Testing Shorter Duration Radiation Therapy Versus the Usual Radiation Therapy in Patients Receiving the Usual Chemotherapy Treatment for Bladder Cancer, ARCHER Study

Official title

The Phase III Adaptive Radiation and Chemotherapy for Muscle Invasive Bladder Cancer Trial (ARCHER)

Overview

This phase III trial compares the effect of decreased number of radiation (ultra-hypofractionated) treatments to the usual radiation number of treatments (hypofractionation) with standard of care chemotherapy, with cisplatin, gemcitabine or mitomycin and 5-fluorouracil for the treatment of patients with muscle invasive bladder cancer. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a short period of time. Ultra-hypofractionated radiation therapy delivers radiation over an even shorter period of time than hypofractionated radiation therapy. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill tumor cells. Chemotherapy drugs, such as mitomycin-C and 5-fluorouracil (5-FU), work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ultra-hypofractionated radiation may be equally effective as hypofractionated therapy for patients with muscle invasive bladder cancer.

Detailed description

PRIMARY OBJECTIVE:

I. Demonstrate non-inferiority of ultra-hypofractionated (stereotactic body radiation therapy \[SBRT\]) compared to hypofractionated radiation therapy (RT) with a 10% non-inferiority margin (from 50% to 40%) in the rate of bladder-intact event-free survival (BI-EFS) at 3 years (corresponding to a hazard ratio \< 1.32).

SECONDARY OBJECTIVES:

I. Compare the rates of urinary and bowel toxicity, patient-reported outcomes (PRO), event-free survival (EFS), metastasis-free survival (MFS), and overall survival (OS) between the two treatment arms.

II. Compare and evaluate symptomatic adverse events and quality of life measures that are most meaningful to patients.

III. Evaluate circulating tumor deoxyribonucleic acid (ctDNA) as a biomarker to determine whether it is predictive of disease recurrence and as a secondary outcome variable.

EXPLORATORY OBJECTIVES:

I. Evaluate ctDNA, tissue-free minimal residual disease (tfMRD) and urine tumor DNA (utDNA) as biomarkers for predicting recurrence.

II. Evaluate tfMRD, obtained at the time of progression, to determine if it captures the presence of disease.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive hypofractionated radiation therapy (RT) once daily (QD), Monday to Friday, for 20 treatments in the absence of disease progression or unacceptable toxicity. Patients also receive one of 3 systemic chemotherapy regimens per treating physician's choice: 1) cisplatin intravenously (IV) weekly for 4 weeks; 2) gemcitabine IV on days 1, 4, 8, 11, 15, 18, 22 and 25 or weekly for 4 weeks; or 3) mitomycin-C IV on day 1 and fluorouracil (5 FU), over 120 hours on days 1-5 and 22-26. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scan and/or magnetic resonance imaging (MRI) or fluorodeoxyglucose (FDG) positron emission tomography (PET) throughout the study. In addition, patients may undergo optional blood and urine sample collection throughout the study, as well as an optional biopsy during cystoscopy during follow up.

ARM II: Patients receive ultra-hypofractionated RT QD, no more than twice weekly, for 5 treatments in the absence of disease progression or unacceptable toxicity. Patients also receive one of 3 systemic chemotherapy regimens per treating physician's choice: 1) cisplatin IV weekly for 4 weeks; 2) gemcitabine IV on days 1, 4, 8, 11, 15, 18, 22 and 25 or weekly for 4 weeks; or 3) mitomycin-C IV on day 1 and 5 FU, over 120 hours on days 1-5 and 22-26. Treatment given in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or MRI or FDG PET throughout the study. In addition, patients may undergo optional blood and urine sample collection throughout the study, as well as an optional biopsy during cystoscopy during follow up.

After completion of study treatment, patients are followed up at week 16, every 3 months for 3 years then every 6 months to year 5.

