Urothelial Carcinoma
Conditions
Keywords
Atezolizumab, MPDL3280A, Bevacizumab, Avastin, Cisplatin-Ineligible, Anti-PD-L1 Antibodies
Brief summary
This is a phase II study assessing the activity of bevacizumab combined with atezolizumab in metastatic urothelial carcinoma patients who are ineligible for cisplatin-based therapy.
Detailed description
This is a multi-center trial. INVESTIGATIONAL TREATMENT: Eligible patients will be receive atezolizumab 1200 mg IV flat dose plus bevacizumab 15 mg/kg IV every 21 days 21 days equals 1 cycle of therapy and patients will be eligible to continue treatment until progressive disease by RECIST v1.1 or unacceptable toxicity for up to 24 months. To demonstrate adequate organ function, all screening labs must be obtained within 14 days prior to Cycle 1 Day 1 (C1D1) of treatment: Hematological: * Absolute Neutrophil Count (ANC): ≥ 1,000 K/mm\^3 * Hemoglobin (Hgb): ≥ 9.0 g/dL * Absolute Lymphocyte Count: ≥ 500/uL * Platelet Count: ≥ 100,000/uL Renal: * Calculated Creatinine Clearance: serum creatinine \< 2.5 or ≥ 25 cc/min using a direct method or the Cockcroft-Gault formula * Urinary Protein Excretion: \< 1.0 g/24 hours (as estimated by urine protein-creatinine ratio) Hepatic: * Bilirubin: ≤ 1.5 × upper limit of normal (ULN) (patients with known Gilbert's Disease who have serum bilirubin ≤ 3.0 x ULN may be enrolled) * Aspartate aminotransferase (AST): ≤ 2.5 × ULN (5.0 x ULN if liver involvement) * Alanine aminotransferase (ALT): ≤ 2.5 × ULN (5.0 x ULN if liver involvement) * Serum Albumin: ≥ 2.5 g/dL Coagulation: * International Normalized Ratio (INR) or Prothrombin Time (PT); Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 × ULN (NOTE: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose)
Interventions
DRUGAtezolizumab
Atezolizumab 1200 mg (flat dose) IV every 21 days
DRUGBevacizumab
Bevacizumab 15 mg/kg IV every 21 days
Sponsors
Roche-Genentech
Hoosier Cancer Research Network
Arjun Balar, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-Label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patient must meet all of the following applicable inclusion criteria to participate in this study: * Written informed consent and Health Insurance Portability and Accountability Act of 1996 (HIPAA) authorization for release of personal health information. * As determined by the enrolling physician or protocol designee, ability of the patient to understand and comply with study procedures for the entire length of the study * Age ≥ 18 years at the time of consent * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 within 28 days prior to registration * Histological or cytological evidence urothelial (transitional cell) carcinoma of the renal pelvis, ureter, bladder or urethra * Locally advanced/unresectable disease as determined by site attending urologic oncologist or metastatic disease * Evaluable untreated tumor tissue for biomarker analysis. Untreated tumor tissue is defined as no intervening intravesical or systemic therapy since acquisition. Patients without tissue available must be willing and safe to undergo biopsy repeat biopsy (core needle or excisional) prior to enrollment. Subjects with \< 25 slides may be enrolled after discussion with the sponsor-investigator or co-investigator. * Willing to undergo a core needle or excisional biopsy on-treatment. Patients will be assessed at the time of biopsy for safety of undergoing the procedure * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 within 28 days prior to registration * No prior chemotherapy for locally advanced or metastatic urothelial cancer * Perioperative chemotherapy previously administered in the neoadjuvant and/or adjuvant setting is permitted * Prior chemotherapy administered in the context of chemoradiation as definitive treatment for bladder preservation is also permitted, provided that disease progression outside the prior radiotherapy field is demonstrated histologically or cytologically * Ineligible for cisplatin as defined by presence of one or more of the following: * (Impaired renal function \[≤ 60 cc/min\]. Glomerular filtration rate (GFR) should be assessed by direct measurement \[i.e., creatinine clearance or ethylenediaminetetra-acetate\] or, if not available, by calculation from serum/plasma creatinine by Cockroft-Gault equation) * Grade ≥ 2 hearing Loss (measured by loss of \>25 dB at two contiguous frequencies in at least one ear for patients undergoing serial audiometry testing) * Grade ≥ 2 peripheral neuropathy * ECOG Performance Status of 2 * Solitary Kidney * Refusing Cisplatin-based chemotherapy * If palliative radiotherapy administered, completion of palliative radiation therapy ≥ 2 weeks prior to Cycle 1 Day 1 of protocol therapy * Females of childbearing potential must have a negative serum pregnancy test within 28 days prior to registration. * Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent until 150 days (5 months) after discontinuation of atezolizumab or 180 days (6 months) after discontinuation of bevacizumab. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method
Exclusion criteria
Patients meeting any of the criteria below may not participate in the study: * Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed: * Palliative radiotherapy for bone metastases or soft tissue lesions should be completed \> 7 days prior to baseline imaging * Hormone-replacement therapy or oral contraceptives * Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment * Active or untreated central nervous system (CNS) metastases or leptomeningeal disease as determined by computed tomography (CT) scan or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments. * Patients with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria: * Evaluable or measurable disease outside the CNS * No metastases to midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm) * No history of intracranial or spinal cord hemorrhage * No evidence of significant vasogenic edema * No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose allowed * No stereotactic radiation, whole-brain radiation within 4 weeks prior to Cycle 1 Day 1 * Patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy within 3 months prior to Cycle 1 Day 1 will be excluded * Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study * Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy or surgical resection and ≥ 2 weeks since discontinuation of corticosteroids * Leptomeningeal disease * Uncontrolled tumor-related pain * Patients requiring pain medication must be on a stable regimen at study entry * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) * Patients with indwelling drainage catheters are allowed. * Uncontrolled hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. NOTE: