• Phase I: Determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of oxaliplatin with fludarabine and cytarabine. Phase II: Assess objective response rates; and including complete response rates, define safety and toxicity.
  

• (a) Determine the duration of response, disease-free survival, & overall survival. (b) Determine pharmacokinetics and pharmacodynamics of oxaliplatin administered alone and following infusion of fludarabine and cytarabine.
  

Cytarabine is designed to insert itself into DNA (the genetic material of cells) and stop the DNA from repairing itself, ultimately causing cell death.

Fludarabine is designed to make cancer cells less able to repair damaged DNA and, therefore, it increases the likelihood of the cells death.

Oxaliplatin is designed to "program" leukemic cells to die.

The rationale for combining oxaliplatin with fludarabine and cytarabine is based on preclinical data demonstrating the synergistic cytotoxicity of oxaliplatin in combination with the nucleoside analogs cytarabine and fludarabine.

We hypothesize that the fludarabine/cytarabine combination may modulate oxaliplatin sensitivity in leukemic blasts by inhibiting DNA and excision repair of the oxaliplatin adducts, thereby resulting in synergistic cytotoxicity in AML and high-risk MDS.

In AML, increases in DNA repair processes have been suggested as the mechanism underlying resistance to agents that form DNA adducts. However, this increased capacity for excision repair could provide an opportunity for incorporation of nucleotide analogs into the DNA repair patch. Such incorporation at once blocks DNA repair and initiates signals for cell death.

We hypothesize that treatment of AML and high-risk MDS with nucleotide analogs and oxaliplatin will create a mechanistic interaction of these agents that will increase the killing of leukemia cells.