Abstract 1743: Phase 1 clinical trial of the base-excision repair inhibitor Methoxyamine-HCl (TRC102; MX) in combination with Temozolomide (TMZ) in patients with solid tumors
Authors: Savvides Panos S. , Xu Yan , Liu Lili , Rogers Lisa , Bokar Joseph , Silverman Paula , Dowlati Afshin , Gerson Stanton L. 
Published: August 2012

Abstract
Background: MX is the first base excision repair (BER) inhibitor evaluated in humans. MX blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. In several preclinical studies, improved therapeutic efficacy has been demonstrated with various chemotherapeutic agents. Final results of the phase I clinical trial of pemetrexed and oral MX have been published (GJ Weiss et al). Initial results and correlative studies of the alkylating agent TMZ and MX were previously presented (AACR Annual Meeting 2009, abstract#5433). As initial PK analyses on patient samples revealed a distinct and prolonged half life in humans, 10-fold greater than estimated in dogs, this report reflects the protocol amendment from MX administration as a 5-day intravenous continuous infusion to a 1-hour intravenous infusion. Methods: This phase I dose-escalation trial investigates the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of MX given as an one-hour intravenous infusion in combination with daily times 5 TMZ. PD markers, including analysis of abasic sites measured on DNA extracted from patients’ mononuclear cells (PBMCs) as well as DNA strand breaks determined by comet assay at multiple time points over 5-days. Results: 23 patients have enrolled, at dose-levels (DL) 1 and 2 (TMZ 150 mg/m2/day, days 1-5 and MX 15 mg/m2 and 30 mg/m2 respectively) in two cohorts. In cohort A (patients with no-CNS disease, n =13 at DL1 and n=4 at DL2) primary tumors include lung, breast, pancreatic, colon, esophageal, ovarian, oropharyngeal, salivary gland, skin adnexal tumors. In cohort B (patients with CNS tumors, n =3 at DL1 and n=3 at DL2) primary tumors include brain, pancreatic, head and neck.The combination of MX and TMZ has been well-tolerated. For the non-CNS involvement cohort, one DLT was observed at DL1; grade 3 psychosis in a patient with progressive disease on increasing doses of opioids. A grade 3 allergic reaction classified as an idiosyncratic event resulted in further expansion to 10 evaluable patients with no additional DLTs observed. To date no DLTs have been observed at DL2 and in the CNS-involved cohort. Three patients had stable disease (lung, ovarian, head and neck) with extended dosing periods of 7, 10 and 11 months. The PK results will be presented separately. In all patients evaluated, abasic sites were blocked by MX resulting in an increase in DNA strand breaks. No significant anemia (the DLT observed in the MX and pemetrexed trial) has been observed at DL1 and 2 to date; possibly because of lower MX dose administered.Conclusions: MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. Ongoing data in this phase I clinical trial demonstrate that the combination of MX with TMZ is well tolerated and hits its target, interrupting base excision repair in all patients. Trial remains open to accrual.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1743. doi:1538-7445.AM2012-1743