Patients with asymptomatic hypercalcemia controlled with medical therapy are eligible. * Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. * Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while in the study. * Malignancies other than urothelial cancer within 5 years prior to Cycle 1 Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (T1/T2a, Gleason score ≤ 3 + 4, and PSA ≤ 0.5 ng/mL undergoing active surveillance and treatment naive) * Pregnant or breastfeeding * 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 or bevacizumab 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 anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis * Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. * Subjects with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study. * Subjects with a history of celiac disease may be eligible if controlled with diet. * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted. * History of confirmed positive test for human immunodeficiency virus (HIV) * Patients with active hepatitis B virus (HBV) (chronic or acute, defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening) or hepatitis C virus (HCV) * Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBc Ab\] and absence of HBsAg) are eligible * Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA * Active tuberculosis * Severe infections within 4 weeks prior to Cycle 1 Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia * Signs or symptoms of active infection within 2 weeks prior to C1D1 * Received therapeutic oral or IV antibiotics within 1 week prior to C1D1 * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible * New York Heart Association Congestive Heart Failure Class II or greater * Myocardial infarction, unstable angina or unstable arrhythmias within 3 months of enrollment. * History of stroke or TIA within 3 months of enrollment * Other clinically significant arterial vascular disease within 6 months of enrollment (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis). Prior history of adequately treated venous thromboembolism \> 7 days prior to C1D1 on stable dose of therapeutic anticoagulation is permitted * Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. * Major surgical procedure other than for diagnosis within 28 days prior to C1D1 or anticipation of need for a major surgical procedure during the course of the study * Prior allogeneic stem cell or solid organ transplant * Administration of a live, attenuated vaccine within 4 weeks before C1D1 or anticipation that such a live attenuated vaccine will be required during the study * 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 subject at high risk from treatment complications ATEZOLIZUMAB-SPECIFIC
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Rate at 1 Year | 1 years | Determine the percentage of overall survival at 1 years from the initiation of treatment. Overall survival is defined as the time from treatment start until death or date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to a maximum of 14 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter(LD) of target lesions; Progressive Disease (PD): \>= 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Overall Response (OR) = CR + PR. |
| Duration of Response (DOR) | Up to a maximum of 14 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. DOR is defined as time from measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented by RECIST v1.1. |
| Progression-Free Survival (PFS) | Time of treatment start until the criteria for disease progression or death, up to a maximum of 36 months. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from the date of treatment start until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs |
| Number of Participants With Adverse Events | Adverse events were recorded from time of registration until 30 days after discontinuation of study drug(s), up to maximum of 12 months | Adverse events were recorded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A - Atezolizumab + Bevacizumab Patients will receive atezolizumab 1200 mg (flat dose) IV plus bevacizumab 15 mg/kg IV every 21 days
Atezolizumab: Atezolizumab 1200 mg (flat dose) IV every 21 days
Bevacizumab: Bevacizumab 15 mg/kg IV every 21 days | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Arm A - Atezolizumab + Bevacizumab |
|---|---|
| Age, Continuous | 77 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 16 |
| other Total, other adverse events | 15 / 16 |
| serious Total, serious adverse events | 8 / 16 |
Outcome results
Primary
Overall Survival (OS) Rate at 1 Year
Determine the percentage of overall survival at 1 years from the initiation of treatment. Overall survival is defined as the time from treatment start until death or date of last contact.
Time frame: 1 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Atezolizumab + Bevacizumab | Overall Survival (OS) Rate at 1 Year | 67 Percentage of participants |
Secondary
Duration of Response (DOR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. DOR is defined as time from measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented by RECIST v1.1.
Time frame: Up to a maximum of 14 months
Population: Only one subject achieve complete or partial response by RECIST v1.1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Atezolizumab + Bevacizumab | Duration of Response (DOR) | 6.54 Months |
Secondary
Number of Participants With Adverse Events
Adverse events were recorded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.
Time frame: Adverse events were recorded from time of registration until 30 days after discontinuation of study drug(s), up to maximum of 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Atezolizumab + Bevacizumab | Number of Participants With Adverse Events | 16 Participants |
Secondary
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter(LD) of target lesions; Progressive Disease (PD): \>= 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Overall Response (OR) = CR + PR.
Time frame: Up to a maximum of 14 months
Population: Out of 16 subjects, one had no response. Therefore 15 subjects were evaluable for ORR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Atezolizumab + Bevacizumab | Objective Response Rate (ORR) | 6.67 Percentage of participants |
Secondary
Progression-Free Survival (PFS)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from the date of treatment start until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs
Time frame: Time of treatment start until the criteria for disease progression or death, up to a maximum of 36 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Atezolizumab + Bevacizumab | Progression-Free Survival (PFS) | 3.25 Months |