Interventions

• Procedure Biospecimen Collection
  Undergo blood, tissue, and urine sample collection
• Drug Cisplatin
  Given IV
• Procedure Computed Tomography
  Undergo CT scan
• Drug Fluorouracil
  Given IV
• Drug Gemcitabine
  Given IV
• Radiation Hypofractionated Radiation Therapy
  Undergo hypofractionated radiation therapy
• Procedure Magnetic Resonance Imaging
  Undergo MRI
• Drug Mitomycin
  Given IV
• Procedure Positron Emission Tomography
  Undergo PET scan
• Other Survey Administration
  Ancillary studies

Primary outcome measures

• Bladder-intact event-free survival (BI-EFS) [Time frame: Up to 3 years]

Secondary outcome measures (8)

• Incidence of urinary adverse events [Time frame: Up to year 2]
• Incidence of bowel adverse events [Time frame: Up to year 2]
• Quality of life [Time frame: At baseline, 4 weeks, 16 weeks, 13 months, 25 months, and 37 months]
• Event free survival [Time frame: From randomization to histologically proven presence of MIBC, radiographic evidence of nodal or metastatic disease, or death from any cause, up to 5 years]
• Metastasis-free survival [Time frame: From randomization to radiographic evidence of metastatic disease or death due to any cause, up to 5 years]
• Overall survival [Time frame: From randomization to death from any cause, up to 5 years]
• Incidence of adverse events (AE) [Time frame: Up to year 2]
• Circulating tumor deoxyribonucleic acid (ctDNA) [Time frame: At baseline, end of treatment (week 4), weeks 16, 28, 40, 56, and at disease progression or last follow-up visit]

Eligibility criteria

Inclusion criteria

• Histologically proven, cT2-T3,N0M0 urothelial carcinoma of the bladder prior to randomization.

• Note: Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible
• Must undergo a transurethral resection of bladder tumor (TURBT) prior to randomization. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection
• Must undergo radiological staging prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI (with or without contrast is acceptable). Patients must not have evidence of T4 or node positive disease. Fluorodeoxyglucose (FDG) PET imaging is acceptable for radiological staging
• If any lymph nodes ≥ 1.0 cm in shortest cross-sectional diameter are noted on imaging (CT / MRI of abdomen and pelvis), then the patient must have had a biopsy of the enlarged lymph node showing no tumor involvement prior to randomization
• No diffuse carcinoma in situ (CIS) based on cystoscopy and biopsy
• No definitive clinical or radiologic evidence of metastatic disease
• Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within 24 months prior to registration except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient had undergone complete nephroureterectomy
• Age ≥ 18
• Zubrod performance status of ≤ 2
• Not pregnant and not nursing

• Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm\^3
• Platelets ≥ 100,000 cells/mm\^3
• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\]) ≥ 8.0 g/dl is acceptable)
• Creatinine clearance (CrCL) of ≥ 30 mL/min by the Cockcroft-Gault formula
• Total bilirubin ≤ 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN
• All adverse events associated with any prior therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 3 prior to randomization
• For patients who have completed neoadjuvant therapy, they are eligible if the pre-neoadjuvant therapy diagnosis (TURBT path) is within 180 days before randomization
• Must not have had prior pelvic radiation
• New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)
• No active infection requiring IV antibiotics
• Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and kidney function meet criteria specified

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 211 centers

• Mercy Hospital Fort Smith — Fort Smith
• UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care — Irvine
• UC San Diego Moores Cancer Center — La Jolla
• UC Irvine Health/Chao Family Comprehensive Cancer Center — Orange
• University of California Davis Comprehensive Cancer Center — Sacramento
• UCHealth University of Colorado Hospital — Aurora
• UCHealth - Cherry Creek — Denver
• UCHealth Highlands Ranch Hospital — Highlands Ranch
• … and 203 more centers

Identifiers

NCT: NCT07097142 · NRG-GU015 · NCI-2025-04136 · NRG-GU015 · NRG-GU015 · U10CA180868

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