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

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 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, 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

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 less than partial response in sum of target lesions. (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) association with treatment-free interval (Arm B) and PFS (both arms separately and together).

V. To evaluate changes in tumor-specific cfMeDNA 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) 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 Organisation 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.

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.

ARM B (DISCONTINUATION OF ICI TREATMENT): Patients receive either pembrolizumab intravenously (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 durvalumab IV over 60 minutes on days 1 and 14 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.

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

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Alliance for Clinical Trials in Oncology

Principal Investigator
Xiao X. Wei

• Primary ID A031901
• Secondary IDs NCI-2020-08395
• Clinicaltrials.gov ID NCT04637594