<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02985658</url>
  </required_header>
  <id_info>
    <org_study_id>9763</org_study_id>
    <secondary_id>RG1716061</secondary_id>
    <secondary_id>NCI-2020-11567</secondary_id>
    <nct_id>NCT02985658</nct_id>
  </id_info>
  <brief_title>Expanded Access With ABT-888 (Veliparib) to Treat Metastatic Breast Cancer</brief_title>
  <official_title>Expanded Access Protocol With ABT-888 (Veliparib) in Patients With Metastatic BRCA-Mutation Associated or Triple Negative Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AbbVie</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Washington</source>
  <brief_summary>
    <textblock>
      This is an expanded access protocol to allow continued maintenance therapy with ABT-888&#xD;
      (veliparib) for three patients with metastatic triple negative breast cancer who are&#xD;
      currently receiving the investigational product in association with clinical trial&#xD;
      participation. Additionally, the protocol will enroll up to 7 new patients with metastatic&#xD;
      BRCA associated or triple negative breast cancer to allow for additional access to veliparib&#xD;
      monotherapy, or at the investigator's discretion, veliparib in combination with cisplatin&#xD;
      and/or vinorelbine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ABT-888 (Veliparib) or Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes&#xD;
      deoxyribonucleic acid (DNA) damage and facilitates DNA repair. Inactive PARPs 1 and 2 bind to&#xD;
      damaged DNA, which leads to their auto-activation. The resulting activated PARP then&#xD;
      poly(ADP-ribosyl)ates many nuclear target proteins, including those that facilitate DNA&#xD;
      repair of both single-stranded or double-stranded DNA breaks. Thus, PARP inhibition will&#xD;
      result in less efficient DNA repair following a DNA damage insult.&#xD;
&#xD;
      Since cancer cells are genetically unstable, often exhibiting complex karyotypes that include&#xD;
      large deletions, insertions, and unbalanced translocations of chromosomal fragment, these&#xD;
      cells are more susceptible than normal tissues to cytotoxicity induced by DNA-damaging&#xD;
      agents.Of these, deficiencies in mismatch repair and homologous recombination are associated&#xD;
      with the largest number of malignancies, including many sporadic TNBCs. These deficiencies&#xD;
      render cells more dependent on PARP for DNA repair and, hence, are more prone to cytotoxicity&#xD;
      induced by PARP inhibition. In particular, tumor cells with BRCA1 or BRCA2 deficiencies are&#xD;
      exquisitely sensitive to PARP inhibition, even in the absence of any other insults.&#xD;
      Identification of sporadic TNBC with defects in homologous recombination and mismatch repair&#xD;
      independent of germline mutation of BRCA 1 and 2 is an active area of research interest.&#xD;
&#xD;
      PARP-enabled DNA repair may also compensate for the loss of other repair pathways. Higher&#xD;
      expression of PARP in cancer cells compared to normal cells has been linked to drug&#xD;
      resistance and the overall ability of cancer cells to sustain genotoxic stress.&#xD;
&#xD;
      The combination of platinum based chemotherapy and PARP inhibition may be most effective in&#xD;
      TNBC, and particularly in subsets of TNBC. This combination may also be active in tumors with&#xD;
      a germline BRCA1-deficiency and/or basal phenotype, since a defect in the DNA double-strand&#xD;
      break repair pathway should increase sensitivity to these agents. The addition of a PARP&#xD;
      inhibitor to platinum based chemotherapy may induce a &quot;double hit&quot; to tumor cells lacking&#xD;
      homologous recombination without causing excess toxicity to normal cells. ABT-888 may be used&#xD;
      in combination with the DNA damaging agent, cisplatin, to potentiate its cytotoxic effect and&#xD;
      with vinorelbine to enhance tumor response rate. Safety and preliminary efficacy of veliparib&#xD;
      in combination with cisplatin and vinorelbine in patients with advanced triple negative and&#xD;
      BRCA-associated breast cancer has been reported.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>No longer available</overall_status>
  <study_type>Expanded Access</study_type>
  <has_expanded_access>No</has_expanded_access>
  <condition>Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation</condition>
  <condition>Triple-Negative Breast Cancer</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Veliparib</intervention_name>
    <description>Patients will start veliparib at 300 mg po BID days 1 through 21 of the first 21 day cycle, then increase to 400 mg po BID days 1 through 21 of each subsequent cycle, as tolerated by the patient.&#xD;
