abnormality that may increase the risk associated with study
participation or study treatment administration or may interfere with the interpretation
of study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
The Estimated Number of Participants
-
Taiwan
30 participants
-
Global
668 participants
