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

Inclusion Criteria

• Subject is at least 18 years of age.
• 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).

• For subjects enrolled in the AML cohort:
• Documented pathological evidence of AML, as defined by WHO criteria (2008)
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.
• Subject is willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow assessments).
• 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.
• Acceptable liver function:
• Total bilirubin ≤ upper limit of normal (ULN).
• AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN.
• 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.
• Female subjects must be:
• Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or
• 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.
• And, not breast feeding at any time during the study.
• Written and voluntary informed consent understood, signed and dated.

Exclusion Criteria

• Neoplasia harbours RAS mutation (NRAS mutant, KRAS mutant or double mutant)
• Acute promyelocytic leukemia or Bcr-Abl positive leukemia (chronic myelogenous leukemia in blast crisis)
• Clinically active CNS leukemia
• CMML with t(5;12) that have not yet received imatinib.
• Participation in any interventional study within 1 week of randomization or 5 half-lives of the prior treatment agent (whichever is longer).
• 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.
• Hematopoietic stem cell transplantation (HSCT) performed within 3 months prior to Cycle 1 Day 1.
• Concurrent use of granulocyte macrophage colony-stimulating factor (GM-CSF).
• Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor.
• 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.
• Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1