1. AbstractSchema Treatment Toxicities Conclusion First in human phase 1 clinical trial of the base-excision repair inhibitor Methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion in combination with Temozolomide (TMZ) in patients with solid tumors. Panos S. Savvides, Yan Xu, Lili Liu, Lisa Rogers, Joseph Bokar, Paula Silverman, Afshin Dowlati, Stanton L. Gerson Seidman Cancer Center and CASE Comprehensive Cancer Center, Cleveland, OH. Best Response 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. The final results of the phase I clinical trial of the combination 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 PK profile in humans, with a 10-fold increase in estimated half-life when compared to the half-life observed in dogs, the protocol has been amended with MX administration adjusted from a 5-day intravenous continuous infusion to a 1-hour intravenous infusion. Methods: This ongoing 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 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 during the 5-day treatment, are included. 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 disease, n =3 at each DL1 and 2) primary tumors include brain, pancreatic, head and neck tumors.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 of the cohort to 10 evaluable patients with no additional DLTs observed. No DLTs have been observed at DL2. For the CNS- involved cohort no DLTs have been observed to date. Three patients had stable disease (lung, ovarian, head and neck primaries) Conclusions: MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen for further development. Ongoing data from the 1- hour infusion MX regimen in the first in humans MX phase I clinical trial demonstrate that MX in combination with TMZ is well tolerated. 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 at DLs 1 and 2 compared to MX DLT dose in the pemetrexed trial. Trial remains open to accrual. Eligibility Criteria Patient CharacteristicsCorrelative studies Cycle 1 (duration: 2 weeks) Week1Day1Day2Day3Day4Day5 TMZ↓ MX↔ Cycle 2 and subsequent (q 4 weeks) Week1Day1Day2Day3Day4Day5 TMZ↓↓↓↓↓ MX↔ ● Histologically confirmed solid tumor; incurable ●Priorchemotherapy and/or radiation are allowed. ●Prior temozolomide treatment is not restricted. ●Age >18 years. ●ECOG performance status <2 ●Life expectancy > 12 weeks. ●Patients must have normal organ and marrow function DOSE-ESCALATION SCHEDULE (cohort A) Dose Level Dose TMZ (mg/m 2 /day) x5days MX (mg/m 2 ) Level -110015 Level 115015 Level 215030 Level 315060 Level 4150100 Level 5150 Cohort A ( No CNS disease) Dose level 1N= 13 Dose level 2N = 4 Primary tumors Lung, breast, pancreatic, colon, esophageal, ovarian, oropharyngeal, salivary gland, skin adnexal tumor Cohort B (CNS disease) Dose level -1N = 3 Dose level 1N = 3 Primary tumorsBrain, pancreatic, head and neck Cohort A ( No CNS disease) Dose level 1 1DLT (grade 3 psychosis) Note: Expansion to 10 evaluable patients b/o 1 idiosyncratic event (gr 3 allergic reaction) with no DLTs Dose level 2No DLTs Cohort B (CNS disease) Dose level -1No DLTs Dose level 1No DLTs Supported in part by NIH grant: R21 CA126149 ClinicalTrials.gov Identifier: NCT00892385 ● TRC102 can be safely administered as a one-hour infusion ● The combination of TRC102 with TMZ is well tolerated ● Correlative studies demonstrate that TRC102 interrupts base excision repair in all treated patients, even at the lowest level ● Stable disease ( n = 3) ● Treatment duration 7, 10, 11 months ● Primary tumors (lung, ovarian, head & neck) Cycle HL_Lambda_z (h) Cmax (ng/mL) AUCINF_obs (h*ng/mL) Vss_obs (L/kg) 1.0064.667.75602.1046.66 2.0060.904.86400.7869.83 3.0063.7514.60653.5145.79 Mean63.1029.070552.13354.093 SD1.9625.002133.56813.632 CV%3.155.224.225.2 DNA strand breaks detected by Comet assay in PBMCs in patients treated with TMZ and MX. (A) DNA double strand breaks detected by neutral comet assay. (B) DNA single strand breaks detected by alkaline comet assay. The cells were mixed with low-melting agarose, lysed and the DNA was electrophoresed in both alkaline and neutral conditions to detect DNA single and double strand breaks, respectively. TRC102 half-life:55.04 h (range:12.2-100.3h, n=20) Typical PK profile: TRC102 15mg/m2, (Pt #13, cycle#1) AP sites formed over time after a single dose of TMZ and low levels of AP sites were detected in cells treated with combination of TMZ and MX.