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

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

Sponsors

Lead Sponsor: Alliance for Clinical Trials in Oncology

Collaborator: National Cancer Institute (NCI)

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 After completion of study treatment, starting new treatment or withdrawn consent, patients are followed up at 4 weeks, and then every 6 months for 5 years following registration.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

Overall Status Not yet recruiting
Start Date December 2020
Completion Date September 2030
Primary Completion Date July 2026
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Overall survival (OS) From randomization until death due to any cause, assessed up to 5 years
Secondary Outcome
Measure Time Frame
Progression-free survival (PFS) From randomization until disease progression or death due to any cause, assessed up to 5 years
Immune-related progression-free survival (iPFS) 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) 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) Up to 5 years
Incidence of adverse events (AEs) Up to 5 years
Enrollment 1038
Condition
Intervention

Intervention Type: Drug

Intervention Name: Pembrolizumab

Description: Given IV

Intervention Type: Drug

Intervention Name: Nivolumab

Description: Given IV

Intervention Type: Drug

Intervention Name: Atezolizumab

Description: Given IV

Intervention Type: Drug

Intervention Name: Durvalumab

Description: Given IV

Intervention Type: Drug

Intervention Name: Avelumab

Description: Given IV

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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Xiao X. Wei, MD, MAS Study Chair Dana-Farber Cancer Institute
Overall Contact

Last Name: Xiao X. Wei, MD, MAS

Phone: 617-632-4524

Email: [email protected]

Verification Date

November 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm A (immune checkpoint inhibitor)

Type: Active Comparator

Description: 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.

Label: Arm B (immune checkpoint inhibitor)

Type: Experimental

Description: 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.

Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov