GTI-2040

The worldwide steady increase in the number of cancer patients motivates the development of innovative drug delivery systems for combination therapy as an effective clinical modality for cancer treatment. Here, we explored a design concept based on poly(ethylene glycol)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-hydroxyethyl methacrylate-formylbenzoic acid) [PEG-b-PDMAEMA-b-P(HEMA-FBA)] for the dual delivery of doxorubicin (DOX) and GTI2040 (an antisense oligonucleotide for ribonucleotide reductase inhibition) to MCF-7 breast cancer cells. PEG-b-PDMAEMA-b-PHEMA, the precursor copolymer, was prepared through chain extensions from a PEG-based macroinitiator via two consecutive atom transfer radical polymerization (ATRP) steps. Then, it was modified at the PHEMA block with 4-formylbenzoic acid (FBA) to install reactive aldehyde moieties. A pH-responsive polymer-drug conjugate (PDC) was obtained by conjugating DOX to the polymer structure via acid-labile imine linkages, and subsequently self-assembled in an aqueous solution to form DOX-loaded self-assembled nanoparticles (DOX-SAN) with a positively charged shell. DOX-SAN condensed readily with negatively charged GTI2040 to form GTI2040/DOX-SAN nanocomplexes. Gel-retardation assay confirmed the affinity between GTI2040 and DOX-SAN. The GTI2040/DOX-SAN nanocomplex at N/P ratio of 30 exhibited a volume-average hydrodynamic size of 136.4 nm and a zeta potential of 21.0 mV. The pH-sensitivity of DOX-SAN was confirmed by the DOX release study based on the significant cumulative DOX release at pH 5.5 relative to pH 7.4. Cellular uptake study demonstrated favorable accumulation of GTI2040/DOX-SAN inside MCF-7 cells compared with free GTI2040/DOX. In vitro cytotoxicity study indicated higher therapeutic efficacy of GTI2040/DOX-SAN relative to DOX-SAN alone because of the downregulation of the R2 protein of ribonucleotide reductase. These outcomes suggest that the self-assembled pH-responsive triblock copolymer is a promising platform for combination therapy, which may be more effective in combating cancer than individual therapies.

GTI-2040 is a novel antisense oligonucleotide inhibitor of the R2 subunit of ribonucleotide reductase. This phase I study assessed safety and maximum tolerated dose (MTD) of GTI-2040 in combination with weekly gemcitabine in patients with advanced solid tumors.

GTI-2040 was given as a 14-day continuous intravenous infusion, while gemcitabine was administered on days 1, 8, and 15. This combination was repeated every 4 weeks and study followed a modified 3 + 3 Fibonacci schema. Incidence, severity of adverse events, pharmacokinetics (PK), and pharmacodynamics (PD) was assessed. Responses were assessed using RECIST criteria version 1.0 with CT scans performed after every other cycle.

A total of 16 patients received at least one dose of GTI-2040/gemcitabine and were included in the safety analysis. The MTD of this regimen is 100 mg/m²/day of GTI-2040 over 14 days combined with 400 mg/m²/day of gemcitabine administered weekly on days 1, 8, and 15. The dose-limiting toxicities (DLTs) included grade 3 fatigue and thrombocytopenia with hematemesis (both at 100/600 mg/m²/day). The most common adverse events were grade 1/2 fatigue, nausea, vomiting, diarrhea, and anorexia. There was no evidence of alteration in gemcitabine PKs. PD modulation of R2mRNA expression in peripheral blood mononuclear cells was observed. No objective tumor response was observed although stable disease was seen in 25% patients.

The combination of GTI-2040 and gemcitabine has an acceptable safety profile in a heavily pre-treated patient population with advanced solid tumors. No clear signal of anti-tumor activity was observed; however, several patients had prolonged stable disease.