Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
Condition: Metastatic Urothelial Cancer
Intervention: Olaparib
Intervention description: 1 cycle = 28 days. Subject's with calculated creatinine clearance (CrCl) of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of > 30 to < 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.
Intervention MeSH terms: Olaparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a single arm open label multi-institutional phase II trial of olaparib monotherapy in
      subjects with metastatic urothelial cancer harboring somatic DNA damage response (DDR)
      alterations. The primary objective of the study is to estimate the objective response rate
      (per RECIST 1.1) to treatment with olaparib.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent and HIPAA authorization for release of personal health
             information prior to registration. NOTE: HIPAA authorization may be included in the
             informed consent or obtained separately.

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status of ≤ 1 within 14 days prior to registration.
             Cisplatin-ineligible chemotherapy-naïve subjects (see inclusion criteria #8) may have
             an ECOG Performance Status of ≤ 2.

          -  Histological or cytological evidence/confirmation of urothelial cancer.

          -  Metastatic and/or unresectable (cT4b) urothelial cancer.

          -  Metastatic disease evaluable on imaging studies. Subjects may have measurable disease
             according to RECIST 1.1 or bone-only disease within 30 days prior to registration.

               -  NOTE: Bone-only subjects are eligible if their disease can be documented/
                  evaluated by bone scans, CT or MRI. Their disease will be assessed using MD
                  Anderson criteria.34

               -  NOTE: Previously irradiated lesions are eligible as a target lesion only if there
                  is documented progression of the lesion after irradiation.

          -  Somatic alteration considered pathogenic/likely pathogenic in one of the following DDR
             genes as determined by genomic sequencing performed in a Clinical Laboratory
             Improvement Amendments (CLIA) laboratory. Somatic alterations will include nonsense,
             frameshift, splice-site or missense mutations or homozygous deletions. Subjects with
             alterations in DDR genes not included in the list below will be considered on a case
             by case basis after discussion with the sponsor-investigator(s). Subjects with
             germline alterations in DDR genes will be considered on a case by case basis and will
             be reviewed by the sponsor-investigator(s). At least 6 subjects will have BRCA or ATM
             alterations.

          -  Nucleotide Excision Repair: ERCC2, ERCC3,ERCC4, ERCC5, ERCC6

          -  Homologous Recombination: BRCA1, RAD52, BRCA2, RAD54L, RAD50, NBN RAD51, MRE11A,
             RAD51B, RAD51D, RAD51C, CTIP

          -  DNA Sensor: ATM, ATR, MDC1, ATRX, CHEK1, CHEK2

          -  Fanconi Anemia Pathway: PALB2, FANCE, BRIP1, FANCF, FANCA, FANCG FANCB, BLM, FANCC,
             FANCD2

          -  Base Excision Repair: XRCC2, XRCC3, XRCC4, XRCC5, XRCC6

          -  Other: MUTYH, RECQL4, POLQ, POLE, WRN

          -  A subject with prior brain metastasis may be considered if they have completed their
             treatment for brain metastasis at least 4 weeks prior to study registration, have been
             off of corticosteroids for ≥ 2 weeks, and are asymptomatic

          -  Subjects must have progressed despite at least 1 prior line of treatment for
             metastatic and/or unresectable urothelial cancer. However, cisplatin-ineligible
             (defined by a calculated creatinine clearance of >30 but < 60 mL/min OR CTCAE v4 Grade
             ≥ 2 audiometric hearing loss OR CTCAE v4 Grade ≥ 2 peripheral neuropathy OR ECOG PS =
             2), and chemotherapy-naïve subjects are also eligible.

          -  Prior cancer treatment (systemic therapy or radiation therapy) must be completed at
             least 3 weeks prior to registration and the subject must have recovered from all
             reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or
             baseline.

          -  Demonstrate adequate organ function as defined in the table below. All screening labs
             to be obtained within 28 days prior to registration.

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L

               -  Hemoglobin (Hgb) ≥ 9 g/dL

               -  Platelets ≥ 100 x 109/L

               -  Calculated creatinine clearance ≥ 30 mL/min

               -  Bilirubin ≤ 1.5 × upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases)

               -  Alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases)

          -  Female subjects must be postmenopausal or there must be 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.

          -  Females of childbearing potential must be willing to abstain from heterosexual
             activity or to use 2 forms of highly effective methods of contraception from the time
             of informed consent until 90 days after treatment discontinuation. The two
             contraception methods can be comprised of two barrier methods, or a barrier method
             plus a hormonal method. Males must be willing to abstain from heterosexual activity or
             to use 2 forms of highly effective methods of contraception from the time of informed
             consent until 90 days after treatment discontinuation.

          -  As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study

          -  15. All subjects must have adequate archival tissue available prior to registration
             (i.e., at least 15 unstained slides or paraffin block). Archival tissue should
             represent invasive or metastatic urothelial cancer with a preference for metastatic
             tissue if available. Archival tissue should be identified at screening and shipped by
             C1D1. Subjects without adequate tissue may be considered on a case by case basis after
             discussion with the sponsor-investigator.

        Exclusion Criteria

          -  Active infection requiring systemic therapy.

          -  Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study).

          -  Known additional malignancy that is active and/or progressive requiring treatment;
             subjects with other malignancies that have been definitively treated and who have been
             rendered disease free will be eligible.

          -  Prior treatment with a PARP inhibitor, including olaparib.

          -  Treatment with any investigational drug within 30 days prior to registration.

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site).

          -  Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or
             family history of long QT syndrome.

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

          -  Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

          -  Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features
             suggestive of MDS/AML.

          -  Major surgery within 2 weeks of starting study treatment and subjects must have
             recovered from any effects of any major surgery.

          -  Subjects considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
             cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
             disease on High Resolution Computed Tomography (HRCT) scan, history of pneumonitis, or
             any psychiatric disorder that prohibits obtaining informed consent.

          -  Subjects unable to swallow orally administered medication and subjects with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

          -  Immunocompromised subjects, e.g., subjects who are known to be serologically positive
             for human immunodeficiency virus (HIV).

          -  Subjects with a known hypersensitivity to olaparib or any of the excipients of the
             product.

          -  Subjects with known active hepatitis (i.e. Hepatitis B or C) due to risk of
             transmitting the infection through blood or other body fluids

          -  Previous allogeneic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)