Clinical Trials /

Intermittent Checkpoint Inhibitor Therapy In Patients With Advanced Urothelial Carcinoma

NCT04322643

Description:

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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intermittent Checkpoint Inhibitor Therapy In Patients With Advanced Urothelial Carcinoma
  • Official Title: A Phase II Study of Intermittent Checkpoint Inhibitor Therapy in Patients With Advanced Urothelial Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: CASE6819
  • NCT ID: NCT04322643

Conditions

  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDACPI therapy
AtezolizumabTECENTRIQCPI therapy
DurvalumabIMFINZICPI therapy
NivolumabOPDIVOCPI therapy
AvelumabBAVENCIOCPI therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
CPI therapyExperimentalPatients 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.
  • Pembrolizumab
  • Atezolizumab
  • Durvalumab
  • Nivolumab
  • Avelumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants that sustain a response post CPI suspension
Time Frame:at 36 weeks post CPI suspension
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Median Treatment Free Interval (TFI) in months
Time Frame:up to 36 weeks from end of treatment, an average of 24 weeks
Safety Issue:
Description: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.
Measure:Overall response rate (ORR)
Time Frame:up to 36 weeks from end of treatment, an average of 24 weeks
Safety Issue:
Description: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
Measure:Progression free survival (PFS)
Time Frame:up to 36 weeks from end of treatment, an average of 24 weeks
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:up to 36 weeks from end of treatment, an average of 24 weeks
Safety Issue:
Description:Overall Survival (OS) defined as the time from randomization to death due to any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Last Updated

March 24, 2020