Clinical Trials /

Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer

NCT04779489

Description:

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.

Related Conditions:
  • Bladder Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer
  • Official Title: Checkpoint Inhibitor and Radiation Therapy in Bulky, Node-Positive Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: STU-2021-0114
  • NCT ID: NCT04779489

Conditions

  • Bladder Cancer

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
PULSARExperimentalEligible patients will receive next-generation stereotactic radiotherapy (PULSAR) 30-36 Gy in 3 fractions to the bladder and targetable, pathologically enlarged lymph nodes

    Eligibility Criteria

            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.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:protocol completion
    Time Frame:16 weeks
    Safety Issue:
    Description:proportion of patients completing PULSAR and undergoing radical cystectomy

    Secondary Outcome Measures

    Measure:progression-free survival
    Time Frame:2 years
    Safety Issue:
    Description:proportion of patients without disease progression

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:University of Texas Southwestern Medical Center

    Trial Keywords

    • bladder cancer
    • lymph node metastasis
    • immunotherapy
    • radiation therapy

    Last Updated

    May 11, 2021