<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/NCT02210858</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2014-01606</org_study_id>
    <secondary_id>NCI-2014-01606</secondary_id>
    <secondary_id>SUMC-NCI-38</secondary_id>
    <secondary_id>NCI-38</secondary_id>
    <secondary_id>CDR0000067864</secondary_id>
    <secondary_id>CTEP 38</secondary_id>
    <secondary_id>38</secondary_id>
    <secondary_id>P30CA124435</secondary_id>
    <secondary_id>IRB-13343</secondary_id>
    <nct_id>NCT02210858</nct_id>
    <nct_alias>NCT00005846</nct_alias>
  </id_info>
  <brief_title>Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders</brief_title>
  <official_title>Phase I/II Study of Tipifarnib [Zarnestra, Farnesyltransferase Inhibitor R115777 (NSC 702818)] in Patients With Myeloproliferative Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase 1-2 trial studies the side effects and how well tipifarnib works in treating&#xD;
      patients with chronic myeloid leukemia, chronic myelomonocytic leukemia, or undifferentiated&#xD;
      myeloproliferative disorders. Tipifarnib may stop the growth of cancer cells by blocking some&#xD;
      of the enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
        -  To describe the toxicities of R115777 (tipifarnib) in adult patients with&#xD;
           myeloproliferative disorders.&#xD;
&#xD;
        -  To assess hematologic responses, including changes in white blood cell count and&#xD;
           erythroid responses.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
        -  To assess bone marrow cytogenetic responses to R115777.&#xD;
&#xD;
        -  To analyze for the presence of neuroblastoma (N)/Kirsten rat sarcoma viral oncogene&#xD;
           homolog (K-Ras) mutations in patient bone marrow samples.&#xD;
&#xD;
        -  To analyze the effect of R115777 on Ras /DnaJ (Hsp40) homolog, subfamily A, member&#xD;
           1(HDJ-2) farnesylation in patient bone marrow/peripheral blood mononuclear cells.&#xD;
&#xD;
        -  To analyze the effect of R115777 on mitogen-activated protein (MAP) kinase activation in&#xD;
           patient bone marrow mononuclear cells.&#xD;
&#xD;
        -  To perform colony forming unit granulocyte-macrophage (CFU-GM) cytotoxicity assays using&#xD;
           patients' hematopoietic cells with R115777.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive tipifarnib orally (PO) twice daily (BID) on days 1-21. Treatment repeats&#xD;
      every 28 days for up to 4 courses in the absence of disease progression or unacceptable&#xD;
      toxicity. Patients achieving a good hematologic response may continue treatment at the&#xD;
      discretion of the treating physician.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2000</start_date>
  <completion_date type="Actual">March 2017</completion_date>
  <primary_completion_date type="Actual">November 12, 2004</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Erythroid response in non-transfusion dependent patients</measure>
    <time_frame>Up to 16 weeks</time_frame>
    <description>Major response is defined as a &gt; 2.0 g/dL rise in the hemoglobin after 2 to 4 cycles of therapy. Minor response is defined as a &gt; 1.0 to &lt; 2.0 g/dL rise in the hemoglobin after 2 to 4 cycles of therapy.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Erythroid response in transfusion-dependent patients</measure>
    <time_frame>Up to 16 weeks</time_frame>
    <description>Major response is defined as transfusion-independent after 2 to 4 cycles of therapy or a &gt; 2.0 g/dL rise in hemoglobin without transfusion. Minor response is defined as &gt; 1 to &lt; 2.0 g/dL incremental rise in hemoglobin with a decrease in transfusion requirements of at least 50% compared to the mean transfusion requirement during the 8-week pre-study period.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of adverse events related to tipifarnib assessed by National Cancer Institute Common Toxicity version 2.0</measure>
    <time_frame>Up to 16 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>WBC response (complete response, defined as normalization of WBC count in patients with an elevated WBC count prior to treatment and partial response, defined as &gt; 50% reduction in WBC count without normalization of WBC count)</measure>
    <time_frame>Up to 16 weeks</time_frame>
    <description>For all hematologic responses, the duration of response must be at least 2 months.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cytogenetic response (including Philadelphia chromosome-positive cells in metaphases in CML)</measure>
    <time_frame>Up to 16 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In vitro correlative studies (including N/K-Ras mutation analysis, N/K-Ras/HDJ-2 farnesylation, MAP kinase activation, and bone marrow CFU-GM cytotoxicity assays using tipifarnib with patients' hematopoietic cells)</measure>
    <time_frame>Up to week 3 (course 4)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Accelerated Phase of Disease</condition>
  <condition>Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative</condition>
  <condition>Chronic Myelogenous Leukemia, BCR-ABL1 Positive</condition>
  <condition>Chronic Myelomonocytic Leukemia</condition>
  <condition>Chronic Phase of Disease</condition>
  <condition>Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable</condition>
  <condition>Recurrent Disease</condition>
  <arm_group>
    <arm_group_label>Treatment (tipifarnib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive tipifarnib PO BID on days 1-21. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (tipifarnib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tipifarnib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (tipifarnib)</arm_group_label>
    <other_name>R115777</other_name>
    <other_name>Zarnestra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients with a diagnosis (&gt; 3 months prior to enrollment) of:&#xD;
&#xD;
               -  Chronic myeloid leukemia (CML) (Philadelphia chromosome positive or polymerase&#xD;
                  chain reaction [PCR] positive for breakpoint cluster region [BCR]-Abelson murine&#xD;
                  leukemia viral oncogene homolog 1 [ABL]) in chronic phase with:&#xD;
