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Atezolizumab With Bevacizumab in Previously Untreated Metastatic/Unresectable Urothelial Cancer

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ClinicalTrials.gov Identifier: NCT03272217
Recruitment Status : Recruiting
First Posted : September 5, 2017
Last Update Posted : July 29, 2019
Sponsor:
Collaborators:
Roche-Genentech
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Arjun Balar, MD, Hoosier Cancer Research Network

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.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Drug: Atezolizumab Drug: Bevacizumab Phase 2

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 < 2.0 or ≥ 30 cc/min using a direct method or the Cockcroft-Gault formula
  • Urinary Albumin 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)

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description: Open-Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Atezolizumab and Bevacizumab in Cisplatin-ineligible Patients With Advanced/Unresectable Urothelial Cancer
Actual Study Start Date : September 13, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A - Atezolizumab + Bevacizumab
Patients will receive atezolizumab 1200 mg (flat dose) IV plus bevacizumab 15 mg/kg IV every 21 days
Drug: Atezolizumab
Atezolizumab 1200 mg (flat dose) IV every 21 days
Other Name: MPDL3280A

Drug: Bevacizumab
Bevacizumab 15 mg/kg IV every 21 days
Other Name: Avastin




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: date at time of randomization up to 1 year ]
    Comparison of 1-year overall survival (OS) rates for cisplatin-ineligible patients


Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: up to 24 months ]
    The objective response rate is the proportion of all patients with confirmed PR or CR according to RECIST 1.1, from the start of treatment until disease progression/recurrence

  2. Duration of Response (DoR) [ Time Frame: 1 year ]
    The period measured from the time that measurement criteria are met for complete response until the first date that recurrent disease is objectively documented.

  3. Disease Control Rate [ Time Frame: up to 25 months ]
    The disease control rate is the proportion of all patients with stable disease (SD) for 8 weeks, or partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment until disease progression/recurrence

  4. Progression-Free Survival (PFS) [ Time Frame: 1 year ]
    A measurement from the date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs.

  5. Assess Safety and Toxicity by CTCAEv4 [ Time Frame: 2 years ]
    by CTCAEv4



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 randomization
  • 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 randomization
  • 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 [GFR ≥ 30 but ≤ 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 (hearing loss measured by audiometry of 25 dB at two contiguous frequencies)
    • Grade ≥ 2 peripheral neuropathy
    • ECOG Performance Status of 2
    • Solitary Kidney
  • 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 activity 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. For subjects randomized to receive bevacizumab the time frame is from the time of informed consent until 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 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
    • Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to enrollment.
    • Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
  • 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.

    • 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

    • Influenza vaccination should be given during influenza season only (approx. Oct. to Mar.). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to C1D1 or at any time 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 EXCLUSION CRITERIA:

  • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies

    • Prior cancer vaccines and cellular immunotherapy are permitted.
  • Treatment with systemic immunostimulatory agents (including but not limited to IFNs, interleukin [IL]-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to C1D1
  • 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 [anti-TNF] agents) within 2 weeks prior to C1D1, or anticipated requirement for systemic immunosuppressive medications during the trial

    • Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
    • The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed

BEVACIZUMAB-SPECIFIC EXCLUSION CRITERIA:

  • Inadequately controlled hypertension (defined as persistent systolic blood pressure (SBP) > 150 and/or diastolic blood pressure (DBP) > 100 mmHg)
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • Current or recent (within 10 days of study enrollment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes
  • History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
  • Minor surgical procedure within 7 calendar days prior to C1D1
  • History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to enrollment
  • Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
  • Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
  • Serious non-healing or dehiscing wound, active ulcer, or untreated or non-healing bone fracture
  • On-going gross hematuria associated with clots

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03272217


Contacts
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Contact: Dylan Cregar 317.634.5842 ext 38 dcregar@hoosiercancer.org
Contact: Arjun Balar, M.D. 212.731.5820 arjun.balar@nyumc.org

Locations
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United States, Minnesota
HealthPartners Institute Recruiting
Minneapolis, Minnesota, United States, 55440
Contact: Jennifer Collier    651-254-3391    Jennifer.Collier@parknicollet.com   
Principal Investigator: Arkadiusz Dudek, MD, PhD         
United States, New York
New York University Clinical Cancer Center Recruiting
New York, New York, United States, 10016
Contact: Karen Martirosyan    212-263-4434    Karen.martirosyan@nyumc.org   
Principal Investigator: Arjun Balar, MD         
United States, Tennessee
West Cancer Center University of Tennessee Recruiting
Memphis, Tennessee, United States, 38120
Contact: Rachel Adams    901-683-0055 ext 63005    raadams@WESTCLINIC.com   
Principal Investigator: Daniel Vaena, MD         
United States, Wisconsin
Froedtert & The Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Stacey Zindars    414-805-8913    szindars@mcw.edu   
Principal Investigator: Deepak Kilari, MD         
Sponsors and Collaborators
Arjun Balar, MD
Roche-Genentech
Hoosier Cancer Research Network
Investigators
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Study Chair: Arjun Balar, M.D. Hoosier Cancer Research Network

Additional Information:
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Responsible Party: Arjun Balar, MD, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03272217     History of Changes
Obsolete Identifiers: NCT03133390
Other Study ID Numbers: HCRN GU15-215
First Posted: September 5, 2017    Key Record Dates
Last Update Posted: July 29, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Arjun Balar, MD, Hoosier Cancer Research Network:
Atezolizumab
MPDL3280A
Bevacizumab
Avastin
Cisplatin-Ineligible
Anti-PD-L1 Antibodies

Additional relevant MeSH terms:
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Carcinoma, Transitional Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Cisplatin
Bevacizumab
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Antineoplastic Agents, Immunological
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors