Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer (CIRTiN-BC)

Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer (CIRTiN-BC): A Phase II, Single-Arm Trial

Clinically node positive (cN+) bladder cancer carries a poor prognosis, especially in patients who are unable to receive or fail to respond to neoadjuvant chemotherapy. Immune checkpoint inhibitor (ICI) therapy is FDA-approved in advanced bladder cancer for patients unable to receive or failing to respond to platinum-based chemotherapy. The present study seeks to determine if next-generation radiation therapy (personalized ultrafractionated stereotactic ablative radiotherapy, or PULSAR) is feasible and effective in patients receiving ICI for bulky cN+ bladder cancer.

Study Overview

• Status: Terminated
• Conditions: Bladder Cancer
• Intervention / Treatment: Radiation: personalized ultrafractionated stereotactic ablative radiotherapy

Detailed Description

Patients are eligible for the trial if they have bulky, clinically node-positive (cN+) bladder cancer and have either recently initiated (within ≤ 1 week) or are planned to initiate immune checkpoint inhibitor (ICI) therapy due to either 1) ineligibility for/refusal of platinum-based downstaging chemotherapy; or 2) failure to achieve a complete clinical response to platinum-based downstaging chemotherapy. Patients will initiate PULSAR treatment 1-2 weeks after initiating ICI. PULSAR will be administered in 3 fractions of 12 Gy each (36 Gy total) at 12-16 day intervals and patients will undergo radical cystectomy with bilateral extended pelvic lymph node dissection within 4-8 weeks after completion of PULSAR. ICI therapy will be administered according to the FDA-approved dosing route and schedule and will be continued during PULSAR treatments.

PULSAR treatment will be initiated 1-2 weeks after the patient is initiated on an FDA-approved ICI agent. PULSAR will be administered in 3 fractions of 12 Gy each at 12-16 day intervals. Target areas will include the region of the bladder containing the primary tumor (confirmed, if necessary, on office flexible cystoscopy at UTSW) and to up to five targetable, pathologically enlarged bulky lymph nodes (as deemed feasible by the treating radiation oncologist). Non-enlarged pelvic lymph nodes will be spared to minimize adverse effects on the tumor immune response.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Bladder cancer, confirmed pathologically on transurethral resection of bladder tumor (TURBT) or on bladder biopsy. Pure urothelial, variant urothelial, or any proportion of squamous cell carcinoma are permitted. Questions about eligibility may be resolved by consultation with UTSW pathology but formal pathologic review is not required.
• Bulky, clinically node positive disease (cN+) defined as: 1) a single pelvic lymph node of ≥ 1.5 cm largest diameter on CT or MRI; or 2) multiple pelvic lymph nodes ≥ 1 cm largest diameter on CT or MRI. Pathologic confirmation is not required. Imaging to establish eligibility must have been obtained no more than 60 days prior to trial enrollment. The scans must be personally reviewed by the enrolling clinician. For imaging studies obtained outside of UT Southwestern, imaging review of node status and sign off by the enrolling investigator is required. Review and sign off by a UTSW radiologist is optional in ambiguous or questionable cases, but is not mandatory.
• Age ≥ 18 years.
• ECOG performance status 0-1.
• Appropriate candidate for radical cystectomy, as determined by the treating urologist.
• Appropriate candidate for stereotactic ablative radiotherapy, as determined by the treating radiation oncologist.
• Patient is planned to initiate or is within 1-3 weeks of initiation of FDA-approved immune checkpoint inhibitor therapy based on ineligibility to receive platinum-based downstaging chemotherapy (DCT) (Cohort 1, as detailed below) or failure to achieve clinical complete response to platinum-based DCT (Cohort 2, as detailed below).

Cohort 1 (chemotherapy-ineligible) - either of:

• patient staged with bulky cN+ disease as defined above, medically ineligible to receive any platinum-based chemotherapy or, after appropriate and documented counseling, refusing to receive any-platinum-based chemotherapy; or
• patient staged with bulky cN+ disease as defined above, medically ineligible to receive cisplatin-based chemotherapy, with PD-L1 positive tumor (according to methodology described in the FDA approval label for the respective ICI agent)

Cohort 2 (chemotherapy non-responding) - any of:

