Atezolizumab, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients with Metastatic and Muscle Invasive Bladder Cancer

Status: Active

Description

This pilot phase II trial studies the side effects of atezolizumab when given together with gemcitabine hydrochloride and cisplatin and how well it works in treating patients with bladder cancer that has spread to other parts of the body and the muscle. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, gemcitabine hydrochloride, and cisplatin may work better in treating bladder cancer.

Eligibility Criteria

Inclusion Criteria

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count >= 1500 cells/mm^3 (within 14 days of enrollment)
  • Lymphocyte count >= 300/mm^3 (within 14 days of enrollment)
  • Platelets >= 100,000 cells/mm^3 (within 14 days of enrollment)
  • Hemoglobin >= 9.0 g/dL (within 14 days of enrollment)
  • Bilirubin =< 1.5 the upper limit of normal (ULN) for the institution (within 14 days of enrollment) * 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 (within 14 days of enrollment) * 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 (within 14 days of enrollment) * 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 (within 14 days of enrollment)
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN if not on therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose (within 14 days of enrollment)
  • METASTATIC SAFETY 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 formalin-fixed paraffin-embedded (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 Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 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 (eGFR) >= 60 ml/min/1.73m^2 using the chronic kidney disease (CKD)-epidemiology (EPI) equation
  • NEOADJUVANT 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 examination under anesthesia [EUA])
  • Clinical stage T2-4a; N0/X; M0
  • Medically appropriate candidate for radical cystectomy, as per Memorial Sloan-Kettering (MSK) or participating site attending urologic oncologist
  • Estimated glomerular filtration rate (eGFR) >= 50 ml/min/1.73m^2 using the CKD-EPI equation

Exclusion Criteria

  • Evidence of New York Heart Association (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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTACE) 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. quality of life (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 deoxyribonucleic acid (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 bacillus Calmette-Guerin (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 white blood cell (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
  • Adverse events (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%, fluocinolone 0.01%, desonide 0.05%, alclometasone 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-PD-L1 therapeutic antibody or pathway-targeting agents
  • Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-alpha 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
  • METASTATIC SAFETY COHORT EXCLUSION CRITERIA
  • 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)
  • NEOADJUVANT EXCLUSION CRITERIA
  • 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

Locations & Contacts

Connecticut

Hartford
Hartford Hospital
Status: Active
Contact: Jeffrey M. Kamradt
Phone: 860-249-6291

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Samuel A. Funt
Phone: 646-422-4558
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Samuel A. Funt
Phone: 646-422-4558

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Samuel A. Funt
Phone: 646-422-4558
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: Active
Contact: Arjun V. Balar
Phone: 212-731-5820
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Samuel A. Funt
Phone: 626-422-4558
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Samuel A. Funt
Phone: 646-422-4558
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Samuel A. Funt
Phone: 646-422-4558

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: Amir Mortazavi
Phone: 614-293-2886

Pennsylvania

Allentown
Lehigh Valley Hospital-Cedar Crest
Status: Active
Contact: Maged F. Khalil
Phone: 610-402-7880

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To test the safety of the chemotherapy and atezolizumab combination in the metastatic setting. (Metastatic safety cohort)

II. To determine the rate of pathologic downstaging < pT2; N0 in the neoadjuvant setting. (Neoadjuvant cohort)

SECONDARY OBJECTIVES:

I. To determine the clinical efficacy. (Metastatic safety cohort)

II. To determine safety and assess other parameters of clinical efficacy. (Neoadjuvant cohort)

EXPLORATORY OBJECTIVES:

I. To determine changes in immune microenvironment (immune infiltrate, PD-L1, T-cell receptor [TCR] repertoire, immune gene expression) that occur in research tumor biopsies in metastatic patients after atezolizumab alone, and after the addition of chemotherapy to atezolizumab. (Metastatic safety cohort)

II. To use whole exome and ribonucleic acid (RNA) sequencing to identify predicted neoantigens associated with response.

III. To determine whether baseline tumor infiltrating immune cells and PD-L1 expression are associated with response.

IV. To determine mediators of resistance by interrogating resistant tumors for immune cell subsets.

V. To determine whether changes in the peripheral T-cell phenotype and myeloid derived suppressor cell profiles before, during and after therapy are associated with response.

OUTLINE:

METASTATIC SAFETY COHORT: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day -14 of course 1 and day 8 of all subsequent cycles, dexamethasone IV on day 1 and orally (PO) on day 2, gemcitabine hydrochloride IV on days 1 and 8, and cisplatin IV on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with objective response, stable disease, or evidence of clinical benefit continue to receive atezolizumab every 21 days until disease progression or unacceptable toxicity.

NEOADJUVANT COHORT: Patients receive atezolizumab IV over 30-60 minutes on day -14 of course 1, and on day 8 and 21 days after the last dose of gemcitabine hydrochloride of all subsequent cycles. Patients also receive dexamethasone IV on day 1 and PO on day 2, gemcitabine hydrochloride IV on days 1 and 8, and cisplatin IV on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 weeks after chemotherapy, and every 3 months for 18 months, every 6 months for 18 months, and then yearly for up to 2 years after surgery.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Samuel A. Funt

Trial IDs

Primary ID 16-1428
Secondary IDs NCI-2017-00228, S16-02066
Clinicaltrials.gov ID NCT02989584