Abstract C131: CBP501 (CBP), a novel cell cycle dysregulator, in combination with cisplatin (CDDP) and pemetrexed (PM) - pharmacokinetics (PK) in two phase I/II studies

Abstract

Abstract Background: CBP is a synthetic peptide that enhances intracellular CDDP and enhances DNA damage caused by bleomycin or CDDP. Activity has been demonstrated in various tumor models. Two clinical trials have evaluated CBP combinations, determining maximum tolerated dose (MTD), DLT, safety, activity and PK: Study A, phase I, CBP with CDDP in solid tumor pts; Study B, phase I part, CBP with CDDP and PM in solid tumors, randomized phase II part CDDP/ PM with or without CBP in mesothelioma pts. Materials and Methods: Eligibility criteria were standard. CBP was given i.v. over 1 hr, with prophylactic anti-allergics for a histamine release syndrome, and folic acid vitamin supplementation (PM treated pts). Study A: q3w, CBP 3.6 to 36.5 mg/m2, CDDP 75 mg/m2, with PK assessed on cycle (C) 1 Day (D) −7 (CBP alone) and C1D1. Study B: q3w, CBP/CDDP/PM doses 16 or 25/75/500 mg/m2, with PK assessed on C1D1, C2D1 (CBP) and C2D2 (CDDP/PM). Samples were drawn at 6 timepoints over 8 hours (h) and at 24 h. An LC-MS/MS assay method was used, with a 10 ng/mL limit of detection for CBP. PK parameters were determined by non-parametric methods. Results: The studies were conducted in 12 US centers. 50 pts were assessed for PK (35 Study A, 15 Study B). CBP Cmax and AUC were doseproportional over the studied dose range (r2>0.8). Variability of CBP PK was moderate (Coefficient of variation [CV] 20–30%). PK of CBP 25 mg/m2 were comparable in 7 pts when CBP was administered alone and with CDDP in study A, and appeared to be comparable between C1 and C2 in study B (only 3 pts so far). Results for CBP alone and in combination with CDDP are consistent with a single agent trial (Wong et al, ASCO 2008, abstract 2528). However, CBP Cmax and AUC appear to be lower in pts receiving PM; whether this is due to the co-administration of PM or to differences between study A and B has not yet been determined. PM and platinum plasma and ultrafiltrate PK parameters were consistent with those reported in the literature (Dickgreber et al, 2009, Clin Cancer Res, 15, 382–9). No significant variations according to cycle, regimen or study were observed. Conclusion: CBP displays dose-proportional PK in combination with both CDDP and PM, without any apparent effect on CDDP or PM PK, and without any observed effects over 2 cycles. PK evaluations are ongoing in study B, which should allow the clarification of the eventual effect of PM on CBP PK. Mean PK parameters (CV) on Cycle 1 Day 1 CBP 25 mg/m2 With PM/without PM N=5/N=8 CDDP 75 mg/m2 Plasma Pt/ultrafiltrate PT N=43 PM 500 mg/m2 With CBP/without CBP N=8/N=5 Cmax (µg/mL) 5.30 (24)/6.16 (26) 3.33 (22)/1.78 (46) 113.55 (19)/110.30 (25) AUC0−∞ (µg.h/mL) 15.10 (19)/18.81 (22) 142.00 (47)/4.64 (38) 248.27 (33)/275.38 (30) t½ (h) 3.48 (31)/3.79 (17) 47.68 (61)/11.01 (140) 2.57 (27)/3.19 (24) Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C131.