Clinical Trials /

Atezolizumab + Guadecitabine in Patients With Checkpoint Inhibitor Refractory or Resistant Urothelial Carcinoma

NCT03179943

Description:

This is a single arm Phase II study with a safety run-in to identify the recommended phase II dose of the combination therapy of atezolizumab and guadecitabine. Patients with recurrent/advanced urothelial carcinoma (stage IV) who had previously progressed on check-point inhibitor therapy with PD-1 or PD-L1 targeting agents are eligible for this study. After a dose that is safe and tolerable has been established, a dose expansion phase (Phase II) will begin. This study will enroll a total of 4 to 53 patients depending upon the number of patients treated in the safety run-in phase and the number of subjects replaced during the phase II portion.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab + Guadecitabine in Patients With Checkpoint Inhibitor Refractory or Resistant Urothelial Carcinoma
  • Official Title: GU-114: Overcoming Checkpoint Inhibitor Resistance With Epigenetic Therapy in Urothelial Cancer

Clinical Trial IDs

  • ORG STUDY ID: GU-114
  • SECONDARY ID: SU2C-AACR-CT08-17
  • NCT ID: NCT03179943

Conditions

  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab + Guadecitabine
GuadecitabineAtezolizumab + Guadecitabine

Purpose

This is a single arm Phase II study with a safety run-in to identify the recommended phase II dose of the combination therapy of atezolizumab and guadecitabine. Patients with recurrent/advanced urothelial carcinoma (stage IV) who had previously progressed on check-point inhibitor therapy with PD-1 or PD-L1 targeting agents are eligible for this study. After a dose that is safe and tolerable has been established, a dose expansion phase (Phase II) will begin. This study will enroll a total of 4 to 53 patients depending upon the number of patients treated in the safety run-in phase and the number of subjects replaced during the phase II portion.

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab + GuadecitabineExperimental
  • Atezolizumab
  • Guadecitabine

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have histologically confirmed urothelial carcinoma that is advanced or
             metastatic.

          2. Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension in accordance with RECIST criteria v.
             1.1 and ≥ 1 site safe for biopsy.

          3. Patient must agree to provide fresh biopsy specimens and peripheral blood samples at
             the time of screening and during the study.

          4. 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.

          5. Age > 18 years.

          6. ECOG performance status ≤ 2

          7. Life expectancy ≥ 12 weeks

          8. Patients must have normal organ and marrow function as defined below

               -  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).

               -  AST/ALT (SGOT/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 24h
                  urine)

               -  INR or PTT/PT ≤ 1.5 ULN unless patient is on stable therapeutic dose of warfarin

          9. Ability to understand and willingness to sign a written informed consent and HIPAA
             consent document

         10. 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:

          1. Patients who have had anti-cancer therapy within 2 weeks prior to entering the study.

          2. Patients receiving any other investigational agents

          3. Patients with active or untreated 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.

          4. Patients with active auto-immune disease requiring immunosuppressive medication.

          5. 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.

          6. Treatment with systemic corticosteroids within 2 weeks prior to the start of the
             treatment. Patients that require inhaled or low-dose corticosteroids for COPD or
             asthma, mineralocorticoids are allowed.

          7. Patients with active malignancies in addition to urothelial carcinoma.

          8. Patients with prior treatment with hypomethylating agents.

          9. History of leptomeningeal disease

         10. Prior allogeneic stem cell or solid organ transplant.

         11. Uncontrolled effusion, pericardial effusion, or ascites requiring recurrent drainage
             procedures (once monthly or more frequently)

         12. Uncontrolled symptomatic hypercalcemia (>1.5mmol/L ionized calcium or calcium >
             12mg/dl or corrected serum calcium > ULN)

         13. Mean QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 3 ECGs using
             Frediricia's correction.

         14. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1 except for endocrine 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.

         15. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to the start of the
             study treatment.

         16. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease,
             ulcerative colitis)

         17. History of severe allergic, anaphylactic or hypersensitivity reactions to chimeric or
             humanized antibodies or fusion proteins.

         18. 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.

         19. Active tuberculosis

         20. Known hypersensitivity to Chinese hamster ovary cell products or any of the study
             drugs.

         21. 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.

         22. 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.

         23. Known HIV-positive patients on combination antiretroviral therapy are ineligible.

         24. Known history of HBV or HCV infection.

         25. Pregnant or breast feeding.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of Guadecitabine in combination of Atezolizumab in safety run-in phase
Time Frame:2-3 months
Safety Issue:
Description:Dose de-escalation study based on standard 3+3 design will be conducted to test two dose levels of guadecitabine: 45mg/m2 and 36mg/m2 to determine MTD

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

Trial Keywords

  • bladder cancer
  • Ureteral Cancer
  • Urothelial cancer
  • Urethral cancer

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