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.
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
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)
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
9. Female subjects must be:
1. Of non-child-bearing potential (surgically sterilized or at least 2 years
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.
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
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.