Pharmacokinetic profile of the base-excision repair inhibitor methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion with temozolomide (TMZ) in the first-in-human phase I clinical trial.
2010; Lippincott Williams & Wilkins; Volume: 28; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2010.28.15_suppl.e13662
ISSN1527-7755
AutoresP. Sawides, Yan Xu, L. Liu, Joseph A. Bokar, Paula Silverman, Afshin Dowlati, S L Gerson,
Tópico(s)Polyomavirus and related diseases
Resumoe13662 Background: MX, the first base excision repair (BER) inhibitor evaluated in humans, blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. Initial results of the administration of MX have been presented (AACR Annual Meeting 2009, abstract #5433). Pharmacokinetic (PK) analyses revealed a distinct PK profile different from that observed in mice and dogs, where half- life of MX was 19 minutes and 4.5 hours (h) respectively. In humans, MX half life is estimated to be 45.3 h (range: 32 − 68.8 h). As a result, the MX administration was adjusted from a 5-day intravenous (iv) continuous infusion (CI) to a 1-hour iv infusion. Methods: This ongoing phase I dose-escalation trial investigates the safety, PK, and pharmacodynamic (PD) profile of MX given as an one-hour iv infusion in combination with TMZ. PD markers, including analysis of AP sites measured on DNA extracted from patients' mononuclear cells (PBMCs) as well as DNA strand break determined by comet assay at multiple time points, are included. Results: 4 patients enrolled, at dose-level 1 (TMZ 100 mg/m2/day po, days 1-5 and MX 15 mg/m2 IV on day 1). Various primary tumors (lung, breast, pancreatic, skin adnexal) included. The average half-life of MX was 46.8 h (range: 20.4–62.7 h, based on 8 treatment cycles from 3 patients), not statistically different from the 5-day CI regimen. Treatment has been well tolerated. One grade 3 toxicity possibly treatment related (hallucinations in one patient with progressive disease and on opioids). PD results showed that administration of the combination of TMZ and MX resulted in 30–60% reduction in detectable AP sites. Comet assay results revealed that the combination of TMZ and MX induced a 2 to 3-fold higher levels of DNA strand breaks compared to TMZ alone. Conclusions: Initial data demonstrate that MX in combination with TMZ is well tolerated. MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. PD demonstration of MX's biologic activity on patients' mononuclear cells has been demonstrated even at the first dose level. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRACON TRACON
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