Olaparib in Treating Patients With Metastatic or Advanced Urothelial Cancer With DNA-Repair Defects

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of olaparib in two cohorts of patients with metastatic/advanced
urothelial carcinoma (UC) pre-selected by deoxyribonucleic acid (DNA)-repair defects as
measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

I. To describe the effect of therapy on progression free survival (PFS). II. To describe the
effect of therapy on overall survival (OS). III. To describe the safety/tolerability and
drug-related toxicities of olaparib.

TERTIARY OBJECTIVES:

I. To determine the proportion of patients with DNA-repair pathway-mutated genes in
metastatic UC (patient cohort referred for screening).

II. To explore tumor-mutational profiles in metastatic tumor biopsies, saliva "normal" DNA,
changes in tumor or peripheral immune characteristics, or tumor associated somatic mutation
load in blood DNA in response to treatment.

III. To explore changes in plasma cytokines and correlate with clinical response.

IV. To correlate levels of circulating endothelial cells with clinical outcome. V. To
correlate levels of circulating tumor cells (CTCs) with clinical outcome. VI. To correlate
peripheral immune and DNA damage response transcriptional signatures with clinical outcomes.

VII. To determine the effectiveness of using next-generation sequencing (NGS) to identify
DNA-repair pathway gene defects in tumor samples and circulating DNA and identify patients
with UC suitable for PARP inhibition.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, every 3 months for
1 year, and annually thereafter.

Inclusion Criteria:

- Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the
urothelial tract/bladder cancer

- Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed presence of a
somatic or germline alteration considered pathogenic/likely pathogenic by FM and/or
the Genetics Review Panel in one or more of the following genes: BRCA1, BRCA2, ATM,
BAP1, FANCF, PALB2, and BRIP1 or in one or more of the DNA-repair genes tested in the
FoundationOne panel including the following genes: ABL1, ATR, ATRX, BARD1, BLM, BRD4,
CCND1, CHEK1, CHEK2, DOT1L, FANCC, FANCD2, FANCE, FANCG, FANCL, IKBKE, MEN1, MLH1,
MSH2, MSH6, MUTYH, NPM1, PMS2, POLD1, POLE, PRKDC, RAD50, RAD51, SMARCB1, STK11

- Note: FoundationOne is a comprehensive and fully informative genomic profile that
can reveal both somatic and germinal gene alterations in the tumor tissue sample;
if the patient has prior evidence of a somatic or germline alterations that are
considered actionable (pathogenic/likely pathogenic) by FoundationOne panel and
the Genetics Review Panel in one of the genes listed in cohort 1 and 2 using
FoundationOne panel prior to enrollment in this protocol, confirmation of this
alteration won't be required

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
imaging (MRI), or calipers by clinical exam

- Evidence of disease progression as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) (version 1.1) during treatment or after the most recent dose of
therapy with at least one platinum-based regimen of chemotherapy and/or an
immune-checkpoint inhibitor (atezolizumab, pembrolizumab, nivolumab, avelumab or
durvalumab) (2-week washout from chemotherapy and 4-weeks washout from monoclonal
antibodies is required)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >=
60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (for subjects with documented
Gilbert's disease total bilirubin =< 3.0 mg/dL)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal (for subjects with liver metastasis
AST/ALT =< 5 x ULN)

- Creatinine =< 1.5 x ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Hemoglobin >= 9 g/dL

- Prothrombin time (PT)/international normalized ratio (INR) and activated partial
thromboplastin time (aPTT) within 1.25 x ULN institutional limits, except where a
lupus anti-coagulant has been confirmed

- Patients must be able to tolerate oral medications and not have gastrointestinal
illnesses that would preclude absorption of olaparib

- Women of child-bearing potential and their partners should agree to use two (2) highly
effective forms of contraception throughout study participation and for at least one
(1) month after the last dose of olaparib; male study participants should avoid
fathering a child or donating sperm during the study and for three (3) months after
the last dose of olaparib

- Note: breastfeeding should be discontinued if the mother is treated with olaparib

- Ability to understand and the willingness to sign a written informed consent document
or patients with impaired decision making capacity (IDMC) if they are represented by a
legally authorized representative (LAR)

- Patients must provide tumor sample for mutation analysis or be willing to undergo
mandatory screening biopsy

- Human immunodeficiency virus (HIV)-positive patients will be eligible if they are on
an effective combination antiretroviral therapy (cART) regimen (and if there are no
known pharmacokinetic interactions of the cART agents with olaparib) for >= 4 weeks
with an HIV viral load < 200 copies/mL and CD4+ count >= 100 cells/uL; for CD4+ count
< 200 cells/uL, requires CD4+/CD8+ ratio greater than 0.4

- Patients seropositive for hepatitis B virus (HBV) and/or hepatitis C virus (HCV) will
be eligible if HBV and/or HCV viral load are undetectable

Exclusion Criteria:

- Patients with benign or variants of unknown significance as determined by
FoundationOne panel and Genetics Review Panel review will be excluded

- Patients who have had prior treatment with olaparib

- Patients with myelodysplastic syndrome/acute myeloid leukemia; or baseline features
suggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheral
blood smear or bone marrow biopsy, if clinically indicated

- Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE] grade
2) with the exception of alopecia, caused by previous cancer therapy

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition of olaparib

- Patients receiving any medications or substances that are inhibitors or inducers of
CYP3A are ineligible

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study

- Any chronic or concurrent acute liver disease

- History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6
months prior to enrollment

- Uncontrolled concurrent disease or illness including but not limited to:

- Symptomatic congestive heart failure, unstable angina pectoris, clinically
significant cardiac arrhythmia

- Unstable or untreated cardiac conditions or ejection fraction of < 50% as
determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)

- Uncontrolled diabetes mellitus

- Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or that may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for the
study