Clinical Trials /

Atezolizumab With Bevacizumab in Previously Untreated Metastatic/Unresectable Urothelial Cancer

NCT03272217

Description:

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.

Related Conditions:
  • Bladder Urothelial Carcinoma
  • Renal Pelvis Urothelial Carcinoma
  • Ureter Urothelial Carcinoma
  • Urethral Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab With Bevacizumab in Previously Untreated Metastatic/Unresectable Urothelial Cancer
  • Official Title: A Phase II Trial of Atezolizumab and Bevacizumab in Cisplatin-ineligible Patients With Advanced/Unresectable Urothelial Cancer

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU15-215
  • NCT ID: NCT03272217
  • NCT ALIAS: NCT03133390

Conditions

  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL3280AArm A - Atezolizumab + Bevacizumab
BevacizumabAvastinArm A - Atezolizumab + Bevacizumab

Purpose

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 < 2.0 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)
    

Trial Arms

NameTypeDescriptionInterventions
Arm A - Atezolizumab + BevacizumabExperimentalPatients will receive atezolizumab 1200 mg (flat dose) IV plus bevacizumab 15 mg/kg IV every 21 days
  • Atezolizumab
  • Bevacizumab

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:date at time of randomization up to 1 year
Safety Issue:
Description:Comparison of 1-year overall survival (OS) rates for cisplatin-ineligible patients

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:up to 24 months
Safety Issue:
Description: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
Measure:Duration of Response (DoR)
Time Frame:1 year
Safety Issue:
Description:The period measured from the time that measurement criteria are met for complete response until the first date that recurrent disease is objectively documented.
Measure:Disease Control Rate
Time Frame:up to 25 months
Safety Issue:
Description: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
Measure:Progression-Free Survival (PFS)
Time Frame:1 year
Safety Issue:
Description:A measurement from the date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs.
Measure:Assess Safety and Toxicity by CTCAEv4
Time Frame:2 years
Safety Issue:
Description:by CTCAEv4

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Arjun Balar, MD

Trial Keywords

  • Atezolizumab
  • MPDL3280A
  • Bevacizumab
  • Avastin
  • Cisplatin-Ineligible
  • Anti-PD-L1 Antibodies

Last Updated