Trying to Find the Correct Length of Treatment with Immune Checkpoint Therapy in Locally Advanced or Metastatic Urothelial Carcinoma

Status: closed to accrual and intervention

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, 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 the treatment with immune checkpoint inhibitors early in patients who have been responding to such therapy for approximately 1 year, may not change the benefit of treatment. This is because their immune system may continue to attack the tumor cells even if the treatment has stopped. A possible reason may be that the immune system has memory and remembers what it sees, including the cancer cells that it attacks. Stopping treatment with checkpoint inhibitors early may result in similar survival rate as if the treatment had not stopped and may also lead to fewer treatment-related side effects, an improvement in mental health, and a lower cost burden to patients.

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, 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 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 12-18 months of ICI treatment
REGISTRATION ELIGIBILITY CRITERIA: No toxicity from ICI therapy that makes continuation of treatment clinically unacceptable
REGISTRATION ELIGIBILITY CRITERIA: Adequate bone marrow and organ functions to continue PD-1/L1 ICI as judged by the treating physician
REGISTRATION ELIGIBILITY CRITERIA: Age >= 18 years
REGISTRATION ELIGIBILITY CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
REGISTRATION ELIGIBILITY CRITERIA: Central nervous system (CNS) metastasis is allowed if radiographically stable, clinically asymptomatic, and prior local therapy (if received) was completed > 6 months before registration

PRIMARY OBJECTIVE:

I. To compare overall survival (OS).

MAJOR 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.

BIOMARKER OBJECTIVES:

I. To evaluate archival tumor biomarkers associated with attaining an initial complete response (CR), partial response (PR), or stable disease (SD). (Arm A and B)

II. To evaluate archival tumor biomarkers associated with time to progression after ICI discontinuation and radiographic response after treatment rechallenge. (Arm B)

III. To explore peripheral biomarkers associated with clinical outcomes. (Arms A and B)

IV. To evaluate baseline tumor-specific cell-free methylated deoxyribonucleic acid (DNA) (cfMeDNA) and circulating tumor DNA (ctDNA) association with treatment-free interval (Arm B) and PFS (both arms separately and together).

V. To evaluate changes in tumor-specific cfMeDNA and ctDNA as a biomarker for early detection of disease progression prior to radiographic progression. (Arm A and B)

VI. To evaluate normal organ-specific cfMeDNA as a biomarker for early detection of immune-related adverse events (irAE). (Arm A and B)

QUALITY OF LIFE (QOL) AND HEALTH ECONOMICS OBJECTIVES:

I. To compare quality-adjusted survival using European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L) (primary) and Patient Reported Outcomes Measurement Information System (PROMIS) PROPr (exploratory).

II. To compare global QOL using European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30).

III. To compare patient-reported fatigue using PROMIS-Fatigue.

IV. To compare healthcare utilization.

V. To compare incremental cost effectiveness and cost utility ratios.

VI. To compare financial toxicity.

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, 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, and avelumab in the absence of disease progression or unacceptable toxicity.

ARM B (DISCONTINUATION OF ICI TREATMENT): Patients receive either pembrolizumab IV over 30 minutes on day 1 of cycle 1 or nivolumab IV over 30 minutes on days 1 and 14 of cycle 1, or atezolizumab IV over 30-60 minutes on day 1 of cycle 1, or avelumab IV over 60 minutes on days 1 and 14 of cycle 1. After cycle 1, patients discontinue treatment. At disease progression patients may restart treatment as in Arm A.

Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the study. Patients may undergo blood sample collection and bone scan on study.

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

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Trying to Find the Correct Length of Treatment with Immune Checkpoint Therapy in Locally Advanced or Metastatic Urothelial Carcinoma

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