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Steven M Horwitz Assistant Attending Memorial Sloan Kettering Cancer Center New York, New York

Steven M Horwitz Assistant Attending Memorial Sloan Kettering Cancer Center New York, New York. Clofarabine for T-cell Lymphomas Not as yet preliminary results from a phase I/II trial. clofarabine structure . C. l. Clofarabine is a Hybrid Purine Nucleoside Analog. N. H. N. H. N. N. H.

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Steven M Horwitz Assistant Attending Memorial Sloan Kettering Cancer Center New York, New York

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  1. Steven M HorwitzAssistant AttendingMemorial Sloan Kettering Cancer CenterNew York, New York Clofarabine for T-cell Lymphomas Not as yet preliminary results from a phase I/II trial

  2. clofarabine structure C l Clofarabine is a Hybrid Purine Nucleoside Analog N H N H N N H H N H 2 2 2 2 2 N N N N N N N N N N N N N N N N N N N N C l F H O O H O O H H O O O O H O O F H O H O H O O H H O O H O deoxyadenosine Cladribine Fludarabine Clofarabine Montgomery, J. Med. Chem. 1992, 35: 397-401

  3. Addition of chlorine provides resistance to deamination clofarabine stability N H 2 N N Addition of fluorine provides resistance to phosphorylytic cleavage N N C l H O O F H O Montgomery, J. Med. Chem. 1992, 35: 397-401 Xie KC, Plunkett W, Cancer Research. 1996, 56:3030-37

  4. comparison of metabolism Fludarabine Cladribine Clofarabine Glycosidic bond cleavage pH < 3 stable labile stable Major metabolites in cells TP MP+TP MP+TP Triphosphate Half-life hrs in CLL >24 13 >24

  5. stereospecificity for cytotoxicityThe arabino configuration is important Parker, Mol Pharmacol. 55, 515, 1999

  6. Mechanism of Action: Clofarabine DNA incorporation Inhibition of DNA synthesis/ repair moa • Inhibits ribonucleotide reductase (RnR), resulting in decreased nucleotide pools • Substrate for DNA polymerases to prevent DNA strand elongation • Clofarabine disrupts the mitochondrial membrane. dNTP pool dNTP pool dNTP pool dNTP pool dNTP pool RNR incorporation P P P P P P P P P P P P a a a a a Polymerase Polymerase Polymerase Polymerase Polymerase , , , , , ε ε ε ε ε Clofarabine Inhibition of DNA synthesis/ Mitochondria ΔΨ ΔΨ ΔΨ ΔΨ ΔΨ 5 5 5 ’ ’ ’ ’ NT NT NT m m m m m dCK dCK dCK dCK Cytochrome C Cytochrome C Cytochrome C Cytochrome C Clofarabine Release Release Release Release Transporter CELL DEATH Clofarabine Parker, Cancer Res 1991, 51: 2386-2394 Xie and Plunkett, Cancer Res 1996;56:3030-3037 Genini, Blood 2000, 96: 3537-43

  7. clofarabine as a single agent in relapsed/refractory adult AML *Genzyme-sponsored study

  8. anecdotes 23 y/o male with relapsed T-lymphoblastic lymphoma (s/p ALL-2) Biopsy at relapse showed NK/T-cell lymphoma (CD3+, CD56+, TdT-) Refractory Hyper-CVAD CR to first cycle of clofarabine, then proceeded to allo transplant In previous cloforabine studies 2 other patients with T-cell disase, T-ALL, both CR

  9. clofarabine in combination

  10. rationale • Anecdotal responses in T-cell and NK/T lymphoma • Long intracellular half-life • Moderate dose dependent toxicities • Good penetration into tissues (extranodal disease) • Potential for combination studies with other active drugs for T-cell lymphoma

  11. objectives-phase I/II study • Determine the MTD and DLT for clofarabine on a q3 week cycle in relapsed/refractory T-cell lymphoma • Preliminary assessment of Efficacy in T-cell lymphoma • Explore basis for future combination studies

  12. design clofarabine clofarabine Phase I/II Study Relapsed/Refractory NK/T or T-cell lymphoma Post transplantation allowed 22 23 24 1 2 3 4 5 Accelerated titration design-start at 4 mg/m2 daily x 3 Grade 2 non-hematologic toxicity-traditional dose escalation 3-6 pt/cohorts Can modify to 5d regimen of q2week regimen Treat expanded cohort at MTD So far-2nd dose level (8mg/m2)

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