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

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 After completion of study treatment, starting new treatment or withdrawn consent, patients are followed up at 4 weeks, and then every 6 months for 5 years following registration.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

Official Title
-----------------
Duration of Immune Checkpoint Therapy in Locally Advanced or Metastatic Urothelial Carcinoma: A Randomized Phase 3 Non-Inferiority Trial (IMAGINE)

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

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Drug: Nivolumab
* Drug: Atezolizumab
* Drug: Durvalumab
* Drug: Avelumab


Participation Criteria
=================
Eligibility 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, urethra, or prostate Patients must have received at least one cycle of 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 Patients without progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 guidelines (i.e., with an ongoing [complete response] CR, partial response [PR], or stable disease [SD]) following completion of 12-15 months of ICI treatment 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 REGISTRATION ELIGIBILITY CRITERIA: Patients without progressive disease per RECIST v 1.1 guidelines (i.e., with an ongoing CR, PR or SD) following completion of 12-15 months of ICI treatment No toxicity from ICI therapy that makes continuation of treatment clinically unacceptable Adequate bone marrow and organ functions to continue PD-1/L1 ICI as judged by the treating physician Age >= 18 years 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 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 RNA 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (immune checkpoint inhibitor)<br>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. | Drug: Pembrolizumab<br>* Given IV<br>Drug: Nivolumab<br>* Given IV<br>Drug: Atezolizumab<br>* Given IV<br>Drug: Durvalumab<br>* Given IV<br>Drug: Avelumab<br>* Given IV<br>|
| Experimental: Arm B (immune checkpoint inhibitor)<br>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. | Drug: Pembrolizumab<br>* Given IV<br>Drug: Nivolumab<br>* Given IV<br>Drug: Atezolizumab<br>* Given IV<br>Drug: Durvalumab<br>* Given IV<br>Drug: Avelumab<br>* Given IV<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | 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. | From randomization until death due to any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | 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. | From randomization until disease progression or death due to any cause, assessed up to 5 years | 
| Immune-related progression-free survival (iPFS) | 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. | From randomization until disease progression as assessed by irRECIST criteria or death due to any cause, assessed up to 5 years | 
| Treatment-free interval (Arm B) | Treatment-free Interval is the length of time patients are off treatment. A Stratified Cox model will be used to evaluate this outcome. | From last dose of immune checkpoint inhibitor (ICI) to initiation of a subsequent systemic treatment or death, assessed up to 5 years | 
| Rate of response after immune checkpoint inhibitor (ICI) rechallenge (Arm B) | 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. | Up to 5 years | 
| Incidence of adverse events (AEs) | 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. | Up to 5 years |