Clinical Trials /

A Phase II Study of Atezolizumab in Combination With Cisplatin + Gemcitabine Before Surgery to Remove the Bladder Cancer

NCT02989584

Description:

The purpose of this study is to test the safety of the study drug, atezolizumab, when combined with the standard chemotherapy drugs, gemcitabine and cisplatin (or GC). This study will help researchers begin to understand whether combining GC with atezolizumab is better, the same, or worse than the usual approach of using GC alone.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II Study of Atezolizumab in Combination With Cisplatin + Gemcitabine Before Surgery to Remove the Bladder Cancer
  • Official Title: A Pilot Safety Study and Single Arm Phase II Study of Gemcitabine and Cisplatin With Atezolizumab (MPDL3280A) in Patients With Metastatic and Muscle Invasive Bladder Cancer, Respectively

Clinical Trial IDs

  • ORG STUDY ID: 16-1428
  • NCT ID: NCT02989584

Conditions

  • Bladder Cancer
  • Metastatic Bladder Cancer
  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab, Gemcitabine, Cisplatin
GemcitabineAtezolizumab, Gemcitabine, Cisplatin
CisplatinAtezolizumab, Gemcitabine, Cisplatin

Purpose

The purpose of this study is to test the safety of the study drug, atezolizumab, when combined with the standard chemotherapy drugs, gemcitabine and cisplatin (or GC). This study will help researchers begin to understand whether combining GC with atezolizumab is better, the same, or worse than the usual approach of using GC alone.

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab, Gemcitabine, CisplatinExperimentalThis is a two phase study with a single study arm for each phase. For Phase 1: Following enrollment participants will be treated with combination therapy on a 21 day cycle x 6 cycles. Gemcitabine (1000 mg/m2 on Day 1 and Day 8), cisplatin (70 mg/m2 on Day 1), and atezolizumab (1200 mg on Day 8) will be administered intravenously. Phase 2: Following enrollment participants will be treated with a single dose of atezolizumab alone followed by combination therapy on a 21-day cycle x 4 cycles, followed by a single dose of atezolizumab alone. Gemcitabine 1000mg/m2, cisplatin (70 mg/m2 on Day 1), and atezolizumab (1200 mg on Day 8) will be administered intravenously.
  • Atezolizumab
  • Gemcitabine
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years

          -  ECOG Performance Status of 0 or 1

          -  Required Initial Laboratory Values within 14 days of enrollment:

               -  Absolute Neutrophil Count ≥ 1500 cells/mm^3

               -  Lymphocyte count ≥ 300/mm^3

               -  Platelets ≥ 100,000 cells/mm^3

               -  Hemoglobin ≥ 9.0 g/dL

               -  Bilirubin ≤ 1.5 the upper limit of normal (ULN) for the institution For patients
                  with known Gilbert's disease: bilirubin ≤ 3 x ULN

               -  Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN for the
                  institution.

                    -  For patients in the metastatic cohort with documented liver or bone
                       metastases: AST and/or ALT ≤ 5.0 x ULN

               -  Alkaline phosphatase ≤ 2.5 x ULN for the institution

                    -  For patients in the metastatic cohort with documented liver or bone
                       metastases: alkaline phosphatase ≤ 5 x ULN

               -  If female of childbearing potential, urine pregnancy test is negative.

               -  INR and aPTT ≤ 1.5 x ULN if not on therapeutic anticoagulation. Patients
                  receiving therapeutic anticoagulation should be on a stable dose.

        Phase I Cohort

          -  Archival tumor specimens must be submitted prior to enrollment. Samples collected from
             fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases,
             and lavage are not acceptable. Acceptable samples include core-needle biopsies for
             deep tumor tissue (minimum of three cores) or excisional, incisional, punch, or
             forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. If archival tissue
             is being used, representative urothelial carcinoma FFPE tumor specimens (tumor blocks
             or 30 unstained slides) must be provided. Patients with < 30 slides may be enrolled
             after discussion with the principal investigator. Primary or metastatic specimens may
             be submitted.

          -  Subject must agree to undergo two research-directed biopsies during treatment.

          -  The patient must have measurable disease according to RECIST v1.1 and must have one
             site amenable to biopsy that, in the opinion of the investigator and/or interventional
             radiologist, is likely to yield acceptable tumor sample for a core biopsy per the
             above pathology criteria.

