1 / 12

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.

tcolon
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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)

More Related