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

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.