Clinical Trials /

Trying to Find the Correct Length of Treatment With Immune Checkpoint Therapy

NCT04637594

Description:

This phase III trial compares survival in urothelial cancer patients who stop immune checkpoint inhibitor treatment after being treated for about a year to those patients who continue treatment with immune checkpoint inhibitors. Immunotherapy with monoclonal antibodies, such as avelumab, durvalumab, pembrolizumab, atezolizumab, and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stopping immune checkpoint inhibitors early may still make the tumor shrink and patients may have similar survival rates as the patients who continue treatment. Stopping treatment early may also lead to fewer treatment-related side effects, an improvement in mental health, and a lower cost burden to patients.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Trying to Find the Correct Length of Treatment With Immune Checkpoint Therapy
  • Official Title: Duration of Immune Checkpoint Therapy in Locally Advanced or Metastatic Urothelial Carcinoma: A Randomized Phase 3 Non-Inferiority Trial

Clinical Trial IDs

  • ORG STUDY ID: A031901
  • SECONDARY ID: NCI-2020-08395
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04637594

Conditions

  • Locally Advanced Bladder Urothelial Carcinoma
  • Locally Advanced Renal Pelvis Urothelial Carcinoma
  • Locally Advanced Ureter Urothelial Carcinoma
  • Locally Advanced Urethral Urothelial Carcinoma
  • Locally Advanced Urothelial Carcinoma
  • Metastatic Bladder Urothelial Carcinoma
  • Metastatic Renal Pelvis Urothelial Carcinoma
  • Metastatic Ureter Urothelial Carcinoma
  • Metastatic Urethral Urothelial Carcinoma
  • Metastatic Urothelial Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabArm A (immune checkpoint inhibitor)
NivolumabArm A (immune checkpoint inhibitor)
AtezolizumabArm A (immune checkpoint inhibitor)
DurvalumabArm A (immune checkpoint inhibitor)
AvelumabArm A (immune checkpoint inhibitor)

Purpose

This phase III trial compares survival in urothelial cancer patients who stop immune checkpoint inhibitor treatment after being treated for about a year to those patients who continue treatment with immune checkpoint inhibitors. Immunotherapy with monoclonal antibodies, such as avelumab, durvalumab, pembrolizumab, atezolizumab, and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stopping immune checkpoint inhibitors early may still make the tumor shrink and patients may have similar survival rates as the patients who continue treatment. Stopping treatment early may also lead to fewer treatment-related side effects, an improvement in mental health, and a lower cost burden to patients.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare overall survival (OS).

      SECONDARY OBJECTIVES:

      I. To compare progression free survival (PFS) by (Response Evaluation Criteria in Solid
      Tumors) RECIST 1.1 criteria.

      II. To compare PFS by immune-related (ir)RECIST criteria. III. To determine treatment-free
      interval (TFI) after immune checkpoint inhibitor (ICI) discontinuation. (Arm B) IV. To
      determine the rate of response by RECIST 1.1 criteria after ICI rechallenge. (Arm B) V. To
      assess adverse events in each study arm by Common Terminology Criteria for Adverse Events
      (CTCAE) 5.0.

      OUTLINE: Patient are randomized to 1 of 2 arms.

      ARM A (CONTINUATION OF ICI TREATMENT): Patients receive either pembrolizumab intravenously
      (IV) over 30 minutes on day 1, nivolumab IV over 30 minutes on days 1 and 15, atezolizumab IV
      over 30-60 minutes on day 1, durvalumab IV over 60 minutes on days 1 and 15, or avelumab IV
      over 60 minutes on days 1 and 15. Cycles repeat every 21 or 42 days for pembrolizumab, every
      21 days for atezolizumab, and 28 days for nivolumab, durvalumab, and avelumab in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, starting new treatment or withdrawn consent, patients
      are followed up at 4 weeks, and then every 6 months for 5 years following registration.

      ARM B (DISCONTINUATION OF ICI TREATMENT): Patients receiving ICI treatment will discontinue
      ICI treatment within 1 cycle length after randomization. Cycle length is determined by the
      ICI regimen the patient is receiving at randomization. At disease progression patients may
      restart the same ICI treatment they were receiving upon randomization at physician
      discretion.

      After initiation of new treatment (after ICI rechallenge or without ICI rechallenge), or
      progression (after ICI rechallenge or without ICI rechallenge), patients are followed up at 4
      weeks, and then every 6 months for 5 years following registration.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (immune checkpoint inhibitor)Active ComparatorCONTINUATION OF ICI TREATMENT: Patients receive either pembrolizumab intravenously (IV) over 30 minutes on day 1, nivolumab IV over 30 minutes on days 1 and 15, atezolizumab IV over 30-60 minutes on day 1, durvalumab IV over 60 minutes on days 1 and 15, or avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 21 or 42 days for pembrolizumab, every 21 days for atezolizumab, and 28 days for nivolumab, durvalumab, and avelumab in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Nivolumab
  • Atezolizumab
  • Durvalumab
  • Avelumab
Arm B (immune checkpoint inhibitor)ExperimentalDISCONTINUATION OF ICI TREATMENT: Patients receiving ICI treatment will discontinue ICI treatment within 1 cycle length after randomization. Cycle length is determined by the ICI regimen the patient is receiving at randomization. At disease progression patients may restart the same ICI treatment they were receiving upon randomization at physician discretion.
  • Pembrolizumab
  • Nivolumab
  • Atezolizumab
  • Durvalumab
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          -  Documentation of disease

