Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations

Inclusion Criteria:

- Written informed consent and HIPAA authorization for release of personal health
information prior to registration. NOTE: HIPAA authorization may be included in the
informed consent or obtained separately.

- Age ≥ 18 years at the time of consent.

- ECOG Performance Status of ≤ 1 within 14 days prior to registration.
Cisplatin-ineligible chemotherapy-naïve subjects (see inclusion criteria #8) may have
an ECOG Performance Status of ≤ 2.

- Histological or cytological evidence/confirmation of urothelial cancer.

- Metastatic and/or unresectable (cT4b) urothelial cancer.

- Metastatic disease evaluable on imaging studies. Subjects may have measurable disease
according to RECIST 1.1 or bone-only disease within 30 days prior to registration.

- NOTE: Bone-only subjects are eligible if their disease can be documented/
evaluated by bone scans, CT or MRI. Their disease will be assessed using MD
Anderson criteria.34

- NOTE: Previously irradiated lesions are eligible as a target lesion only if there
is documented progression of the lesion after irradiation.

- Somatic alteration in one of the following DDR genes as determined by genomic
sequencing performed in a Clinical Laboratory Improvement Amendments (CLIA)
laboratory. Somatic alterations will include nonsense, frameshift, splice-site or
missense mutations or homozygous deletions. Subjects with alterations in DDR genes not
included in the list below will be considered on a case by case basis after discussion
with the sponsor-investigator. Subjects with germline alterations in DDR genes will be
considered on a case by case basis and will be reviewed by the sponsor-investigator.
At least 6 subjects will have BRCA or ATM alterations.

- Nucleotide Excision Repair: ERCC2, ERCC3,ERCC4, ERCC5, ERCC6

- Homologous Recombination: BRCA1, RAD52, BRCA2, RAD54L, RAD50, NBN RAD51, MRE11A,
RAD51B, RAD51D, RAD51C, CTIP

- DNA Sensor: ATM, ATR, MDC1, ATRX, CHEK1, CHEK2

- Fanconi Anemia Pathway: PALB2, FANCE, BRIP1, FANCF, FANCA, FANCG FANCB, BLM, FANCC,
FANCD2

- Base Excision Repair: XRCC2, XRCC3, XRCC4, XRCC5, XRCC6

- Other: MUTYH, RECQL4, POLQ, POLE, WRN

- A subject with prior brain metastasis may be considered if they have completed their
treatment for brain metastasis at least 4 weeks prior to study registration, have been
off of corticosteroids for ≥ 2 weeks, and are asymptomatic

- Subjects must have progressed despite at least 1 prior line of treatment for
metastatic and/or unresectable urothelial cancer. However, cisplatin-ineligible
(defined by a calculated creatinine clearance of >30 but < 60 mL/min OR CTCAE v4 Grade
≥ 2 audiometric hearing loss OR CTCAE v4 Grade ≥ 2 peripheral neuropathy OR ECOG PS =
2), and chemotherapy-naïve subjects are also eligible.

- Prior cancer treatment (systemic therapy or radiation therapy) must be completed at
least 3 weeks prior to registration and the subject must have recovered from all
reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or
baseline.

- Demonstrate adequate organ function as defined in the table below. All screening labs
to be obtained within 28 days prior to registration.

- Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L

- Hemoglobin (Hgb) ≥ 10 g/dL

- Platelets ≥ 100 x 109/L

- Calculated creatinine clearance ≥ 30 mL/min

- Bilirubin ≤ 1.5 × upper limit of normal (ULN)

- Aspartate aminotransferase (AST) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases)

- Alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases)

- Female subjects must be postmenopausal or there must be evidence of non-childbearing
status for women of childbearing potential: negative urine or serum pregnancy test
within 28 days of study treatment and confirmed prior to treatment on day 1.

- Females of childbearing potential must be willing to abstain from heterosexual
activity or to use 2 forms of highly effective methods of contraception from the time
of informed consent until 30 days after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method. Males must be willing to abstain from heterosexual activity or
to use 2 forms of highly effective methods of contraception from the time of informed
consent until 90 days after treatment discontinuation.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study

- All subjects must have adequate archival tissue available prior to registration (i.e.,
at least 15 unstained slides or paraffin block). Archival tissue should represent
invasive or metastatic urothelial cancer with a preference for metastatic tissue if
available. Subjects without adequate tissue may be considered on a case by case basis
after discussion with the sponsor-investigator.

Exclusion Criteria

- Active infection requiring systemic therapy.

- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).

- Known additional malignancy that is active and/or progressive requiring treatment;
subjects with other malignancies that have been definitively treated and who have been
rendered disease free will be eligible.

- Prior treatment with a PARP inhibitor, including olaparib.

- Treatment with any investigational drug within 30 days prior to registration.

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).

- Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or
family history of long QT syndrome.

- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib is 2 weeks.

- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents.

- Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features
suggestive of MDS/AML.

- Major surgery within 2 weeks of starting study treatment and subjects must have
recovered from any effects of any major surgery.

- Subjects considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on High Resolution Computed Tomography (HRCT) scan, history of pneumonitis, or
any psychiatric disorder that prohibits obtaining informed consent.

- Subjects unable to swallow orally administered medication and subjects with
gastrointestinal disorders likely to interfere with absorption of the study
medication.

- Immunocompromised subjects, e.g., subjects who are known to be serologically positive
for human immunodeficiency virus (HIV).

- Subjects with a known hypersensitivity to olaparib or any of the excipients of the
product.

- Subjects with known active hepatitis (i.e. Hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids

- Previous allogeneic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)