At the treating investigator's discretion, and with principal investigator approval, veliparib may be used in combination with cisplatin and/or vinorelbine. Veliparib (300mg) will be dosed po BID on Days 1 through 14 of each 21-day cycle.&#xD;
The patient will receive therapy as long as there is therapeutic benefit</description>
    <other_name>ABT-888</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Cisplatin will be administered intravenously (75 mg/m2) on Day 1 of each cycle</description>
    <other_name>Platinol-AQ</other_name>
    <other_name>Platinol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vinorelbine</intervention_name>
    <description>Vinorelbine will be administered intravenously on Day 1 and Day 8 of each 21-day cycle</description>
    <other_name>Navelbine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        1. Inclusion Criteria Roll-over patients: This protocol allows for the inclusion of 3&#xD;
             patients actively participating in protocol 7161 who are expected to continue to&#xD;
             benefit from uninterrupted dosing of veliparib monotherapy.&#xD;
&#xD;
             For newly enrolled patients the following criteria should be satisfied within 28 days&#xD;
             of Day 1 of protocol treatment. Results from routine clinical evaluations within 28&#xD;
             days prior to enrollment may be used to determine eligibility:&#xD;
&#xD;
               -  Locally recurrent and not amenable to surgical therapy, and/or metastatic breast&#xD;
                  cancer&#xD;
&#xD;
               -  Confirmed HER2-, BRCA1 or BRCA2 mutation-associated breast cancer or sporadic&#xD;
                  triple negative breast cancer.&#xD;
&#xD;
               -  No opportunity to receive veliparib under a current clinical trial.&#xD;
&#xD;
               -  Patients may have had any number of prior lines of chemotherapy, endocrine&#xD;
                  therapy, immunologic, or biologic regimens for metastatic breast cancer.&#xD;
&#xD;
               -  Patients receiving bisphosphonates, denosumab or LHRH-agonists are eligible.&#xD;
&#xD;
               -  18 years and older.&#xD;
&#xD;
               -  Performance status &gt; 60% on the Karnofsky scale (ECOG &lt; 2).&#xD;
&#xD;
               -  Adequate hematologic, renal and hepatic function as follows:&#xD;
&#xD;
               -  Bone Marrow: Absolute neutrophil count (ANC) &gt; 1,500/mm3 (1.5 × 109/L); Platelets&#xD;
                  &gt; 100,000/mm3 (100 × 109/L); Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
               -  Serum creatinine &lt; 1.5 × upper normal limit of institution's normal range OR&#xD;
                  creatinine clearance &gt; 50 mL/min/1.73m2 for patients with creatinine levels above&#xD;
                  institutional normal;&#xD;
&#xD;
               -  Hepatic function: AST and/or ALT &lt; 2.5 × the upper normal limit of institution's&#xD;
                  normal range.&#xD;
&#xD;
                  o For patients with liver metastases, AST and/or ALT &lt; 5 × the upper normal limit&#xD;
                  of institution's normal range;&#xD;
&#xD;
               -  Bilirubin &lt; 1.5 × the upper normal limit of institution's normal range;&#xD;
&#xD;
                  o Patients with Gilbert's Syndrome may have a bilirubin &gt; 1.5 × the upper normal&#xD;
                  limit of institution's normal range.&#xD;
&#xD;
               -  Women of childbearing potential must agree to use adequate contraception (one of&#xD;
                  the following listed below) prior to protocol entry, for the duration of protocol&#xD;
                  participation and for 90 days following completion of therapy. Women of&#xD;
                  childbearing potential must have a negative serum pregnancy test within 21 days&#xD;
                  prior to initiation of treatment and/or be confirmed as having postmenopausal&#xD;
                  status. Criteria for determining menopause include any of the following: prior&#xD;
                  bilateral oopherectomy; age &gt; 60 years; age &lt; 60 years and amenorrheic for at&#xD;
                  least 12 months in the absence of chemotherapy, endocrine therapy, or ovarian&#xD;
                  suppression and FSH and estradiol in the postmenopausal range.&#xD;
&#xD;
               -  Total abstinence from sexual intercourse (minimum one complete menstrual cycle);&#xD;
&#xD;
               -  Vasectomized partner of female patients;&#xD;
&#xD;
               -  Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months&#xD;
                  prior to study drug administration;&#xD;
&#xD;
               -  Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring&#xD;
                  with spermicidal jellies or cream);&#xD;
&#xD;
               -  IUD (Intra-Uterine Device).&#xD;
&#xD;
               -  Additionally, male patients (including those who are vasectomized) whose partners&#xD;
