A phase I study of GTI-2040 (G), an antisense to ribonucleotide reductase (RNR), in combination with high-dose AraC (HiDAC) in acute myeloid leukemia (AML)

Abstract

6561 Background: RNR converts ribonucleotides to deoxyribonucleotides for DNA synthesis. AraC is converted into AraC triphosphate (AraCTP) and competes with deoxycytidine for DNA incorporation. We hypothesized that RNR downregulation by G leads to lower deoxycytidine levels, preferential AraCTP incorporation into DNA and increased cytotoxicity. A CTEP-sponsored Phase I dose escalation study of G +HiDAC in relapsed/refractory AML tested this hypothesis. Methods: Cohort I (18–59 yrs) received G (dose level (DL) 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 + AraC IV q12 hrs on d 2, 4, 6 (DL1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received G CIVI on d 1–6 +AraC IV on d 2 −6 (DL1: 1500 mg/m2/d). An ELISA-based assay measured plasma and intracellular concentration (IC) of G. Results: To date, cohort I included 9 pts with relapsed and 9 with refractory AML; 9 had intermediate and 9 adverse risk cytogenetics (CyG); 8 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory AML; 8 pts had intermediate and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC alone. The younger pts had higher AUC and longer t1/2. Of 16 pts evaluable in cohort I (median time to 1st relapse 6 mos), 6 had complete remission (CR) and 1 incomplete CR (no disease and incomplete blood count recovery). In cohort II, no responses were observed. At 120 hrs of antisense infusion, median G IC in marrow cells was higher (i.e., 175 vs75 nM) in younger than in older pts. A median 50% decrease in RNR protein was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I, a median 50% decrease and 200% increase in RNR was noted in CR (n=4) and non-responder (NR; n=9) pts, respectively. In cohort II R2 downregulation did not predict response. In cohort I 62% of the ICs was in nucleus and 21.2% in cytoplasm in CR pts (n=3) vs. 20.3% and 53.5% in NR pts(n=5). Conclusions: G/HiDAC is feasible. Robust plasma and IC levels of G and target downregulation are achievable in vivo. Responses (41%) were observed only in the younger cohort, where CR pts had higher G nuclear IC and target downregulation than NR pts. Dose escalation continues in the younger cohort to establish a dose for Phase II trials. No significant financial relationships to disclose.