               -  Histologic documentation: Histologically or cytologically confirmed urothelial
                  carcinoma (UC) with predominantly transitional-cell features

               -  Stage: Locally advanced or metastatic disease prior to starting immune checkpoint
                  blockade

               -  Tumor Site: Bladder, renal pelvis, ureter, or urethra

          -  Patients must be receiving current active treatment with standard of care (SOC) Food
             and Drug Administration (FDA) approved PD-1/L1 immune checkpoint inhibitor
             (ICI)-containing therapy for locally advance or metastatic UC

          -  Radiographic response 12-15 months after starting ICI-containing treatment, defined as
             any percent decrease in target and/or non-target lesion(s) criteria that is confirmed
             by repeat assessment(s) no less than 4 weeks after the criteria for response are first
             met without evidence of progressive disease

          -  Adequate bone marrow and organ functions to continue PD-1/L1 ICI as judged by the
             treating physician

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Central nervous system (CNS) metastasis is allowed if radiographically stable,
             clinically asymptomatic, and prior local therapy (if received) was completed > 6
             months before registration

        Exclusion Criteria:

          -  No toxicity from ICI therapy that makes continuation of treatment clinically
             unacceptable

          -  No history of tuberculosis, active hepatitis B (HBV) or hepatitis C (HCV), or
             uncontrolled human immunodeficiency virus (HIV)

               -  Patients with resolved HBV infection, defined as positive hepatitis B core
                  antibody (anti-Hb) and negative hepatitis B surface antigen (HbsAg), are eligible

               -  Patients with positive HCV antibody are eligible if HCV ribonucleic acid (RNA)
                  polymerase chain reaction (PCR) is negative

               -  Patients with HIV who are compliant with highly active antiretroviral therapy
                  (HAART) and have normal CD4 count and undetectable viral load are eligible

          -  No history of allogeneic organ transplantation

          -  No current immunosuppressive medication exceeding 10 mg/day of prednisone or its
             equivalent

             * Patients with pre-existing or treatment-emergent autoimmune or inflammatory
             disorders which do not require systemic immunosuppressive treatment exceeding 10
             mg/day of prednisone or its equivalent may be included

          -  No history of another primary malignancy except for malignancy treated with curative
             intent with no known active disease for >= 2 years, and adequately treated
             non-melanomatous skin cancer or carcinoma in situ (e.g. cervical carcinoma in situ
             [CIS]) without evidence of disease

          -  No female patients who are pregnant or breastfeeding, or male or female patients of
             reproductive potential who are not willing to employ effective birth control, because
             this study involves investigational agents whose genotoxic, mutagenic, and teratogenic
             effects on the developing fetus and newborn are unknown. Therefore, for women of
             childbearing potential only, a negative urine or serum pregnancy test pregnancy test
             done =< 14 days prior to registration is required
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From randomization until death due to any cause, assessed up to 5 years
Safety Issue:
Description:OS is the length of time patients are alive after registering to receive protocol treatment. Patients who are lost to follow-up or are not known to be deceased at the time of study analysis will be censored at the time of last patient contact. Cox models will be used to compare the outcome between the two treatment groups.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From randomization until disease progression or death due to any cause, assessed up to 5 years
Safety Issue:
Description:Progression-free survival (PFS) is the length of time patients are alive without disease progression. Progression will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Stratified Cox models will be used to compare the outcomes between the two treatment groups.
Measure:Immune-related progression-free survival (iPFS)
Time Frame:From randomization until disease progression as assessed by irRECIST criteria or death due to any cause, assessed up to 5 years
Safety Issue:
Description:Immune-related progression-free survival (iPFS) is the length of time patients are alive without immune-related progression. Progression will be assessed using immune related (ir)RECIST criteria. Stratified Cox models will be used to compare the outcomes between the two treatment groups.
Measure:Treatment-free interval (Arm B)
Time Frame:From last dose of immune checkpoint inhibitor (ICI) to initiation of a subsequent systemic treatment or death, assessed up to 5 years
Safety Issue:
Description:Treatment-free Interval is the length of time patients are off treatment. A Stratified Cox model will be used to evaluate this outcome.
Measure:Rate of response after immune checkpoint inhibitor (ICI) rechallenge (Arm B)
Time Frame:Up to 5 years
Safety Issue:
Description:Rate of response is the percentage of patients with response after re-initiation of immune checkpoint inhibitor (ICI) therapy after progression post-registration. Rate of response will be assessed using RECIST 1.1. A chi-square test (or Fisher's exact test) will be used to determine whether there is an association between the best tumor response prior to trial enrollment and that achieved upon ICI re-challenge.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 5 years
Safety Issue:
Description:Adverse events (AEs) are ailments occurring during treatment. AEs will be assessed using Common Terminology Criteria for Adverse Events version 5.0. Frequencies and relative frequencies will be produced in a descriptive manner.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Last Updated

April 19, 2021