&#xD;
                    -  Persistent or progressive disease on maximum tolerated interferon therapy,&#xD;
                       or STI571 (if eligible and able to receive this drug), as evidenced by&#xD;
                       increasing white blood cell (WBC) count, peripheral blood myeloid immaturity&#xD;
                       and/or progressive anemia, and/or persistence or relapse of abnormal&#xD;
                       cytogenetic and/or molecular findings&#xD;
&#xD;
                    -  Interferon or STI571 intolerant&#xD;
&#xD;
               -  CML (Philadelphia chromosome positive or PCR positive for BCR-ABL) in accelerated&#xD;
                  phase (&lt; 20% blasts in the peripheral blood and bone marrow) with persistent or&#xD;
                  progressive disease on STI571 (if eligible and able to receive this drug)&#xD;
&#xD;
               -  CML patients are eligible if they have not received interferon or STI571 because&#xD;
                  they are allergic to these drugs or refuse their use&#xD;
&#xD;
          -  Chronic myelomonocytic leukemia (CMML)&#xD;
&#xD;
               -  Proliferative-type (WBC &gt; 12,000/mL)&#xD;
&#xD;
               -  Less than 5% blasts in the peripheral blood and &lt; 20% blasts in the bone marrow&#xD;
&#xD;
          -  Undifferentiated myeloproliferative disorder (UMPD)&#xD;
&#xD;
          -  Atypical (i.e. Philadelphia chromosome-negative) CML&#xD;
&#xD;
          -  Four weeks must have elapsed since the use of any previous pharmacotherapy including&#xD;
             interferon, hematopoietic growth factors, and cytotoxic chemotherapy (6 weeks for&#xD;
             prior mitomycin or nitrosoureas); hydroxyurea may be used to manage elevated cell&#xD;
             counts in patients up to the time they begin investigational therapy&#xD;
&#xD;
          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of&#xD;
             0, 1, or 2&#xD;
&#xD;
          -  Patients are capable of swallowing capsules&#xD;
&#xD;
          -  Total bilirubin is &gt; 1.5 X the upper limit of normal (ULN) where the analysis is&#xD;
             performed; for example, for Stanford University Hospital, the ULN for total bilirubin&#xD;
             is 1.3&#xD;
&#xD;
          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are &gt; 2 X the ULN; for&#xD;
             example, for Stanford University Hospital, the ULN for ALT is 35, and the ULN for AST&#xD;
             is 41&#xD;
&#xD;
          -  Serum creatinine of &lt; 2.0&#xD;
&#xD;
          -  Life expectancy &gt; 4 months&#xD;
&#xD;
          -  Written inform consent must be obtained&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Blast crisis phase of CML and atypical CML/ undifferentiated myeloproliferative&#xD;
             disorders&#xD;
&#xD;
          -  Patients with &gt; 20% blasts in the peripheral blood or bone marrow are excluded&#xD;
&#xD;
          -  Prior allogeneic bone marrow transplantation&#xD;
&#xD;
          -  Patients with severe disease other than CML, CMML, or UMPD which is expected to&#xD;
             prevent compliance with the protocol&#xD;
&#xD;
          -  Patients with septicemia or other severe infections&#xD;
&#xD;
          -  Pregnant or breast-feeding females&#xD;
&#xD;
          -  Women of reproductive age should use contraception while on study&#xD;
&#xD;
          -  Patients may not receive androgens during the study&#xD;
&#xD;
          -  Requirement for ongoing therapy with corticosteroids (&gt; 10 mg/d prednisone or&#xD;
             equivalent steroid dosage) other than as pre-medication for transfusions&#xD;
&#xD;
          -  Patients with iron deficiency; if a marrow aspirate is not available, transferrin&#xD;
             saturation must be &gt; 20% and serum ferritin &gt; 50 ng/mL; this exclusion criterion will&#xD;
             be removed if the iron deficiency state is corrected before enrollment&#xD;
&#xD;
          -  Patients with other contributing causes of anemia such as autoimmune or hereditary&#xD;
             hemolytic disorders, gastrointestinal (GI) blood loss, B12 or folate deficiency, or&#xD;
             hypothyroidism; patients who require platelet transfusions, or have&#xD;
             thrombocytopenia-related bleeding&#xD;
&#xD;
          -  Inability to return for follow-up visits/studies to assess toxicity and response to&#xD;
             therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Greenberg</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford Cancer Institute</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>August 5, 2014</study_first_submitted>
  <study_first_submitted_qc>August 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 7, 2014</study_first_posted>
  <last_update_submitted>May 31, 2018</last_update_submitted>
  <last_update_submitted_qc>May 31, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 4, 2018</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>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myelogenous, Chronic, BCR-ABL Positive</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Acute</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Chronic</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Juvenile</mesh_term>
    <mesh_term>Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative</mesh_term>
    <mesh_term>Myeloproliferative Disorders</mesh_term>
    <mesh_term>Myelodysplastic-Myeloproliferative Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tipifarnib</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/NCT02210858
org study id: NCI-2014-01606
secondary id: NCI-2014-01606
secondary id: SUMC-NCI-38
secondary id: NCI-38
secondary id: CDR0000067864
secondary id: CTEP 38
secondary id: 38
secondary id: P30CA124435
secondary id: IRB-13343
nct id: NCT02210858
nct alias: NCT00005846
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase 1-2 trial studies the side effects and how well tipifarnib works in treating
      patients with chronic myeloid leukemia, chronic myelomonocytic leukemia, or undifferentiated
      myeloproliferative disorders. Tipifarnib may stop the growth of cancer cells by blocking some
      of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

