A Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase (RNR) in Combination with High-Dose Cytarabine (HiDAC) in Relapsed or Refractory Acute Myeloid Leukemia (AML): Pharmacokinetics (PK), Pharmacodynamic (PD) and Clinical Results.

GTI-2040 is a 20-mer antisense to the R2 component of RNR mRNA. RNR is required for the conversion of ribonucleotides to deoxyribonucleotides, a crucial step during DNA synthesis and repair. Cytarabine (AraC) is a cytotoxic agent that is converted into AraC triphosphate (Ara-CTP) and is the backbone of several regimens in AML. Ara-CTP competes with deoxycytidine for DNA incorporation. We hypothesize that RNR downregulation by GTI-2040 results in decrease of levels of deoxycytidine thereby leading to a preferential DNA incorporation of ARA-CTP and increase in its cytotoxic activity. To test this hypothesis we undertook a CTEP-sponsored Phase I dose-escalation study of GTI-2040 plus HiDAC in patients (pts) with relapsed or refractory AML. Pts were stratified in 2 cohorts according to age. Cohort I (18–59 yrs) received escalating doses of GTI-2040 (dose level 1: 3.5 mg/m²/d) by continuous IV infusion (CIVI) on d 1–6 combined with escalating doses of cytarabine IV over 2 hrs q12 hrs on d 2, 4, and 6 (dose level 1: 2500 mg/m²/dose). Cohort II (≥60 yrs) received GTI CIVI on d 1–6 and cytarabine IV over 4 hrs on d 2 to 6 (dose level 1: 1500 mg/m²/d). To date, 30 pts were enrolled. Pts received median of 1 prior regimen (range 1–3). Cohort I included 8 pts with relapsed and 6 with refractory disease; 7 had intermediate risk cytogenetics (CyG) and 7 adverse CyG; 6 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory disease; 8 pts had intermediate risk CyG and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC therapy alone. Grade 3/4 non-hematologic toxicities included fatigue, fevers, anorexia, pneumonitis, and catheter related infections; a grade 3 reversible cerebellar toxicity (n=1) was observed at level 1/cohort I. An ELISA-based assay with a limit of quantification of 50 pMol was used to determine GTI2040 plasma and intracellular (IC) concentrations. Dose-dependent increase in plasma steady state concentration (Css) and area under the curve (AUC) of GTI2040 was observed in both cohorts, although higher AUC and longer t1/2 were demonstrated in the younger pts compared to the older ones. In cohort I, disease responses were seen at all dose levels Five of 14 pts achieved complete remission (CR) and one achieve incomplete CR (CRi; i.e., no marrow disease and incomplete blood count recovery). In cohort II, no disease response was observed. Median IC GTI2040 concentration in BM mononuclear cells at 120 hours following start of antisense infusion was higher in younger (i.e., 175 nM) than in older (i.e., 75 nM) pts. A median decrease in R2 protein levels of 50% (range 50–90%) detected by immunoblotting was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I CR pts (n=4) had a median 50% decrease and non-responders (n=9) had a median 200% increase in R2 levels. In cohort II changes in R2 levels did not predict disease response. In summary, combination of GTI-2040/HiDAC is feasible. PK/PD studies demonstrate achievable plasma and IC levels of the antisense and target downregulation. Disease response was observed only with the dose/schedule administered to younger pts. Dose escalation in this group continues to establish a recommended dose for Phase II trials. [NCI U01 CA 76576-05].