Platelet Transfusion Dependence in Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) according to FAB criteria
Conditions
Interventions
Product Name: Lonafarnib
Product Code: SCH 66336
Pharmaceutical Form: Capsule*
INN or Proposed INN: Lonafarnib
CAS Number: 193275-84-2
Sponsors
Schering-Plough Research Institute
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subject has pathologically documented MDS according to FAB classification confirmed by bone marrow aspirate (BMA) conducted prior to randomization To be eligible for prospective screening: Subject has platelet and RBC transfusion data, and hemoglobin and platelet values available for the immediately preceding 8-week period (i.e., the retrospective screening period) prior to study enrollment. In addition, the following requirements must be satisfied. Subjects must have received 1 to 8 platelet transfusion events during the first 4-week interval (Day -84 to Day -57) and 1 to 8 platelet transfusion events during the second 4-week interval (Day -56 to Day -29) of the 8-week retrospective screening period. The number of platelet transfusion events during the first 4 weeks of the retrospective screening period (Day -84 to Day -57) and the second 4 weeks of the retrospective screening period (Day -56 to Day -29) must not differ by greater than 4. If the subject is RBC transfusion-dependent, the number of RBC transfusion events during the first 4 weeks of the retrospective screening period (Day -84 to Day -57) and the second 4 weeks of the retrospective screening period (Day -56 to Day -29) must not differ by greater than 4. To be eligible for randomization: The platelet and RBC transfusion values obtained during the 4-week prospective screening (Day -28 to Day -1) should confirm the results of the retrospective screening phase. In addition, subject must meet the following other requirements in order to be randomized. Subject must have received 1 to 8 platelet transfusion events during each of the three 4-week periods (Day -84 to -57, Day -56 to Day -29, Day -28 to Day -1) prior to randomization. The number of platelet transfusion events during each of the three 4-week periods prior to randomization must be within +/- 2 of the average number of the transfusion events per 4-week period during the entire 12-week period (Day -84 to Day -1) prior to randomization. For RBC transfusion independent subjects, the average hemoglobin value during the first 4- weeks and second 4-weeks retrospective screening period, must not differ by greater than 2g/dL from the average hemoglobin value obtained during the prospective screening period (day -28 to Day -1). For RBC transfusion dependent subjects, the number of RBC transfusion events during each of the three 4-week periods must be within +/- 2 of the average number of RBC transfusion events during the entire 12 –week period prior to randomization. There should be no change in the reasons for transfusions given during the retrospective versus the prospective screening period (i.e. fixed transfusion criteria selected on Day -28 should apply for all transfusions given during the prospective screening period). Subject is =18 years old at the start of the study drug administration Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 on Day -1 Subject is either refractory to, not eligible for, or unwillingly to undergo other existing standard tumor treatments. Greater than 12 weeks (from randomization on Day-1) from any treatment with Oprelvekin, and treatment with erythropoetin or darbopoetin, unless given in stable doses over the 12 week s
Exclusion criteria
Exclusion criteria: Subject has chemotherapy- or radiotherapy-associated MDS (i.e., secondary MDS) Subject has a history of AML (> 30% bone marrow blasts) Subject has received a bone marrow or peripheral blood stem cell transplant or has received a donor lymphocyte infusion. Subject has a known history of immune thrombocytopenic purpura (ITP). Subject has received chemotherapy, radiotherapy, immunotherapy, or other MDS-directed therapy (except best supportive care) within 12 weeks prior to randomization. Subject has Grade =2 nausea or Grade =1 vomiting (despite adequate antiemetic medication) or any condition that could interfere with administration of an oral medication Subject has a marked baseline prolongation of the QTc interval, CTCAE Grade =1 Subject has known HIV or AIDS- related illness Subject has previously received a farnesyl transferase inhibitor Subject has been administered ketoconazole within 72 hours prior to study drug administration. No serum creatinine > 1.5 x upper limit of normal (ULN). No bilirubin > 2mg/dl with the exception of documented Gilbert's Syndrome. No AST/SGOT or ALT/SGPT > 2.5 x ULN, or Alkaline phosphatase > 4 x ULN.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the clinical benefit of lonafarnib compared to placebo, where benefit is measured by proportion of subjects that achieved platelet transfusion independence for any 8-consecutive-week period after randomization without worsening of red blood cell (RBC) transfusion requirements or hemoglobin (untransfused) during the same 8-consecutive-week period of platelet transfusion independence.;Secondary Objective: To compare the hematologic response rate (complete remission, partical remission, hematologic improvement), 4-weekly RBC transfusion events (number of RBC transfusion events during a 4-week period), active bleeding events (number and severity), infections (number of CTCAE Grade 3 and 4 infections and days of acute antibiotic, antifungal and/or antiviral intervention), and safety between the two groups. Additionally subjects will be followed for survival (In Germany for an maximum of 5 years per patient). Pharmacokinetics, pharmacodynamics and pharmacogenomics will be assessed at participating sites in subjects who consented to participate. (This substudy will not be performed in Germany).;Primary end point(s): The achievement of platelet transfusion independence for any 8-consecutive-week period with no worsening of RBC transfusion requirements or hemoglobin (untransfused) during the same 8-consecutive-week period. | — |
Countries
Austria, Czech Republic, Germany, Italy
Outcome results
None listed