A Study of the Experimental Medicine Olaparib For Advanced Urothelial Cancer With DNA-Repair Defects

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Age: 18 years or older
Healthy Volunteers: No
Keywords: urothelial carcinoma, urothelial cancer, kidney cancer, bladder cancer
Type: Other study, Phase 2
60 Participants
This study is being done to answer the following question:

Does the presence of changes in specified genes increase the response of your urothelial carcinoma to a new study drug?

We are doing this study because we want to find out if this approach is better or worse than the usual approach for your urothelial cancer. The usual approach is defined as care most people get for urothelial cancer.
This study requires

The study team will make sure you qualify to take part in the study. Qualified participants will receive detailed information about the study. This may include a list of study-related tests and procedures.

Who can participate

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
Benefits and risks of participating

We cannot promise any benefits to you as a result of taking part in this research study.


The study doctor will discuss the risks associated with taking part in this research study.
You will not be paid to take part in this research study.
Study duration and period
If you decide to take part in this study, you will get the study drug for as long as you respond to it. After you finish the study drug, your doctor will follow your condition for 4 weeks after dosing ends. They will check you for side effects every 3 months for up to year by phone interview. After 1 year, we will contact you once a year to check on your survival status.
Recruitment period
From Aug. 31, 2018
UC Davis Comprehensive Cancer Center
4501 X Street
Sacramento, CA 95817
Research Topic
  • 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

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