Clinical Trials /

Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia, Other MDS/MPN, and Acute Myeloid Leukemia

NCT02807272

Description:

A Phase 2 study to investigate the antitumor activity in terms of overall response rate (ORR) of tipifarnib in approximately 36 eligible subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN), including Chronic Myelomonocytic Leukemia (CMML), and 36 eligible subjects with Acute Myeloid Leukemia (AML). Subjects (amendment 3 Cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, orally with food, twice a day (bid) for 21 days in 28 day cycles.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia, Other MDS/MPN, and Acute Myeloid Leukemia
  • Official Title: A Phase 2 Study of Tipifarnib in Subjects With Chronic Myelomonocytic Leukemia, Other Myelodysplastic /Myeloproliferative Neoplasias, and Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: KO-TIP-004
  • NCT ID: NCT02807272

Conditions

  • Leukemia, Myelomonocytic, Chronic

Interventions

DrugSynonymsArms
TipifarnibR115777, ZarnestraTipifarnib, Oral

Purpose

A Phase 2 study to investigate the antitumor activity in terms of overall response rate (ORR) of tipifarnib in approximately 36 eligible subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN), including Chronic Myelomonocytic Leukemia (CMML), and 36 eligible subjects with Acute Myeloid Leukemia (AML). Subjects (amendment 3 Cohorts 1-4) will receive tipifarnib administered at a dose of 400 mg, orally with food, twice a day (bid) for 21 days in 28 day cycles.

Detailed Description

      This Phase 2 study will investigate the antitumor activity in terms of ORR of tipifarnib in
      subjects with Myelodysplastic/Myeloproliferative Neoplasias (MDS/MPN cohorts) and Acute
      Myeloid Leukemia (AML cohorts). For MDS/MPN cohorts, this study will assess the antitumor
      activity of tipifarnib, in terms of ORR, in subjects with MDS/MPN, including CMML, who have a
      high ratio of expression of CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrow and in those
      with a low CXCR4/2 ratio. For AML cohorts, this study will assess the antitumor activity of
      tipifarnib, in terms of ORR, in subjects with AML who have a high ratio of expression of
      CXCR4 to CXCR2 (CXCR4/2 ratio) in their bone marrow and in those with low CXCR4/2 ratio.
      Subjects enrolled in the study will consist of patients with KRAS, NRAS wild type status.

        1. Subjects with MDS/MPN with high CXCR4/2 ratio

        2. Subjects with MDS/MPN with low CXCR4/2 ratio

        3. Subjects with AML with high CXCR4/2 ratio

        4. Subjects with AML with low CXCR4/2 ratio
    

Trial Arms

NameTypeDescriptionInterventions
Tipifarnib, OralExperimentalSingle arm
  • Tipifarnib

Eligibility Criteria

        Inclusion Criteria:

          1. Subject is at least 18 years of age.

          2. For subjects to be enrolled in the CMML or MDS/MPN cohorts:

             a. Diagnosis of CMML or MDS/MPN as defined by the World Health Organization (WHO)
             criteria (2008).

          3. For subjects enrolled in the AML cohort:

               1. Documented pathological evidence of AML, as defined by WHO criteria (2008)

               2. Refractory to previous induction chemotherapy, relapsed disease, or age ≥ 60 and
                  not appropriate for standard cytotoxic therapy due to age, performance status,
                  and/or adverse risk factors according to the treating physician

          4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.

          5. Subject is willing and able to comply with scheduled visits, treatment plans,
             laboratory tests and other procedures (including bone marrow assessments).

          6. At least 1 week since the last systemic therapy regimen prior to Cycle 1 Day 1.
             Subjects on a stable dose of hydroxyurea for at least 2 weeks prior to Cycle 1 Day 1
             may continue on hydroxyurea until Cycle 1 Day 14. Subjects must have recovered to NCI
             CTCAE v. 4.03 < Grade 2 from all acute toxicities (excluding Grade 2 toxicities that
             are not considered a safety risk by the Sponsor and Investigator) or toxicity must be
             deemed irreversible by the Investigator.

          7. Acceptable liver function:

               1. Total bilirubin upper limit of normal (ULN).

               2. AST (SGOT) and ALT (SGPT) 1.5 x ULN.

          8. Acceptable renal function with serum creatinine 1.5 x ULN or a calculated creatinine
             clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal
             Disease formulas.

