A phase I and pharmacokinetic (PK) study of high dose selenomethionine (SLM) in combination with irinotecan (IRI) in patients with advanced solid tumors

Abstract

2080 Background: SLM, an organic selenium (Se) compound, potentiates IRI activity, protects against toxicity, and allows dose-escalation of IRI in pre-clinical models. IRI dose-escalation in mice models was possible only in association with serum Se concentrations > 1200ng/ml. We initiated a phase I study of daily SLM with weekly IRI to investigate: 1) the maximum tolerated dose (MTD) of IRI when combined with high dose SLM; 2) the pharmacokinetics (PK) of both compounds. Methods: IRI was escalated in a standard 3+3 design. SLM was administered at a fixed dose of 2200 μg/day starting 1 week before the 1st dose of IRI. IRI was administered intravenously weekly x 4 repeated every 6 weeks (1cycle). Dose level (DL) 1 and DL2 consisted of IRI 125mg/m2 and 160mg/m2 respectively. Blood for Se was drawn on days 1, 2, 8, 15, 29 and 50 (and later where possible). Results: 10 evaluable pts were treated on study (M/F: 6/4; median age: 59; ECOG 0/1: 3/7; prior chemo: 10). At DL2, 3 out of 4 pts had G3 diarrhea (DLT). None of the 6 DL1 pts had a DLT (declared MTD). Diarrhea was ≤ G2 (1 pt with G2) and neutropenia ≤ G2 at DL1 except for 1 pt with G4 neutropenia. SLM was associated with mild intermittent garlic-like breath. Se PK showed a suboptimal concentration <1000 ng/ml on day 1 of IRI. The mean Se (SD) serum half-life was 183 (94) h, and CLt/F 0.10 (0.04) L/h. Modeling of data suggests steady state attainment after ∼30 days, with a median Se steady state level of 844 (range 585 -1300) ng/ml. Responses were evaluable in 8 patients: 1 pt with prior IRI-refractory colon cancer had a partial response that is ongoing (11 months +). This patient had complete reversal of total alopecia upon built up of Se concentrations > 1200 ng/ml. 4pts had prolonged stable disease (Colon, NSCL, pancreatic, and gastric cancer). Conclusions: The administration of SLM at 2200 μg PO QD is safe but does not allow IRI escalation > 125mg/m2/week. Unexpected responses and disease stabilizations were noted at the MTD suggesting possible synergy between SLM and IRI. The inability to escalate IRI may be related to suboptimal concentrations of Se on D1 of IRI. SLM escalation in combination with fixed dose IRI is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sabinsa Sabinsa