Biomarker discovery study to identify patients with advanced urothelial cancer benefitting from pembrolizumab treatment

1. Should have signed informed consent for CPCT-02
Note: when a safe biopsy of a metastatic or locally advanced lesion is not
deemed possible by the treating investigator, subject may be included in the
trial without participation in the CPCT-02 trial only upon approval by the
central principal investigator.
2. Be willing and able to provide written informed consent for the trial.
3. Be ><= 18 years of age on day of signing informed consent.
4. Have histologically or cytologically-confirmed urothelial cancer that is not
amenable to curative treatment with local and/or systemic therapies.
5. Second-line treatment: Have progressive disease after platinum containing
chemotherapy as defined by:
a. Disease progression after treatment with a platinum-containing regimen for
recurrent (disease not amenable to curative treatment)/metastatic disease
b. Recurrence/progression within 12 months of prior therapy containing platinum
OR
First-line treatment: have received no prior systemic chemotherapy for
advanced/ unresectable (inoperable) or metastatic urothelial
a. Adjuvant platinum based chemotherapy, following radial cystectomy, with
recurrence > 12 months from completion of therapy is permitted
b. Neoadjuvant platinum based chemotherapy, with recurrence > 12 months since
completion of therapy is permitted.
Note: Low-dose chemotherapy (e.g., low dose cisplatin, cisplatin+5FU,
mytomycin+5FU, or cisplatin+paclitaxel) given concurrent with radiation to the
primary tumor site is not considered as systemic therapy.
And subject must be considered ineligible to receive cisplatin-based
combination therapy, based on having at least one of the following criteria:
a. Creatinine clearance (calculated or measured) < 60 mL/min but >30 mL/min
Note: Subjects with a creatinine clearance (calculated or measured) < 30 mL/min
or on dialysis are excluded from the trial.
b. CTCAE v.4, Grade >2 audiometric hearing loss (25dB in two consecutive wave
ranges)
c. CTCAE v.4, Grade >2 peripheral neuropathy
d. NYHA Class III heart failure (Appendix 13.1)
6. Cisplatin-unfit patients should have a PD-L1 CPS of *10, determined with the
use of the commercially available PD-L1 IHC 22C3 pharmDx assay on a DAKO
stainer. PD-L1 expression may be determined prior to enrollment or during the
screening phase.
7. Have measurable disease based on RECIST 1.1. Tumor lesions located in a
previously irradiated area are considered measurable if progression has been
demonstrated in these lesions.
8. Be willing to provide tissue from a newly obtained core or excisional biopsy
of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6
weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom
newly-obtained samples cannot be provided (e.g. inaccessible or subject safety
concern) may submit an archived specimen only upon agreement from the Sponsor.
Note: when a safe biopsy of a metastatic or locally advanced lesion is not
deemed possible by the treating investigator, subject may be included in the
trial without participation in the CPCT-02 trial only upon approval by the
central principal investigator.
9. Have a performance status of 0 or 1 on the ECOG Performance Scale.
10. Demonstrate adequate organ function according to screening labs, which
should be performed within 10 days of treatment initiation.
11. Female subject of childbearing potential should have a negative urine or
serum pregnancy within 72 hours prior to receiving the first
dose of study medication. If the urine test is positive or cannot be confirmed
as negative, a serum pregnancy test will be required.
12. Female subjects of childbearing potential must be willing to use an
adequate method of contraception as outlined in Section 5.7.2 * Contraception,
for the course of the study through 120 days after the last dose of study
medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
13. Male subjects of childbearing potential must agree to use an adequate
method of contraception as outlined in Section 5.7.1-
Contraception, starting with the first dose of study therapy through 120 days
after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

1. Treamtent with an investigational agent and received study therapy or used
an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving high dose systemic
steroid therapy (defined as > 20 mg prednisone or equivalent per day) or any
other form of immunosuppressive therapy within 7 days prior to the first dose
of trial treatment.
3. Has a known history of active TB (Bacillus Tuberculosis).
4. Hypersensitivity to pembrolizumab or any of its excipients.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior
to study Day 1 or who has not recovered (i.e., * Grade 1 or at baseline) from
adverse events due to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., *
Grade 1 or at baseline) from adverse events due to a previously administered
agent.
- Note: Subjects with * Grade 2 neuropathy are an exception to this criterion
and may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
- Note: Radiation therapy to a symptomatic solitary lesion to the brain may be
allowed at the investigator's discretion.
7. Has a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin or
squamous cell carcinoma of the skin that has undergone potentially curative
therapy or in situ cervical cancer. Diagnosis of prostate carcinoma in
cystectomy material is not an exclusion criterium.
8. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain
metastases may participate provided they are stable (without evidence of
progression by imaging for at least four weeks prior to the first dose
of trial treatment and any neurologic symptoms have returned to baseline), have
no evidence of new or enlarging brain metastases, and
are not using high dose steroids (defined as > 20 mg prednisone or
equivalent per day) for at least 7 days prior to trial treatment. This
exception does not include carcinomatous meningitis which is excluded
regardless of clinical stability.
9. Has active autoimmune disease that has required systemic treatment in the
past 2 years (i.e. with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Replacement therapy (eg.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment.
10. Has known history of, or any evidence of active, (non-infectious)
pneumonitis that required steroids, evidence of interstitial lung disease or
active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject's participation for the full duration of the trial, or is not in the
best interest of the subject to participate, in the opinion of the treating
investigator.
13. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the trial, starting with the prescreening
or screening visit through 120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti- PD-L2
agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
17. Has a known history of or is positive for hepatitis B (hepatitis B surface
antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV]
RNA [qualitative] is detected). Note: Without known history, testing needs to
be performed to determine eligibility. Hepatitis C antibody (Ab)
testing is allowed for screening purposes in countries where HCV RNA is not
part of standard of care.
18. Has received a live vaccine within 30 days of planned start of study
therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g.,
Flu-Mist®) are live attenuated vaccines, and are not allowed.