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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03375307
Recruitment Status : Recruiting
First Posted : December 18, 2017
Last Update Posted : June 4, 2019
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well olaparib works in treating patients with urothelial cancer with DNA-repair defects that has spread to other places in the body and usually cannot be cured or controlled with treatment. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Abnormal DNA Repair ATM Gene Mutation ATR Gene Mutation BAP1 Gene Mutation BARD1 Gene Mutation BLM Gene Mutation BRCA1 Gene Mutation BRCA2 Gene Mutation BRIP1 Gene Mutation CHEK1 Gene Mutation CHEK2 Gene Mutation FANCC Gene Mutation FANCD2 Gene Mutation FANCE Gene Mutation FANCF Gene Mutation MEN1 Gene Mutation Metastatic Urothelial Carcinoma MLH1 Gene Mutation MSH2 Gene Mutation MSH6 Gene Mutation MUTYH Gene Mutation NPM1 Gene Mutation PALB2 Gene Mutation PMS2 Gene Mutation POLD1 Gene Mutation POLE Gene Mutation PRKDC Gene Mutation RAD50 Gene Mutation RAD51 Gene Mutation SMARCB1 Gene Mutation Stage III Bladder Urothelial Carcinoma AJCC v6 and v7 Stage IV Bladder Urothelial Carcinoma AJCC v7 STK11 Gene Mutation Urothelial Carcinoma Other: Laboratory Biomarker Analysis Drug: Olaparib Phase 2

Detailed Description:


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).


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.


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.


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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Olaparib (AZD2281) in Patients With Metastatic/Advanced Urothelial Carcinoma With DNA-Repair Defects
Actual Study Start Date : August 3, 2018
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Primary Outcome Measures :
  1. Overall response rate (ORR) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 5 years ]
    ORR will be reported along with 95% exact confidence intervals.

Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: From the date of olaparib initiation to investigator-assessed clinical progression or radiographic progression (by RECIST), or death from any cause, whichever occurs first, assessed up to 5 years ]
    PFS will be determined using a Kaplan-Meier curve, with probabilities at various time points indicated along with appropriate confidence intervals.

  2. Incidence of adverse events according to the Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
  3. Individual deoxyribonucleic acid (DNA)-repair defects [ Time Frame: Up to 5 years ]
    The association between individual DNA-repair defects and ORR will be determined using Fisher's exact test.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03375307

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United States, California
Los Angeles County-USC Medical Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: David I. Quinn         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Site Public Contact    323-865-0451      
Principal Investigator: David I. Quinn         
USC Norris Oncology/Hematology-Newport Beach Recruiting
Newport Beach, California, United States, 92663
Contact: Site Public Contact    323-865-0451      
Principal Investigator: David I. Quinn         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    720-848-0650      
Principal Investigator: Thomas W. Flaig         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Peng Wang         
United States, Maryland
NCI - Center for Cancer Research Recruiting
Bethesda, Maryland, United States, 20892
Contact: Site Public Contact    800-411-1222      
Principal Investigator: Andrea B. Apolo         
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Andrea B Apolo National Cancer Institute LAO

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Responsible Party: National Cancer Institute (NCI) Identifier: NCT03375307     History of Changes
Other Study ID Numbers: NCI-2017-02296
NCI-2017-02296 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10144 ( Other Identifier: National Cancer Institute LAO )
10144 ( Other Identifier: CTEP )
ZIABC011078 ( U.S. NIH Grant/Contract )
First Posted: December 18, 2017    Key Record Dates
Last Update Posted: June 4, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents