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Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations

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ClinicalTrials.gov Identifier: NCT03448718
Recruitment Status : Recruiting
First Posted : February 28, 2018
Last Update Posted : February 1, 2019
Sponsor:
Collaborators:
Icahn School of Medicine at Mount Sinai
AstraZeneca
Information provided by (Responsible Party):
Matthew Galsky, Hoosier Cancer Research Network

Tracking Information
First Submitted Date  ICMJE February 22, 2018
First Posted Date  ICMJE February 28, 2018
Last Update Posted Date February 1, 2019
Actual Study Start Date  ICMJE April 17, 2018
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 25, 2018)
Objective Response Rate [ Time Frame: 36 Months ]
Estimate the objective response rate (per RECIST 1.1 or MD Anderson Criteria for bone-only metastatic disease) to treatment with olaparib in subjects with metastatic urothelial cancer harboring somatic DDR alterations. Objective response rate will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST 1.1.
Original Primary Outcome Measures  ICMJE
 (submitted: February 22, 2018)
Objective Response Rate [ Time Frame: 36 Months ]
Estimate the objective response rate (per RECIST 1.1) to treatment with olaparib in subjects with metastatic urothelial cancer harboring somatic DDR alterations. Objective response rate will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST 1.1.
Change History Complete list of historical versions of study NCT03448718 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 22, 2018)
Progression-Free Survival [ Time Frame: 36 Months ]
Progression-free survival is defined as the time from Day 1 of treatment until the criteria for disease progression is met as defined by RECIST 1.1 or death as a result of any cause.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 22, 2018)
  • Overall Survival [ Time Frame: 36 Months ]
    Overall survival is defined as the time from Day 1 of treatment until death as a result of any cause.
  • Adverse Event Assessment [ Time Frame: 36 Months ]
    Assess all grade 3 and 4 adverse events as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
Official Title  ICMJE Phase 2 Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
Brief 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Urothelial Cancer
Intervention  ICMJE Drug: Olaparib
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.
Other Name: Lynparza
Study Arms  ICMJE Experimental: Olaparib Monotherapy
The starting dose of olaparib tablets will be dependent on the subject's calculated creatinine clearance (CrCl). Subjects with a 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: Drug: Olaparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 22, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2023
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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. Subjects with germline alterations in DDR genes will be considered on a case by case basis and will be reviewed by the sponsor-investigator. 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) ≥ 10 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 30 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
  • 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. 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Matthew Galsky, MD 212-824-5452 matthew.galsky@mssm.edu
Contact: Ahran Lee 317-634-5842 ext 14 alee@hoosiercancer.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03448718
Other Study ID Numbers  ICMJE HCRN GU15-262
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Matthew Galsky, Hoosier Cancer Research Network
Study Sponsor  ICMJE Matthew Galsky
Collaborators  ICMJE
  • Icahn School of Medicine at Mount Sinai
  • AstraZeneca
Investigators  ICMJE
Principal Investigator: Matthew Galsky, MD Mt Sinai School of Medicine
PRS Account Hoosier Cancer Research Network
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP