| Eligibility |
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.
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