        -  To describe the toxicities of R115777 (tipifarnib) in adult patients with
           myeloproliferative disorders.

        -  To assess hematologic responses, including changes in white blood cell count and
           erythroid responses.

      SECONDARY OBJECTIVES:

        -  To assess bone marrow cytogenetic responses to R115777.

        -  To analyze for the presence of neuroblastoma (N)/Kirsten rat sarcoma viral oncogene
           homolog (K-Ras) mutations in patient bone marrow samples.

        -  To analyze the effect of R115777 on Ras /DnaJ (Hsp40) homolog, subfamily A, member
           1(HDJ-2) farnesylation in patient bone marrow/peripheral blood mononuclear cells.

        -  To analyze the effect of R115777 on mitogen-activated protein (MAP) kinase activation in
           patient bone marrow mononuclear cells.

        -  To perform colony forming unit granulocyte-macrophage (CFU-GM) cytotoxicity assays using
           patients' hematopoietic cells with R115777.

      OUTLINE:

      Patients receive tipifarnib orally (PO) twice daily (BID) on days 1-21. Treatment repeats
      every 28 days for up to 4 courses in the absence of disease progression or unacceptable
      toxicity. Patients achieving a good hematologic response may continue treatment at the
      discretion of the treating physician.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Erythroid response in non-transfusion dependent patients
time frame: Up to 16 weeks
description: Major response is defined as a > 2.0 g/dL rise in the hemoglobin after 2 to 4 cycles of therapy. Minor response is defined as a > 1.0 to < 2.0 g/dL rise in the hemoglobin after 2 to 4 cycles of therapy.
measure: Erythroid response in transfusion-dependent patients
time frame: Up to 16 weeks
description: Major response is defined as transfusion-independent after 2 to 4 cycles of therapy or a > 2.0 g/dL rise in hemoglobin without transfusion. Minor response is defined as > 1 to < 2.0 g/dL incremental rise in hemoglobin with a decrease in transfusion requirements of at least 50% compared to the mean transfusion requirement during the 8-week pre-study period.
measure: Incidence of adverse events related to tipifarnib assessed by National Cancer Institute Common Toxicity version 2.0
time frame: Up to 16 weeks
measure: WBC response (complete response, defined as normalization of WBC count in patients with an elevated WBC count prior to treatment and partial response, defined as > 50% reduction in WBC count without normalization of WBC count)
time frame: Up to 16 weeks
description: For all hematologic responses, the duration of response must be at least 2 months.
measure: Cytogenetic response (including Philadelphia chromosome-positive cells in metaphases in CML)
time frame: Up to 16 weeks
measure: In vitro correlative studies (including N/K-Ras mutation analysis, N/K-Ras/HDJ-2 farnesylation, MAP kinase activation, and bone marrow CFU-GM cytotoxicity assays using tipifarnib with patients' hematopoietic cells)
time frame: Up to week 3 (course 4)
arm group label: Treatment (tipifarnib)
arm group type: Experimental
description: Patients receive tipifarnib PO BID on days 1-21. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (tipifarnib)
intervention type: Drug
intervention name: Tipifarnib
description: Given PO
arm group label: Treatment (tipifarnib)
other name: R115777
other name: Zarnestra
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Peter Greenberg
role: Principal Investigator
affiliation: Stanford Cancer Institute
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
mesh term: Leukemia, Myelomonocytic, Acute
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Leukemia, Myelomonocytic, Juvenile
mesh term: Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
mesh term: Myeloproliferative Disorders
mesh term: Myelodysplastic-Myeloproliferative Diseases
mesh term: Tipifarnib