• patient, initially staged with bulky cN+ disease as defined above, with radiologic progression after two cycles of platinum-based DCT (per RECIST 1.1 criteria: ≥20% increase in summed short-axis diameter of visible lesions with ≥ 5 mm absolute increase)
• patient, initially staged with bulky cN+ disease as defined above, failing to achieve radiologic complete response after three or four cycles of platinum-based DCT (failure of all enlarged lymph nodes to decrease to < 1 cm short-axis diameter)
• patient, initially staged with bulky cN+ disease as defined above, failing to achieve radiologic complete response after one or two cycles of platinum-based DCT which was discontinued due to patient intolerance
• patient, initially not staged with bulky cN+ disease as defined above, who progresses to cN+ disease as defined above after two or more of cycles of platinum-based DCT
• Permitted downstaging chemotherapy regimens are gemcitabine/cisplatin (gem/cis), gemcitabine/carboplatin (gem/carbo), and methotrexate/vinblastine/doxorubin/cisplatin (MVAC, in any dose variant).
• Permitted immune checkpoint inhibitor agents are those FDA-approved for platinum-ineligible (Cohort 1) or platinum-refractory (Cohort 2) bladder cancer: atezolizumab or pembrolizumab for Cohort 1; atezolizumab, avelumab, nivolumab, or pembrolizumab for Cohort 2. If additional immune checkpoint inhibitor (anti-PD1, anti-PD-L1, and/or anti-CTLA4) agents are approved for use in advanced urothelial carcinoma during the study, these agents will be permitted as well.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria

• Medical or anatomic contraindication to any of the study treatment modalities (radical cystectomy, stereotactic ablative radiotherapy, immune checkpoint inhibitor therapy).
• Non-urothelial histology (other than pure squamous cell, which is permitted) including pure adenocarcinoma, pure small cell carcinoma, sarcoma, lymphoma, non-genitourinary primary (e.g. colorectal).
• Metastatic (cM1) disease, defined as 1) lymph nodes ≥ 1 cm above the aortic bifurcation (cM1a), or metastases to bone, brain, or any visceral site (cM1b). Patients with a single enlarged retroperitoneal lymph node will be eligible with an adequately performed lymph node biopsy showing no metastatic disease or with a PET scan showing absence of FDG avidity.
• Second primary malignancy, except: 1) non-metastatic (cM0) prostate cancer, 2) non-metastatic (cM0) endometrial cancer, 3) non-melanoma skin cancer, 4) cervical squamous cell carcinoma in situ, 4) any AJCC Stage I/II or organ-confined primary malignancy for which the patient has undergone curative treatment and has been without evidence of disease for three years.
• Prior pelvic radiation therapy.
• Autoimmune disease rendering the patient ineligible for ICI.
• Treatment with any immunosuppressive agent within 14 days of study entry, excluding topical or inhaled corticosteroids or adrenal-replacement steroids.
• End stage renal disease requiring dialysis.
• HIV infection, unless stable on HAART with CD4+ count > 400.
• Subjects may not be receiving any other investigational agents for the treatment of the cancer under study.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab, or other agents used in study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (other than atrial fibrillation / atrial flutter), or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PULSAR; Eligible patients will receive next-generation stereotactic radiotherapy (PULSAR) 30-36 Gy in 3 fractions to the bladder and targetable, pathologically enlarged lymph nodes	Radiation: personalized ultrafractionated stereotactic ablative radiotherapy; next-generation stereotactic ablative radiotherapy to bladder and enlarged lymph nodes; Other Names: PULSAR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Protocol Completion	proportion of patients completing PULSAR and undergoing radical cystectomy	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	proportion of patients without disease progression	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Complication Rate	patients experiencing Clavien-Dindo Grade III+ surgical complication	90 days
Pathologic Complete Response	patients achieving pathologic ypT0 N0 status	at time of radical cystectomy
Pathologic Non-muscle Invasive Downstaging	patients achieving pathologic ≤ ypT1 N0 status	at time of radical cystectomy
Pathologic Organ-confined Downstaging	patients achieving pathologic ≤ ypT2 N0 status	at time of radical cystectomy
Pathologic Complete Nodal Response	patients achieving pathologic ypN0 status	at time of radical cystectomy
Residual Disease at Surgery	patients with microscopic (R1) or gross (R2) residual disease	at time of radical cystectomy
Ureteroenteric Stricture Rate	proportion of patients requiring procedural intervention for ureteroenteric stricture	2 years

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Investigators: Principal Investigator: Solomon L Woldu, MD, University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2021
• Primary Completion (Actual): June 2, 2023
• Study Completion (Actual): June 2, 2023

Study Registration Dates

• First Submitted: February 26, 2021
• First Submitted That Met QC Criteria: February 26, 2021
• First Posted (Actual): March 3, 2021

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: immunotherapy; bladder cancer; radiation therapy; lymph node metastasis
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: STU-2021-0114

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No