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A Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of GTI2040 (GTI), a novel ribonucleotide reductase inhibitor in combination with gemcitabine (Gem) in adult patients (pts) with advanced solid tumors.

2007; American Association for Cancer Research; Volume: 6; Linguagem: Inglês

1538-8514

Chris H. Takimoto, Quincy Chu, Yun Yen, Patricia O'Rourke, J. C. Cooper, Sam Pardo, Anthony W. Tolcher, Amita Patnaik, Kyriakos P. Papadopoulos, Muralidhar Beeram, Alejandro D. Ricart, Chia‐Chi Lin, Alain C. Mita, Emiliano Calvo, Igor Espinoza‐Delgado, Jamie Zwiebel, John Sarantopoulos,

Colorectal Cancer Treatments and Studies

C160 Background: GTI2040 is a 20-mer oligonucleotide complementary to the R2 component of ribonucleotide reductase (RNR) mRNA. Inhibition of R2 mRNA translation decreases RNR activity and impairs the formation of deoxynucleotides necessary for DNA synthesis. Down regulation of RNR can enhance DNA incorporation of nucleoside analogues, such as gemcitabine, and in some cases can overcome gemcitabine resistance. In preclinical models, the combinations of GTI-2040 and gemcitabine demonstrated enhanced antitumor efficacy. Based upon these promising findings, a Phase I PK-PD study of this combination was initiated in adult solid tumor pts.
 Methods: Pts ≥18 years with a confirmed cancer diagnosis, adequate organ function, ECOG performance status of 0 to 2 and no remaining standard treatment options were eligible. Prior gemcitabine therapy was permitted. Dose escalation was performed in a standard 3+3 design. Dose level (DL) 1 consisted of Gem 400 mg/m2 given on days 1, 8, and 15 and GTI was infused continuously at 100 mg/m2/d from days 2 to 15, with cycles repeated every 4 weeks (wks). Beginning cycle 2, both drugs were administered starting on day 1 of each cycle. Dose-limiting toxicities (DLT) were assessed during the first cycle prior to dose escalation. DL 2 Dose consisted of GTI 100 mg/m2 and Gem at 600 mg/m2 on the same schedule. Gem plasma kinetics and intracellular peripheral blood mononuclear cells (PBMC) Gem metabolites (dFdCTP) were monitored on days 1 and 8 in cycle 1. The PD effect of GTI on the relative expression of R2 RNR mRNA in PBMC was also assessed by quantitative PCR at baseline and after initiation of GTI therapy during cycle 1.
 Results: Overall, 16 pts were enrolled, and the first 3 pts treated with GTI/Gem at 100/400 tolerated therapy well. At DL2 consisting of GTI/Gem at 100/600, 2/6 evaluated pts experienced a DLT (grade 3 fatigue and 2 wks of interrupted Gem therapy due to gr 3 platelets and anemia). This exceeded the MTD, and 7 additional patients were enrolled at the MTD of GTI/Gem of 100/400. No further DLTs were observed. Other common toxicities included thrombocytopenia, fatigue, anemia, and modest leucopenia. One patient died while on study from disease related GI hemorrhage. At the MTD, the Gem Cmax ranged from 5430 to 9210 ng/mL and the AUC ranged from 3170 to 3206 hr·ng/mL, which are comparable to values seen in previous PK studies of single agent Gem. The intracellular Gem metabolite dFdCTP was detected in the PBMCs obtained from 10 of 15 patients analyzed; however, this did not correlate with drug toxicity. Relative R2 RNR mRNA expression in PBMC, a surrogate tissue, decreased after 24 hrs of GTI therapy in 10 of 12 pts analyzed 24 hours after the start of the GTI infusion (mean change = -29.3%, range -85.8 to +38.4%), consistent with the intended molecular effect of this targeted antisense molecule. No objective responses were observed.Correlative studies and evaluation of signals of activity will be presented. Conclusions: GTI at 100 mg/m2/d for 14 days plus Gem at 400 mg/m2/wk x 3 every 28 days is well tolerated in adult cancer patients. Gem kinetics are not altered, but a dose reduction relative to single agent Gem is required.