Clinical Trials /

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

NCT03375307

Description:

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.

Related Conditions:
  • Bladder Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib in Treating Patients With Metastatic or Advanced Urothelial Cancer With DNA-Repair Defects
  • Official Title: A Phase II Study of Olaparib (AZD2281) in Patients With Metastatic/Advanced Urothelial Carcinoma With DNA-Repair Defects

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-02296
  • SECONDARY ID: NCI-2017-02296
  • SECONDARY ID: 10144
  • SECONDARY ID: 10144
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT03375307

Conditions

  • 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

Interventions

DrugSynonymsArms
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      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).

      SECONDARY OBJECTIVES:

      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.

      TERTIARY OBJECTIVES:

      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.

      OUTLINE:

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib)ExperimentalPatients receive olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST)
Time Frame:Up to 5 years
Safety Issue:
Description:ORR will be reported along with 95% exact confidence intervals.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:PFS will be determined using a Kaplan-Meier curve, with probabilities at various time points indicated along with appropriate confidence intervals.
Measure:Incidence of adverse events according to the Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Individual deoxyribonucleic acid (DNA)-repair defects
Time Frame:Up to 5 years
Safety Issue:
Description:The association between individual DNA-repair defects and ORR will be determined using Fisher's exact test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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