          9. Female subjects must be:

               1. Of non-child-bearing potential (surgically sterilized or at least 2 years
                  post-menopausal); or

               2. If of child-bearing potential, subject must use a highly effective method of
                  contraception, such as combined (estrogen and progestogen containing) hormonal
                  contraception associated with inhibition of ovulation, progestogen-only hormonal
                  contraception associated with inhibition of ovulation, intrauterine device,
                  intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised
                  partner or sexual abstinence. Both females and male subjects with female partners
                  of child-bearing potential must agree to use a highly effective method of
                  contraception for 2 weeks prior to screening, during, and at least 28 days after
                  last dose of trial medication for females and 90 days for males. Female subjects
                  must have a negative serum or urine pregnancy test within 72 hours prior to start
                  of trial medication.

               3. And, not breast feeding at any time during the study.

         10. Written and voluntary informed consent understood, signed and dated.

        Exclusion Criteria:

          1. Neoplasia harbours RAS mutation (NRAS mutant, KRAS mutant or double mutant)

          2. Acute promyelocytic leukemia or Bcr-Abl positive leukemia (chronic myelogenous
             leukemia in blast crisis)

          3. Clinically active CNS leukemia

          4. CMML with t(5;12) that have not yet received imatinib.

          5. Participation in any interventional study within 1 week of randomization or 5
             half-lives of the prior treatment agent (whichever is longer).

          6. Ongoing treatment with an anticancer agent for CMML, MDS/MPN or AML not contemplated
             in this protocol. Subjects on a stable dose of hydroxyurea for at least 2 weeks prior
             to Cycle 1 Day 1 may continue on hydroxyurea until Cycle 1 Day 14.

          7. Hematopoietic stem cell transplantation (HSCT) performed within 3 months prior to
             Cycle 1 Day 1.

          8. Concurrent use of granulocyte macrophage colony-stimulating factor (GM-CSF).

          9. Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase
             inhibitor.

         10. Active coronary artery disease requiring treatment, myocardial infarction within the
             prior year, New York Heart Association grade III or greater congestive heart failure,
             cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia
             requiring medication except atrial fibrillation.

         11. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1,
             without complete recovery.

         12. Active, concurrent malignancy requiring radiation, chemotherapy, or immunotherapy
             (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and
             hormonal treatment for castration sensitive prostate cancer).

         13. Active and uncontrolled bacterial, viral, or fungal infections, requiring systemic
             therapy. Known infection with human immunodeficiency virus (HIV), or an active
             infection with hepatitis B or hepatitis C.

         14. Concomitant disease or condition that could interfere with the conduct of the study,
             or that would, in the opinion of the investigator, pose an unacceptable risk to the
             subject in this study.

         15. The subject has legal incapacity or limited legal capacity.

         16. Significantly altered mental status that would limit the understanding or rendering of
             informed consent and compliance with the requirements of this protocol. Unwillingness
             or inability to comply with the study protocol for any reason.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To assess the antitumor activity of tipifarnib in CMML subjects
Time Frame:1 year
Safety Issue:
Description:To assess the antitumor activity of tipifarnib, in terms of Objective Response Rate (ORR), in subjects with CMML and in subjects with CMML whose disease is KRAS/NRAS wild type.

Secondary Outcome Measures

Measure:Rate of complete response (CR)
Time Frame:1 year
Safety Issue:
Description:To assess the effect of tipifarnib on rate of complete response, complete cytogenetic remission, partial remission, marrow response, and clinical benefit
Measure:Duration of Response
Time Frame:1 year
Safety Issue:
Description:To assess the effect of tipifarnib on duration of response.
Measure:Rate of progression free survival (PFS) at 1 year
Time Frame:1 year
Safety Issue:
Description:To assess the effect of tipifarnib on rate of progressive free survival at 1 year.
Measure:Rate of survival at 1 year
Time Frame:1 year
Safety Issue:
Description:To assess the effect of tipifarnib on rate of survival at 1 year.
Measure:Adverse event (AE) profile
Time Frame:Until 30 days following end of study
Safety Issue:
Description:To assess the effect of tipifarnib on adverse event (AE) profile according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v 4.03).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kura Oncology, Inc.

Last Updated

October 14, 2019