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BRIEF TITLE: Study of Olaparib (AZD2281) in Patients With Metastatic/Advanced Urothelial Carcinoma With DNA-Repair Defects

A Phase II Study of Olaparib (AZD2281) in Patients With Metastatic/Advanced Urothelial Carcinoma With DNA-Repair Defects

  • Org Study ID: NCI-2017-02296
  • Secondary ID: NCI-2017-02296,P162941,19C0023,10144,10144,ZIABC011078
  • NCT ID: NCT03375307
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Cancer Institute (NCI)

Brief Summary

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.

Detailed Description


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
rate (ORR).


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
clinical outcomes.

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.

Overal Status Start Date Phase Study Type
Recruiting August 3, 2018 Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Overall response rate (ORR)

Primary Outcome 1 - Time Frame: Up to 5 years


  • 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


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) testing and fit one of/> the following groups:

- Confirmed presence of a cancer-associated 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, MSH2, PALB2, and BRIP1 or in one or more of the
DNA-repair genes tested in the FoundationOne FoundationOneCDx (F1CDx) panel
including the following genes (Foundation One mutation analysis results and
Foundation Liquid results performed prior to enrollment on this study may be
accepted for eligibility review): ABL1, ATR, ATRX, BARD1, BRD4, CCND1, CHEK1,

- Note: FoundationOneCDx (F1CDx) is a next generation sequencing based in
vitro diagnostic device for detection of substitutions, insertion and
deletion alterations (indels), and copy number alterations (CNAs) in 324
genes and select gene rearrangements, as well as genomic signatures
including microsatellite instability (MSI) and tumor mutational burden (TMB)
using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue

- Patients with benign or variants of unknown significance as determined by
FoundationOne FoundationOneCDx (F1CDx) panel and Genetics Review Panel review
will be included to be followed for survival

- 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 =< 1 (or Karnofsky >=

- 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 clearance >= 50 mL/min/1.73 m^2

- Hemoglobin >= 10 g/dL; transfusions are allowed

- 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

- Pre-clinical data indicate that olaparib adversely affects embryofetal survival and
development; therefore, 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: Olaparib is a PARP inhibitor with the potential for teratogenic or
abortifacient effects; because there is a potential risk for adverse events in
nursing infants secondary to treatment of the mother with olaparib, 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

- Postmenopausal or 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. Postmenopausal is defined as:

- Amenorrheic for 1 year or more following cessation of exogenous hormonal

- Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50

- Radiation-induced oophorectomy with last menses > 1 year ago

- Chemotherapy-induced menopause with > 1 year interval since last menses

- Surgical sterilization (bilateral oophorectomy or hysterectomy)

- Patients is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations

Exclusion Criteria:

- Patients who have had prior treatment with olaparib or any other PARP inhibitor

- 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 may be on other
clinical trials or treatment during screening to determine eligibility

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events;
a scan to confirm the absence of brain metastases is not required; patients with
spinal cord compression unless considered to have received definitive treatment for
this and evidence of clinically stable disease for 28 days

- 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; a washout period prior to starting olaparib for patients on
CYP3A inhibitors is 2 weeks; and the required washout period for CYP3A inducers is 5
weeks for enzalutamide or phenobarbital and 3 weeks for other agents

- Because the lists of these agents are constantly changing, it is important to
regularly consult a frequently-updated medical reference texts such as the
Physicians' Desk Reference; as part of the enrollment/informed consent
procedures, the patient will be counseled on the risk of interactions with other
agents, and what to do if new medications need to be prescribed or if the patient
is considering a new over-the-counter medicine or herbal product

- Pregnant women are excluded from this study because olaparib is a PARP inhibitor agent
with the potential for teratogenic or abortifacient effects

- 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:

- Ongoing or active infection

- 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

- Psychiatric illness/social situations that would limit compliance with study

- 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

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

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

- Other malignancy within the last 5 years except: adequately treated non-melanoma skin
cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ
(DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors including
lymphomas (without bone marrow involvement) curatively treated with no evidence of
disease for >= 5 years; patients with a history of localized triple negative breast
cancer or localized resected prostate cancer may be eligible, provided they completed
their adjuvant chemotherapy more than three years prior to registration, and that the
patient remains free of recurrent or metastatic disease

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

- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 2 weeks prior to study treatment

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

- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Andrea B Apolo

Role: Principal Investigator

Affiliation: National Cancer Institute LAO


Facility Status Contact
UC San Diego Moores Cancer Center
La Jolla, California 92093
United States
Recruiting Site Public Contact
Los Angeles County-USC Medical Center
Los Angeles, California 90033
United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California 90033
United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California 92663
United States
University of California Davis Comprehensive Cancer Center
Sacramento, California 95817
United States
Recruiting Site Public Contact
University of Colorado Hospital
Aurora, Colorado 80045
United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky 40536
United States
NCI - Center for Cancer Research
Bethesda, Maryland 20892
United States