A Phase I and Pharmacodynamic Trial of Timed Sequential Administration of the Cyclin Dependent Kinase 4/6 Inhibitor PD 0332991 Followed by Cytarabine plus Mitoxantrone for Adults with Relapsed and Refractory Acute Leukemias and High-Risk Myelodysplasias
1.1 Primary Objectives â?¢To determine the feasibility, tolerability, and toxicities of administering the selective CDK 4/6 inhibitor PD 0332991 prior to the combination of ara-C and Mitoxantrone for adults with relapsed and refractory acute leukemias and high risk myelodysplasias (MDS), including primary refractory disease â?¢To determine the direct cytotoxic effects of single agent PD 0332991 on malignant blasts â?¢To determine the maximal tolerated dose (MTD) of PD 0332991 in timed sequential combination with ara-C and Mitoxantrone â?¢To determine if the timed sequential combination of PD 0332991 with ara-C and mitoxantrone can induce clinical responses in adults with relapsed or refractory acute leukemias and high-risk MDS 1.2 Secondary Objectives: â?¢To determine the ability of PD 0332991 to directly induce apoptosis in malignant cell populations in vivo â?¢To obtain pharmacodynamic (PD) data regarding the ability of PD 0332991 to arrest malignant cells in the G 1 phase of cell cycle, followed by synchronized release of those cells into S phase upon discontinuation of PD 0332991 and resultant enhanced ara-C cytotoxicity
Tumor types: Adults age greater than 18 years with relapsed or refractory acute leukemias or high-risk myelodysplasias (MDS), including primary refractory disease Performance Status: ECOG 0-2 Abnormal Organ Function Permitted: ï¿½ Multilineage bone marrow failure ï¿½ Serum creatinine less than 2.0 mg/dl ï¿½ Hepatic enzymes (AST, ALT) less than 3x upper limit of normal (ULN) ï¿½ Bilirubin less than 2.0 mg/dl, unless due to Gilbert's disease, hemolysis or leukemic infiltration ï¿½ Left ventricular ejection fraction ï¿½ 45% ï¿½ QTc less than 470 msec ï¿½ RB expression is required for the action of PD 0332991. Because rb deletions and mutations are rare in acute leukemias and MDS, screening for RB expression will not be required before enrollment. Pretreatment biopsies will be stored and analyzed for RB expression if needed subsequently. Prior Therapy: ï¿½ No more than 5 cytotoxic regimens ï¿½ Previous allogeneic or autologous stem cell transplantation permitted ï¿½ ï¿½ 3 weeks delay from prior cytotoxic chemotherapy or radiation therapy ï¿½ ï¿½ 2 week delay from prior biologic therapies including hematopoietic growth factors and vidaza or decitabine ï¿½ If using Hydroxyurea, steroids, tyrosine kinase/src kinase inhibitors, arsenic, interferon for count control, must be off therapy for greater than 48 hours prior to beginning PD 0332991 ï¿½ No concomitant use of potent CYP450 3A4 inhibitors (e.g. triazole antifungal agents) or inducers (e.g. omperazole, dilantin, dexamethasone) within 7 days prior to beginning PD 0332991
â?¢PD 0332991 will be given orally days 1,2,3 oLevel 1 equal to 125 mg/day x 3 oLevel 2 equal to 150 mg/day x 3 oLevel 3 equal to 175 mg/day x 3 oLevel 4 equal to 200 mg/day x 3 oLevel 5 equal to 225 mg/day x 3 If 2/3 or 2/6 patients at dose level 1 experience dose limiting toxicities (DLT), we will de-escalate PD 0332991 to 100 mg/day x 3. â?¢Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion at a total dose of 2 gm/m2 beginning on day 6 â?¢Mitoxantrone will be given over 2 hour infusion at a total dose of 40 mg/m2 on day 9, 12 hours after the completion of the ara-C infusion.
05/18/2013 04:02 AM