GTI-2040 + cytarabine

GTI-2040 + cytarabine is a combination therapy under investigation for the treatment of acute myeloid leukemia, particularly in relapsed or refractory settings. **GTI-2040** is a 20-mer antisense oligonucleotide that specifically targets the mRNA of the R2 (M2) subunit of ribonucleotide reductase, an enzyme essential for DNA synthesis. By downregulating this subunit, GTI-2040 reduces the intracellular deoxynucleotide pool, thereby potentially increasing the cytotoxic effectiveness of **cytarabine** (AraC), a nucleoside analogue chemotherapeutic that is incorporated into DNA and interferes with DNA synthesis and repair. Inhibition of ribonucleotide reductase with GTI-2040 is hypothesized to enhance cytarabine's incorporation into leukemic cell DNA and overall cytotoxicity. The combination has been studied in phase I and II trials in both younger and older adult acute myeloid leukemia (AML) patient populations, showing biological activity (target knockdown) and some clinical responses, but limited success especially in elderly patients. Neurotoxicity was noted as a dose-limiting toxicity. The maximum tolerated dose established in phase I was 5 mg/kg/day GTI-2040 (continuous IV infusion, days 1–6) and 3 g/m^2/dose cytarabine every 12 hours for 8 doses in one study.