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Atezolizumab and Guadecitabine in Treating Patients with Advanced or Metastatic Urothelial Cancer

Trial Status: Temporarily Closed to Accrual

This phase II trial studies the side effects and best dose of atezolizumab and guadecitabine and how well they work in treating patients with urothelial cancer that has spread to other places in the body. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Guadecitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab and guadecitabine together may work betting in treating patients with urothelial cancer.

Inclusion Criteria

  • Patients must have histologically confirmed urothelial carcinoma that is advanced or metastatic
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v.) 1.1 and >= 1 site safe for biopsy
  • Patient must agree to provide fresh biopsy specimens and peripheral blood samples at the time of screening and during the study
  • Patients must have received or be ineligible for platinum based chemotherapy and must have received at least one line of therapy with a PD-L1 or PD-1 targeting agent
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Life expectancy >= 12 weeks
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin > 9 g/dl (blood transfusion is allowed to meet the eligibility criteria as long as post transfusion hemoglobin is maintained at >= 9.0 g/dL for 7 days or longer)
  • Total bilirubin =< 2.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times institutional normal limits unless liver metastases are present in which case AST and ALT must be =< 5 x IULN
  • Creatinine within normal institutional limits OR creatinine clearance >= 30 Ml/min (Cockcroft-Gault formula or measured with 24 hour [h] urine)
  • International normalized ratio (INR) or partial thromboplastin time (PTT)/prothrombin time (PT) =< 1.5 ULN, unless the patient is on stable therapeutic dose of warfarin
  • Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
  • Women of child bearing potential and men must agree to remain abstinent or use adequate contraception (failure rate < 1%) for the duration of study and for 90 days after the completion of the therapy

Exclusion Criteria

  • Patients who have had anti-cancer therapy within 2 weeks prior to entering the study
  • Patients receiving any other investigational agents
  • Patients with active or untreated central nervous system (CNS) disease; patients previously treated for CNS disease must be asymptomatic and must not be using steroids for at least 4 weeks prior to starting the study treatment
  • Patients with active auto-immune disease requiring immunosuppressive medication
  • Patients treated with systemic immunostimulatory agents (such as interferons, IL 12) within 6 weeks of the start of the treatment or 5 half-lives of the drug, whichever is shorter
  • Treatment with systemic corticosteroids within 2 weeks prior to the start of the treatment; patients that require inhaled or low-dose corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, mineralocorticoids are allowed
  • Patients with active malignancies in addition to urothelial carcinoma
  • Patients with prior treatment with hypomethylating agents
  • History of leptomeningeal disease
  • Prior allogeneic stem cell or solid organ transplant
  • Uncontrolled effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
  • Uncontrolled symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dl or corrected serum calcium > ULN)
  • Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiography (ECG)s using Frediricia’s correction
  • Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1 except for endocrine adverse events (AEs) managed with replacement therapy; any other AEs unresolved toxicities grade 2 or more from previous anti-cancer therapy, except alopecia, peripheral neuropathy or non-clinically significant lab abnormalities
  • Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to the start of the study treatment
  • Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis)
  • History of severe allergic, anaphylactic or hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterations), drug-induced pneumonitis or idiopathic pneumonitis or evidence of interstitial lung disease or active non-infectious pneumonitis
  • Active tuberculosis
  • Known hypersensitivity to Chinese hamster ovary cell products or any of the study drugs
  • Administration of a live, attenuated vaccine within 4 weeks of the start of treatment or anticipation that such a live, attenuated vaccine will be required during the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  • Pregnant or breast feeding

California

Los Angeles
USC / Norris Comprehensive Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: David Ian Quinn
Phone: 323-865-3956

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Noah M. Hahn
Phone: 443-287-2886

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Elizabeth R. Plimack
Phone: 215-728-3889

PRIMARY OBJECTIVES:

I. To determine a safe and tolerable dose of guadecitabine and atezolizumab combination therapy (safety run-in phase).

II. To evaluate the efficacy of the combination therapy in patients with advanced urothelial cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the overall survival rate in patients with advanced urothelial cancer treated with guadecitabine and atezolizumab combination therapy.

II. Progression free survival in patients with advanced urothelial cancer treated with guadecitabine and atezolizumab combination therapy.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 60 minutes on days 1 and 22. Treatment repeats every 42 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients also receive guadecitabine subcutaneously (SC) on days 1-5. Treatment repeats every 42 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and every 6 months for 1 year.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Fox Chase Cancer Center

Principal Investigator
Elizabeth R. Plimack

  • Primary ID 17-1039
  • Secondary IDs NCI-2017-01917, GU-114
  • Clinicaltrials.gov ID NCT03179943