This phase II trial studies how well olaparib works in treating patients with urothelial
cancer with deoxyribonucleic acid (DNA)-repair defects that has spread to other places in the
body (advanced or metastatic) and usually cannot be cured or controlled with treatment. PARPs
are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP
from working, so tumor cells can't repair themselves, and they may stop growing.
I. To evaluate the efficacy of olaparib in two cohorts of patients with metastatic/advanced
urothelial carcinoma (UC) pre-selected by DNA-repair defects as measured by overall response
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.
IV. To follow patients without the pre-selected DNA-repair defects for survival.
I. To determine the proportion of patients with DNA-repair pathway-mutated genes in
metastatic UC (patient cohort referred for screening).
II. To correlate levels of baseline circulating tumor cells (CTCs) with survival in untreated
III. 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.
IV. To explore changes in plasma cytokines and correlate with clinical response.
V. To correlate levels of circulating endothelial cells with clinical outcome. VI. To
correlate levels of circulating tumor cells (CTCs) with clinical outcome.
VII. To correlate peripheral immune and DNA damage response transcriptional signatures with
VIII. 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.
IX. To determine the expression of Schlafen 11 (SLFN11) in tumor versus (vs.) stroma cells,
and the potential tumor heterogeneity based on SLFN11 expression.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients that have cancer-associated DNA-repair gene mutations receive olaparib
orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
COHORT II: Patients that do not have cancer-associated DNA-repair gene mutations undergo
blood sample collection at baseline.
After completion of study treatment, patients are followed up at 4 weeks, every 2 months for
1 year, then every 3 months thereafter.
Advanced Bladder Carcinoma, Advanced Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage IIIA Bladder Cancer AJCC v8, Stage IIIB Bladder Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8, Stage IVA Bladder Cancer AJCC v8, Stage IVB Bladder Cancer AJCC v8
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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