Tipifarnib in Subjects With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Adaptive Phase 2 Study of Tipifarnib in Subjects With Transfusion-dependent, Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Tipifarnib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is at least 18 years of age. Documented pathological evidence of MDS as defined by the World Health Organization (WHO) criteria Must have transfusion-dependent anemia that meets the following criteria: 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. No consecutive 56 days that was RBC transfusion-free during the 112 days immediately preceding Cycle 1 Day 1. 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: 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 Serum erythropoietin level of > 500 mU/mL in subjects not previously treated with an ESA. Risk category very low, low or intermediate (Revised International Prognostic Scoring System, IPSS-R) 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: Absolute neutrophil count > 500/mm3 Platelet count > 25,000/mm3 Acceptable liver function: 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. 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 either: Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or 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. Not breast feeding at any time during the study. 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 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tipifarnib, Oral<br>900 mg b.i.d. Days 1 -7, 15-21 in 28-day cycle | Drug: Tipifarnib<br>* 900 mg b.i.d. Days 1 -7, 15-21 in 28-day cycle<br>* Other names: Zarnesta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with red blood cell (RBC) transfusion independence (TI), in RBC transfusion-dependent subjects with very low, low or intermediate (INT) risk myelodysplastic syndromes (MDS) following treatment with tipfarnib. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients with positive or negative killer cell immunoglobulin-like receptor (KIR) 2DS2 and KIR2DL2 genotype status following treatment with tipifarnib. |  | 1 year |