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

• ClinicalTrials.gov Identifier: NCT04637594
• Recruitment Status: Active, not recruiting
• First Posted: November 20, 2020
• Last Update Posted: September 14, 2023
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: November 16, 2020
• First Posted Date: November 20, 2020
• Last Update Posted Date: September 14, 2023
• Actual Study Start Date: December 10, 2020
• Estimated Primary Completion Date: July 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 16, 2020)

Overall survival (OS) [ Time Frame: From randomization until death due to any cause, assessed up to 5 years ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 16, 2020)

• Progression-free survival (PFS) [ Time Frame: From randomization until disease progression or death due to any cause, assessed up to 5 years ]
  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.
• 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 ]
  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.
• 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 ]
  Treatment-free Interval is the length of time patients are off treatment. A Stratified Cox model will be used to evaluate this outcome.
• Rate of response after immune checkpoint inhibitor (ICI) rechallenge (Arm B) [ Time Frame: Up to 5 years ]
  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.
• Incidence of adverse events (AEs) [ Time Frame: Up to 5 years ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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 (IMAGINE)
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

• Drug: Pembrolizumab
  Given IV
• Drug: Nivolumab
  Given IV
• Drug: Atezolizumab
  Given IV
• Drug: Durvalumab
  Given IV
• Drug: Avelumab
  Given IV

Study Arms

• Active Comparator: Arm A (immune checkpoint inhibitor)

  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.

  Interventions:

  • Drug: Pembrolizumab
  • Drug: Nivolumab
  • Drug: Atezolizumab
  • Drug: Durvalumab
  • Drug: Avelumab
• Experimental: Arm B (immune checkpoint inhibitor)

  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.

  Interventions:

  • Drug: Pembrolizumab
  • Drug: Nivolumab
  • Drug: Atezolizumab
  • Drug: Durvalumab
  • Drug: Avelumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 13, 2023): 3
• Original Estimated Enrollment (submitted: November 16, 2020): 1038
• Estimated Study Completion Date: September 2030
• Estimated Primary Completion Date: July 2026 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04637594
• Other Study ID Numbers: A031901; NCI-2020-08395 ( Registry Identifier: NCI Clinical Trial Reporting Program ); U10CA180821 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Xiao X. Wei, MD, MAS; Dana-Farber Cancer Institute

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: September 2023