This 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.
- Subject is at least 18 years of age.
- Documented pathological evidence of MDS as defined by the World Health Organization
- Must have transfusion-dependent anemia that meets the following criteria:
1. Average transfusion requirement of ≥ 2 units per 28 days of packed RBCs confirmed
for a minimum of 112 days immediately preceding Cycle 1 Day 1.
2. No consecutive 56 days that was RBC transfusion-free during the 112 days
immediately preceding Cycle 1 Day 1.
3. Hemoglobin levels at the time of or within 7 days prior to transfusions must have
been ≤ 9.0 g/dL for the transfusions to qualify as required for the purpose of
providing evidence of transfusion-dependent anemia.
- Must be unresponsive or refractory to erythropoiesis-stimulating agents (ESA), based
on one of the following:
1. Transfusion-dependence in subjects previously treated with an ESA (requires a
minimum ESA trial of > 40,000 U/week recombinant human erythropoietin (rHuEPO) x
8 weeks or equivalent dose of darbepoetin or other erythropoietin agent), or
2. Serum erythropoietin level of > 500 mU/mL in subjects not previously treated with
- Risk category very low, low or intermediate (Revised International Prognostic Scoring
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Subjects have no known curative treatment.
- 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 > 500/mm3
2. Platelet count > 25,000/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
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
- Female subjects must be either:
1. Of non-child-bearing potential (surgically sterilized or at least 2 years
2. If of child-bearing potential, subject must use an adequate method of
contraception consisting of two-barrier method or one barrier method with a
spermicide or intrauterine device. Both females and male subjects with female
partners of child-bearing potential must agree to use an adequate method of
contraception for 2 weeks prior to screening, during, and at least 4 weeks after
last dose of study medication. Female subjects must have a negative serum or
urine pregnancy test within 72 hours prior to start of study medication.
3. Not breast feeding at any time during the study.
- 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 treatments for MDS. Prior systemic therapies are those
that have been received at standard doses for at least one full treatment cycle.
- Prior cytoreductive therapy.
- Use of an ESA within the 4 weeks prior to Cycle 1 Day 1.
- Participation in any interventional study within 4 weeks 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
- 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.