Intermittent Checkpoint Inhibitor Therapy In Patients With Advanced Urothelial Carcinoma

Phase 2

Terminated

Conditions: Urothelial Carcinoma

Interventions: Drug: Pembrolizumab
Drug: Atezolizumab
Drug: Durvalumab
Drug: Nivolumab
Drug: Avelumab

Registration Number: NCT04322643

Lead Sponsor: Case Comprehensive Cancer Center

Brief Summary: The purpose of this study is to test the safety and effectiveness of immunotherapy (checkpoint inhibitor therapy) in advanced bladder cancer when given intermittently. An unanswered question with the use of CPI (checkpoint inhibitor) is the duration of therapy required for optimal clinical benefit. In the absence of progressive disease or unacceptable toxicities, there are currently no specified criteria for treatment discontinuation. Strategies to reduce toxicity and maximize benefit require investigation. Thus, novel dosing schedules, early discontinuation considerations, and biomarkers of response are needed to identify patients who can sustain disease regression while off of therapy.

Detailed Description: A phase II study design to investigate the use of any CPI on an intermittent dosing schedule. Patients with advanced urothelial carcinoma (aUC) who treatment refractory or cisplatin ineligible will receive CPI of choice as per standard dosing. Patients who have initial \>/=10% tumor burden reduction will discontinue the CPI until they experience a \>/=20% disease progression following 24 weeks +/- 4 weeks of immunotherapy, at which time CPI therapy will be restarted.

All patients who do not meet criteria for the CPI intermittent phase of the study will be treated until unacceptable toxicity or RECIST-defined PD. Patients with RECIST-defined PD may continue CPI therapy at the discretion of the treating MD. These patients will continue with normal imaging every 12 weeks. In cases where a patient is continued on therapy after PD and develops subsequent PD (\> 20% increase in sum of target lesions compared to the initial PD tumor measurements, the patient will come off study).

Patients who meet criteria for the intermittent phase (i.e., have \>/=10% tumor burden reduction) will not receive CPI therapy. Imaging will continue per protocol (every 12 weeks from the initial date they stopped CPI therapy). Patients who have RECIST defined PD on the intermittent phase should reinitiate CPI therapy. Patients who have a subsequent decrease in tumor burden \>/=10% can then restart CPI therapy as per protocol.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

Inclusion Criteria

Men and women ≥ 18 years of age.
Histological confirmation of urothelial carcinoma (any histology)
Advanced or metastatic urothelial carcinoma.
Measurable disease as defined by RECIST 1.1 criteria
Has received at least 24 weeks (+/- 4 weeks) on CPI therapy per standard of care (SOC) for advanced urothelial carcinoma
Karnofsky Performance Score (KPS) ≥70% (for more information on KPS, please see: http://www.npcrc.org/files/news/karnofsky_performance_scale.pdf)
Willing and able to provide informed consent.
Laboratory criteria for study entry must meet the following criteria:
- Serum creatinine ≤ 2 x ULN OR CrCl ≥ 30 mL/min (measured or calculated using the Cockcroft-Gault formula).
- Hb ≥ 8.0g/dL
- AST and ALT ≤ 3.0 x ULN
- Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

Exclusion Criteria

History of severe hypersensitivity reaction to any monoclonal antibody.
Patients are excluded if they have known HIV/AIDS.
Major surgery (eg, cystectomy) less than 28 days prior to the first dose of study drug.
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 7 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
Pregnant women are excluded from this study because animal studies have demonstrated that PD-1/PD-L1 inhibitors can cause fetal harm when administered to pregnant women. Breastfeeding women are excluded from this study because PD-1/PD-L1 inhibitors may be excreted in human milk and the potential for serious adverse reactions in nursing infants.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
CPI therapy	Avelumab	Patients will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy.
CPI therapy	Durvalumab	Patients will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy.
CPI therapy	Pembrolizumab	Patients will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy.
CPI therapy	Atezolizumab	Patients will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy.
CPI therapy	Nivolumab	Patients will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy.

Primary Outcome Measures

Name	Time	Method
Number of Participants That Sustain a Response Post CPI Suspension	At 36 weeks post CPI suspension	Efficiency, as measured by number of participants that sustain a response post CPI suspension. Response is defined as tumor burden reduction of 10% or greater. Response is measured based on RECIST criteria version 1.1. RECIST 1.1 responses include Complete Response (CR) which is defined as disappearance of all lesions and pathologic lymph nodes; Partial Response (PR) defined as ≥ 30% decrease SLD, no new lesions, no progression of non-target lesions; Stable disease (SD) which is defined as no partial or complete responses; or Progressive disease (PD) defined as ≥ 20% increase SLD compared to smallest SLD in study, or progression of non-target lesions, or new lesions.

Secondary Outcome Measures

Name	Time	Method
Median Treatment Free Interval (TFI) in Weeks	Up to 36 weeks from end of treatment, through study completion an average of 160 weeks	Median and range TFI in months. Participants will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy. Participants with a documented increase in ≥ 20% tumor burden (RECIST 1.1 PD) will re-initiate CPI. For those patients who continue to have response, they will remain off therapy.
Overall Response Rate (ORR)	Up to 36 weeks from end of treatment, through study completion an average of 160 weeks	Response to re-initiation of CPI therapy as measured by overall response rate (ORR) defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by RECIST 1.1
Number of Participants With Progression Free Survival (PFS)	Up to 36 weeks from end of treatment, through study completion an average of 160 weeks	Progression free survival (PFS) defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first as assessed by RECIST 1.1 criteria. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions is also considered PD.
Number of Participants With Overall Survival (OS)	Up to 36 weeks from end of treatment, through study completion an average of 160 weeks	Overall Survival (OS) defined as the time from randomization to death due to any cause