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Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders

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ClinicalTrials.gov Identifier: NCT02210858
Recruitment Status : Completed
First Posted : August 7, 2014
Last Update Posted : June 4, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

August 5, 2014
August 7, 2014
June 4, 2018
May 2000
November 12, 2004   (Final data collection date for primary outcome measure)
  • Erythroid response in non-transfusion dependent patients [ Time Frame: Up to 16 weeks ]
    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.
  • Erythroid response in transfusion-dependent patients [ Time Frame: Up to 16 weeks ]
    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.
  • Incidence of adverse events related to tipifarnib assessed by National Cancer Institute Common Toxicity version 2.0 [ Time Frame: Up to 16 weeks ]
  • 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 ]
    For all hematologic responses, the duration of response must be at least 2 months.
  • Incidence of adverse events related to tipifarnib assessed by National Cancer Institute Common Toxicity version 2.0 [ Time Frame: Up to 16 weeks ]
  • 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 ]
    For all hematologic responses, the duration of response must be at least 2 months.
  • Erythroid response in transfusion-dependent patients [ Time Frame: Up to 16 weeks ]
    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.
  • Erythroid response in non-transfusion dependent patients [ Time Frame: Up to 16 weeks ]
    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.
Complete list of historical versions of study NCT02210858 on ClinicalTrials.gov Archive Site
  • Cytogenetic response (including Philadelphia chromosome-positive cells in metaphases in CML) [ Time Frame: Up to 16 weeks ]
  • 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) ]
Same as current
Not Provided
Not Provided
 
Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders
Phase I/II Study of Tipifarnib [Zarnestra, Farnesyltransferase Inhibitor R115777 (NSC 702818)] in Patients With Myeloproliferative Disorders
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.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Accelerated Phase of Disease
  • Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
  • Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Chronic Myelomonocytic Leukemia
  • Chronic Phase of Disease
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Recurrent Disease
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Tipifarnib
    Given PO
    Other Names:
    • R115777
    • Zarnestra
Experimental: Treatment (tipifarnib)
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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Drug: Tipifarnib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
31
25
March 2017
November 12, 2004   (Final data collection date for primary outcome measure)

INCLUSION CRITERIA:

  • Patients with a diagnosis (> 3 months prior to enrollment) of:

    • Chronic myeloid leukemia (CML) (Philadelphia chromosome positive or polymerase chain reaction [PCR] positive for breakpoint cluster region [BCR]-Abelson murine leukemia viral oncogene homolog 1 [ABL]) in chronic phase with:

      • Persistent or progressive disease on maximum tolerated interferon therapy, or STI571 (if eligible and able to receive this drug), as evidenced by increasing white blood cell (WBC) count, peripheral blood myeloid immaturity and/or progressive anemia, and/or persistence or relapse of abnormal cytogenetic and/or molecular findings
      • Interferon or STI571 intolerant
    • CML (Philadelphia chromosome positive or PCR positive for BCR-ABL) in accelerated phase (< 20% blasts in the peripheral blood and bone marrow) with persistent or progressive disease on STI571 (if eligible and able to receive this drug)
    • CML patients are eligible if they have not received interferon or STI571 because they are allergic to these drugs or refuse their use
  • Chronic myelomonocytic leukemia (CMML)

    • Proliferative-type (WBC > 12,000/mL)
    • Less than 5% blasts in the peripheral blood and < 20% blasts in the bone marrow
  • Undifferentiated myeloproliferative disorder (UMPD)
  • Atypical (i.e. Philadelphia chromosome-negative) CML
  • Four weeks must have elapsed since the use of any previous pharmacotherapy including interferon, hematopoietic growth factors, and cytotoxic chemotherapy (6 weeks for prior mitomycin or nitrosoureas); hydroxyurea may be used to manage elevated cell counts in patients up to the time they begin investigational therapy
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Patients are capable of swallowing capsules
  • Total bilirubin is > 1.5 X the upper limit of normal (ULN) where the analysis is performed; for example, for Stanford University Hospital, the ULN for total bilirubin is 1.3
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are > 2 X the ULN; for example, for Stanford University Hospital, the ULN for ALT is 35, and the ULN for AST is 41
  • Serum creatinine of < 2.0
  • Life expectancy > 4 months
  • Written inform consent must be obtained

EXCLUSION CRITERIA:

  • Blast crisis phase of CML and atypical CML/ undifferentiated myeloproliferative disorders
  • Patients with > 20% blasts in the peripheral blood or bone marrow are excluded
  • Prior allogeneic bone marrow transplantation
  • Patients with severe disease other than CML, CMML, or UMPD which is expected to prevent compliance with the protocol
  • Patients with septicemia or other severe infections
  • Pregnant or breast-feeding females
  • Women of reproductive age should use contraception while on study
  • Patients may not receive androgens during the study
  • Requirement for ongoing therapy with corticosteroids (> 10 mg/d prednisone or equivalent steroid dosage) other than as pre-medication for transfusions
  • Patients with iron deficiency; if a marrow aspirate is not available, transferrin saturation must be > 20% and serum ferritin > 50 ng/mL; this exclusion criterion will be removed if the iron deficiency state is corrected before enrollment
  • Patients with other contributing causes of anemia such as autoimmune or hereditary hemolytic disorders, gastrointestinal (GI) blood loss, B12 or folate deficiency, or hypothyroidism; patients who require platelet transfusions, or have thrombocytopenia-related bleeding
  • Inability to return for follow-up visits/studies to assess toxicity and response to therapy
Sexes Eligible for Study: All
21 Years and older   (Adult, Older Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT02210858
NCI-2014-01606
NCI-2014-01606 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
SUMC-NCI-38
NCI-38
CDR0000067864
CTEP 38 ( Other Identifier: Stanford Cancer Institute )
38 ( Other Identifier: CTEP )
P30CA124435 ( U.S. NIH Grant/Contract )
IRB-13343 ( Other Identifier: Stanford IRB )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Peter Greenberg Stanford Cancer Institute
National Cancer Institute (NCI)
May 2018

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