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

NCT03179943 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: GU-114SU2C-AACR-CT08-17
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Urothelial Carcinoma

Keywords

bladder cancer; Ureteral Cancer; Urothelial cancer; Urethral cancer

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose of Guadecitabine in combination of Atezolizumab in safety run-in phase

  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

  2-3 months

• Objective Response Rate (RECIST v 1.1) in Phase II

  2 years

Secondary Outcomes (2)

• Overall Survival

  2 years

• Progression Free Survival

  2 years

Study Arms (1)

Atezolizumab + Guadecitabine

EXPERIMENTAL

Drug: Atezolizumab; Drug: Guadecitabine

Interventions

Atezolizumab DRUG

Patients will be administered atezolizumab intravenously on day 1 and day 22 of a 6 week cycle for the period of 8 cycles.

Atezolizumab + Guadecitabine

Guadecitabine DRUG

Guadecitabine will be administered subcutaneously on days 1 through 5 of the 6 week cycle for the period of 4 cycles

Atezolizumab + Guadecitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 RECIST criteria 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.
• Age \> 18 years.
• ECOG performance status ≤ 2
• Life expectancy ≥ 12 weeks
• 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

You may not qualify if:

• 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 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 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 (\>1.5mmol/L ionized calcium or calcium \> 12mg/dl or corrected serum calcium \> ULN)
• Mean QT interval corrected for heart rate (QTc) ≥ 470ms calculated from 3 ECGs 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 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.

Sponsors & Collaborators

• Fox Chase Cancer Center: lead
• Stand Up To Cancer: collaborator
• Van Andel Research Institute: collaborator

Study Sites (3)

USC Norris Hospital and Clinics

Los Angeles, California, 90033, United States

Location

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21287, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Ureteral Neoplasms; Urethral Neoplasms

Interventions

atezolizumab; guadecitabine

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Ureteral Diseases; Urethral Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2017
• First Posted: June 7, 2017
• Study Start: November 27, 2017
• Primary Completion: July 12, 2020
• Study Completion: July 1, 2022
• Last Updated: November 4, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)