          -  Life expectancy ≥ 12 weeks

          -  Histologically or cytologically confirmed urothelial carcinoma (confirmed at the
             enrolling institution) of the bladder, ureter, urethra, or renal pelvis. Patients with
             mixed histologies are required to have a predominant urothelial component as reviewed
             by the pathologist at the treating institution.

          -  Locally advanced (T4b, any N; any T, N2-3) or metastatic (M1) disease as determined by
             the treating investigator

          -  Estimated glomerular filtration rate ≥ 60 ml/min/1.73m2 using the CKD- EPI equation:
             eGFR = 141 x min(Scr/k, 1)a x max(Scr/k, 1)-1.209 x 0.993Age°x 1.018 [if female] x
             1.159 [if black] Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is
             -0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and
             max indicates the maximum of Scr/k or 1

        Phase 2 Cohort

          -  Pathology: Representative urothelial carcinoma FFPE tumor specimens (tumor blocks or
             30 unstained slides). Patients with < 30 slides may be enrolled after discussion with
             the principal investigator.

          -  Muscle invasive urothelial carcinoma of the bladder histologically confirmed at the
             enrolling institution. (Urothelial carcinoma invading into the prostatic stroma with
             no histologic muscle invasion is allowed provided the extent of disease is confirmed
             via imaging and/or EUA.)

          -  Clinical stage T2-4a;N0/X;M0

          -  Medically appropriate candidate for radical cystectomy, as per MSK or participating
             site Attending Urologic Oncologist

          -  Estimated glomerular filtration rate ≥ 60 ml/min/1.73m2 using the CKD- EPI equation:
             eGFR = 141 x min(Scr/k, 1)a x max(Scr/k, 1)-1.209 x 0.993Age°x 1.018 [if female] x
             1.159 [if black] Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is
             -0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and
             max indicates the maximum of Scr/k or 1

        Exclusion Criteria:

          -  Evidence of NYHA functional class III or IV heart disease

          -  Serious intercurrent medical or psychiatric illness, including serious active
             infection

          -  Preexisting sensory grade ≥ 2 neuropathy

          -  Preexisting grade ≥ 2 hearing loss

          -  Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
             need for a major surgical procedure during the course of the study. Transurethral
             resection or other urinary tract diagnostic procedures, excisional biopsy, or MediPort
             placement, are NOT defined as major surgical procedures.

          -  Any of the following within the 6 months prior to study drug administration:
             myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
             graft, symptomatic congestive heart failure, cerebrovascular accident, or transient
             ischemic attack

          -  Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.0 grade ≥ 2. However, stable
             atrial fibrillation controlled medically or with a device (e.g. pacemaker) or prior
             ablation is allowed.

          -  History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency
             syndrome (AIDS)-related illness

          -  Concurrent treatment on another clinical trial; supportive care trials or
             non-treatment trials, e.g. QOL, are allowed

          -  Pregnancy, lactation, or breast-feeding. Patients must be surgically sterile,
             postmenopausal, or must agree to use effective contraception during the period of
             therapy and for 5 months after the last dose of atezolizumab. The definition of
             effective contraception will be based on the judgment of the principal investigator or
             a designated associate. Male patients must be surgically sterile or agree to use
             effective contraception. Male patients will be encouraged to notify the study team if
             their female partner becomes pregnant while on study.

          -  History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, Wegener's granulomatosis, vascular thrombosis associated
             with antiphospholipid syndrome, Sjogren's syndrome, Guillain-Barre syndrome, multiple
             sclerosis, systemic vasculitis, or glomerulonephritis.

               -  Patients with history of autoimmune related hypothyroidism on stable dose of
                  thyroid replacement hormone may be eligible for this study

               -  Patients with controlled Type I diabetes mellitus on a stable dose of insulin may
                  be eligible for this study

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan

               -  History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

          -  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
             antibody

               -  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. HBV DNA must be obtained in these patients prior to Cycle 1, Day

                  1 and confirmed to be negative.

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction is negative for HCV RNA.

          -  Active tuberculosis or BCG infection

          -  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 infection within 2 weeks prior to Cycle 1, Day 1. Abnormal
             urinalysis does not constitute signs/symptoms of infection unless urine culture
             obtained at screening grows ≥ 100,000 colonies of bacteria. Patients with an ileal
             conduit and a urinalysis and/or culture that are abnormal are eligible unless they
             have peripheral blood WBC > ULN, fever, or other symptoms suggestive of a urinary
             tract infection.