                  are pregnant or might be pregnant must agree to use condoms for the duration of&#xD;
                  the treatment plan and for 90 days following completions of therapy.&#xD;
&#xD;
               -  Radiation therapy must have been completed at least 2 weeks prior to the&#xD;
                  enrollment date.&#xD;
&#xD;
               -  Patients with known brain metastases must have clinically controlled neurologic&#xD;
                  symptoms, defined as surgical excision and/or radiation therapy followed by 14&#xD;
                  days of stable neurologic function prior to the first dose of study drug.&#xD;
&#xD;
               -  Ability to understand and the willingness to sign a written informed consent&#xD;
                  document.&#xD;
&#xD;
          2. Exclusion Criteria&#xD;
&#xD;
               -  Prior treatment with PARP inhibitor (excluding iniparib). Patients participating&#xD;
                  in protocol 7161 (NCI-2010-00356) are eligible.&#xD;
&#xD;
               -  Clinically significant and uncontrolled major medical condition(s) including but&#xD;
                  not limited to:&#xD;
&#xD;
               -  Active uncontrolled infection;&#xD;
&#xD;
               -  Symptomatic congestive heart failure;&#xD;
&#xD;
               -  Unstable angina pectoris or cardiac arrhythmia;&#xD;
&#xD;
               -  Psychiatric illness/social situation that would limit compliance with protocol&#xD;
                  requirements;&#xD;
&#xD;
               -  Any medical condition, which in the opinion of the investigator, places the&#xD;
                  patient at an unacceptably high risk for toxicities;&#xD;
&#xD;
               -  Myelodysplastic syndrome;&#xD;
&#xD;
               -  History of seizures within last 12 months or known neurological disorder&#xD;
                  pre-disposing to seizures&#xD;
&#xD;
               -  Patient is pregnant or lactating.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <location>
    <facility>
      <name>Seattle Cancer Care Allliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Chiarugi A. Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. Trends Pharmacol Sci. 2002 Mar;23(3):122-9. doi: 10.1016/S0165-6147(00)01902-7.</citation>
    <PMID>11879679</PMID>
  </reference>
  <reference>
    <citation>Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002 Sep;54(3):375-429. doi: 10.1124/pr.54.3.375.</citation>
    <PMID>12223530</PMID>
  </reference>
  <reference>
    <citation>Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004 Jan;113(2):160-8. doi: 10.1172/JCI20761.</citation>
    <PMID>14722605</PMID>
  </reference>
  <reference>
    <citation>Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, Webber SE, Durkacz BW, Calvert HA, Hostomsky Z, Newell DR. Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res. 2004 Feb 1;10(3):881-9. doi: 10.1158/1078-0432.ccr-1144-3.</citation>
    <PMID>14871963</PMID>
  </reference>
  <reference>
    <citation>Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14;434(7035):917-21. doi: 10.1038/nature03445.</citation>
    <PMID>15829967</PMID>
  </reference>
  <reference>
    <citation>Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14;434(7035):913-7. doi: 10.1038/nature03443. Erratum In: Nature. 2007 May 17;447(7142):346.</citation>
    <PMID>15829966</PMID>
  </reference>
  <reference>
    <citation>Wielckens K, Garbrecht M, Kittler M, Hilz H. ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem. 1980 Feb;104(1):279-87. doi: 10.1111/j.1432-1033.1980.tb04426.x.</citation>
    <PMID>6245868</PMID>
  </reference>
  <reference>
    <citation>Hirai K, Ueda K, Hayaishi O. Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res. 1983 Jul;43(7):3441-6.</citation>
    <PMID>6406058</PMID>
  </reference>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>December 5, 2016</study_first_submitted>
  <study_first_submitted_qc>December 5, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <last_update_submitted>July 14, 2021</last_update_submitted>
  <last_update_submitted_qc>July 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Vinorelbine</mesh_term>
    <mesh_term>Veliparib</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02985658
org study id: 9763
secondary id: RG1716061
secondary id: NCI-2020-11567
nct id: NCT02985658
lead sponsor: 
collaborator: 
This is an expanded access protocol to allow continued maintenance therapy with ABT-888
      (veliparib) for three patients with metastatic triple negative breast cancer who are
      currently receiving the investigational product in association with clinical trial
      participation. Additionally, the protocol will enroll up to 7 new patients with metastatic
      BRCA associated or triple negative breast cancer to allow for additional access to veliparib
      monotherapy, or at the investigator's discretion, veliparib in combination with cisplatin
      and/or vinorelbine.
