Tipifarnib in Subjects With Myelodysplastic Syndromes

This is a Phase 2 randomized, open-label, two-stage study designed to investigate the antitumor activity of tipifarnib in approximately 36 eligible subjects with MDS who have no known curative treatment. Subjects will be randomized to receive tipifarnib orally with food according to one of 2 treatment regimens.

This Phase 2 study will investigate the antitumor activity in terms of ORR of tipifarnib in approximately 36 eligible subjects with MDS who have no known curative treatment. Eligible subjects may have received no more than 2 prior systemic regimens. Subjects will be randomized to receive tipifarnib orally with food according to one of 2 dose regimens. In the absence of unmanageable toxicities, subjects may continue to receive tipifarnib treatment until disease progression.

Disease assessments will be performed at screening and at least once every approximately 12 weeks starting at the end of cycle 3. Determination of ORR will be assessed by the Investigator according to the MDS International Working Group (IWG) criteria (Cheson 2006). Upon disease progression, all subjects in the study will be followed approximately every 12 weeks for survival and the use of subsequent therapy until either death or 12 months after accrual of the study has been completed, whichever occurs first.

Eligibility Criteria:
Inclusion Criteria:

* Subject is at least 18 years of age.
* Documented pathological evidence of MDS as defined by the World Health Organization (WHO) criteria.
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
* Subjects have no known curative treatment.
* 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 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 hematological function:

  1. Absolute neutrophil count \< 1000/mm3
  2. Platelet count \> 20,000/mm3
* Acceptable liver function:

  1. Total or direct bilirubin ≤ 1.5 times upper limit of normal (x ULN); does not apply to subjects with Gilbert's syndrome diagnosed as per institutional guidelines.
  2. AST (SGOT) and ALT (SGPT) ≤ 2.5 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:

  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 4 weeks after last dose of trial medication. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication.
  3. Not breast feeding at any time during the study.
* Written and voluntary informed consent understood, signed and dated.

Exclusion Criteria:

* Known prior progression to acute myeloid leukemia (AML), defined by at least 20% blasts in the blood or bone marrow.
* Myelodysplastic or myeloproliferative syndrome other than MDS.
* More than two prior systemic regimens for MDS. Prior systemic regimens are those that are considered standard of care for the treatment of MDS, have been received at standard doses for at least one full treatment cycle and exclude ESA.
* Prior cytoreductive therapy for blast reduction.
* Participation in any interventional study within 1 week or 5 half lives (whichever is longer) of Cycle 1 Day 1.
* Ongoing treatment with an anticancer agent for MDS not contemplated in this protocol.
* Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor.
* Clinically significant anemia due to iron, B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding. If marrow stain for iron is not available, the transferrin saturation (iron/total iron binding capacity Fe/TIBC) must be \>20% or serum ferritin must be \>100 ng/dL.
* 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 Day 1, without complete recovery.
* 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).
* Active, 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.
* Subjects who have exhibited allergic reactions to tipifarnib, or structural compounds similar to tipifarnib or to its excipients.
* 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.
* The subject has legal incapacity or limited legal capacity.
* 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.