          -  Therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1

               -  Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
                  tract infection or to prevent chronic obstructive pulmonary disease exacerbation)
                  are eligible.

          -  Prior allogeneic stem cell or solid organ transplant

          -  Administration of intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before
             Cycle 1, Day 1

          -  Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
             anticipation that such a live attenuated vaccine will be required during the study.

               -  Influenza vaccination should be given during influenza season only (approximately
                  October to March). Patients must not receive live, attenuated influenza vaccine
                  (e.g., FluMist ®) within 4 weeks prior to Cycle 1, Day 1 or at any time during
                  the study.

          -  AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for
             alopecia

          -  Bisphosphonate therapy for symptomatic hypercalcemia

               -  Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
                  osteoporosis) is allowed.

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; and inherited liver disease

          -  Patients with a history of or active bone marrow disorders expected to interfere with
             study therapy (e.g. acute leukemias, accelerated/blast-phase chronic myelogenous
             leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or
             non-secretory myeloma)

          -  Known primary central nervous system (CNS) malignancy, active or untreated CNS
             metastases, symptomatic CNS metastases, and/or leptomeningeal disease

          -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
             dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
             excluded) are permitted provided that they meet the following conditions:

               -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
                  ocular manifestations

               -  Rash must cover less than 10% of body surface area (BSA)

               -  Disease is well controlled at baseline and only requiring low potency topical
                  steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone
                  0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

               -  No acute exacerbations of underlying condition within the last 12 months (not
                  requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids,
                  biologic agents, oral calcineurin inhibitors; high potency or oral steroids)

          -  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

          -  Malignancies other than the disease under study within 5 years prior to Cycle 1, Day
             1, with the exception of those with a negligible risk of metastasis or death and with
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, localized prostate cancer treated surgically with
             curative intent, or ductal carcinoma in situ treated surgically with curative intent)
             or undergoing active surveillance per standard-of-care management (e.g. prostate
             cancer with Gleason score ≤ 6, and prostate-specific antigen [PSA] 10 mg/mL, etc).

        Medication-Related Exclusion Criteria:

          -  Prior treatment with anti-PD-1, and CTLA-4, or anti-a PD-L1 therapeutic antibody or
             pathway-targeting agents

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferon [IFN]-a or interleukin [IL]-2) within 6 weeks or five half-lives of the
             drug (whichever is shorter) prior to Cycle 1, Day 1

          -  Concomitant use of another investigational agent and/or treatment with an
             investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five
             half-lives of the investigational product, whichever is longer)

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1

               -  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 or mineralocorticoids (e.g., fludrocortisone)
                  for patients with orthostatic hypotension or adrenocortical insufficiency is
                  allowed.

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Known hypersensitivity to Chinese hamster ovary cell products or any component of the
             atezolizumab formulation

        Phase I Cohort

          -  Prior chemotherapy or immunotherapy for metastatic urothelial bladder cancer. Prior
             neoadjuvant or adjuvant chemotherapy with first progression > 12 months is allowed.

          -  Any approved anti-cancer therapy within 3 weeks prior to enrollment with the following
             exceptions:

               -  Palliative radiotherapy for bone metastases must be completed > 7 days prior to
                  baseline imaging and > 21 days prior to cycle 1 day 1 of treatment.

               -  Hormone replacement therapy or oral contraceptives are permitted

               -  Administration of intravesical bacillus Calmette-Guerin (BCG) >4 weeks before
                  Cycle 1, Day 1 is allowed

          -  Tumor-related pain increased above baseline for 2 weeks and not controlled by a stable
             dose of opiates

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites (indwelling drainage
             catheters allowed)

        Phase 2 Cohort

          -  Prior systemic chemotherapy (prior intravesical therapy is allowed)

          -  Prior radiation therapy to the bladder

          -  Any approved anti-cancer therapy within 3 weeks prior to enrollment

          -  Administration of intravesical bacillus Calmette-Guerin (BCG) >4 weeks before Cycle 1,
             Day 1 is allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Test the safety of atezolizumab in combination with gemcitabine/cisplatin as assessed by dose limiting toxicity rate.
Time Frame:Participants will be followed for survival until 5 years from treatment completion or until disease recurrence/progression.
Safety Issue:
Description:CTCAE version 4.0 will be used for all patients on this trial for evaluation of toxicities during systemic therapy.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • bladder cancer
  • metastatic bladder cancer
  • atezolizumab
  • urothelial carcinoma

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