ABT-888 (Veliparib) or Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes
      deoxyribonucleic acid (DNA) damage and facilitates DNA repair. Inactive PARPs 1 and 2 bind to
      damaged DNA, which leads to their auto-activation. The resulting activated PARP then
      poly(ADP-ribosyl)ates many nuclear target proteins, including those that facilitate DNA
      repair of both single-stranded or double-stranded DNA breaks. Thus, PARP inhibition will
      result in less efficient DNA repair following a DNA damage insult.

      Since cancer cells are genetically unstable, often exhibiting complex karyotypes that include
      large deletions, insertions, and unbalanced translocations of chromosomal fragment, these
      cells are more susceptible than normal tissues to cytotoxicity induced by DNA-damaging
      agents.Of these, deficiencies in mismatch repair and homologous recombination are associated
      with the largest number of malignancies, including many sporadic TNBCs. These deficiencies
      render cells more dependent on PARP for DNA repair and, hence, are more prone to cytotoxicity
      induced by PARP inhibition. In particular, tumor cells with BRCA1 or BRCA2 deficiencies are
      exquisitely sensitive to PARP inhibition, even in the absence of any other insults.
      Identification of sporadic TNBC with defects in homologous recombination and mismatch repair
      independent of germline mutation of BRCA 1 and 2 is an active area of research interest.

      PARP-enabled DNA repair may also compensate for the loss of other repair pathways. Higher
      expression of PARP in cancer cells compared to normal cells has been linked to drug
      resistance and the overall ability of cancer cells to sustain genotoxic stress.

      The combination of platinum based chemotherapy and PARP inhibition may be most effective in
      TNBC, and particularly in subsets of TNBC. This combination may also be active in tumors with
      a germline BRCA1-deficiency and/or basal phenotype, since a defect in the DNA double-strand
      break repair pathway should increase sensitivity to these agents. The addition of a PARP
      inhibitor to platinum based chemotherapy may induce a "double hit" to tumor cells lacking
      homologous recombination without causing excess toxicity to normal cells. ABT-888 may be used
      in combination with the DNA damaging agent, cisplatin, to potentiate its cytotoxic effect and
      with vinorelbine to enhance tumor response rate. Safety and preliminary efficacy of veliparib
      in combination with cisplatin and vinorelbine in patients with advanced triple negative and
      BRCA-associated breast cancer has been reported.
intervention type: Drug
intervention name: Veliparib
description: Patients will start veliparib at 300 mg po BID days 1 through 21 of the first 21 day cycle, then increase to 400 mg po BID days 1 through 21 of each subsequent cycle, as tolerated by the patient.
At the treating investigator's discretion, and with principal investigator approval, veliparib may be used in combination with cisplatin and/or vinorelbine. Veliparib (300mg) will be dosed po BID on Days 1 through 14 of each 21-day cycle.
The patient will receive therapy as long as there is therapeutic benefit
other name: ABT-888
intervention type: Drug
intervention name: Cisplatin
description: Cisplatin will be administered intravenously (75 mg/m2) on Day 1 of each cycle
other name: Platinol-AQ
other name: Platinol
intervention type: Drug
intervention name: Vinorelbine
description: Vinorelbine will be administered intravenously on Day 1 and Day 8 of each 21-day cycle
other name: Navelbine
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
facility: 
country: United States
citation: Chiarugi A. Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesis' revisited. Trends Pharmacol Sci. 2002 Mar;23(3):122-9. doi: 10.1016/S0165-6147(00)01902-7.
PMID: 11879679
citation: Virag L, Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002 Sep;54(3):375-429. doi: 10.1124/pr.54.3.375.
PMID: 12223530
citation: Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004 Jan;113(2):160-8. doi: 10.1172/JCI20761.
PMID: 14722605
citation: Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, Webber SE, Durkacz BW, Calvert HA, Hostomsky Z, Newell DR. Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res. 2004 Feb 1;10(3):881-9. doi: 10.1158/1078-0432.ccr-1144-3.
PMID: 14871963
citation: Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14;434(7035):917-21. doi: 10.1038/nature03445.
PMID: 15829967
citation: Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14;434(7035):913-7. doi: 10.1038/nature03443. Erratum In: Nature. 2007 May 17;447(7142):346.
PMID: 15829966
citation: Wielckens K, Garbrecht M, Kittler M, Hilz H. ADP-ribosylation of nuclear proteins in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells. Eur J Biochem. 1980 Feb;104(1):279-87. doi: 10.1111/j.1432-1033.1980.tb04426.x.
PMID: 6245868
citation: Hirai K, Ueda K, Hayaishi O. Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res. 1983 Jul;43(7):3441-6.
PMID: 6406058
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
mesh term: Cisplatin
mesh term: Vinorelbine
mesh term: Veliparib