Phase I trial of the multi-drug resistance (MDR) Protein-1 (MRP-1) modulating agent sulindac (S) plus epirubicin (E) in patients (pts) with advanced cancer

Abstract

2129 Background: MDR refers to the development of R to multiple chemotherapy (CRx) drugs, either de novo, or, following exposure to a single agent. MDR mediated by the ATPase binding cassettes mdr/pGP and MRP-1 are amongst the best characterised. Clinical trials of pGP substrate CRx together with pGP inhibitors have not been conclusively shown to overcome clinical MDR. We hypothesise that the heterogeneity of R phenotypes in human cancers will mandate an alternative approach in which multiple R mechanisms are simultaneously antagonised. As research in NICB had demonstrated that S antagonises MRP-1 mediated MDR, we performed a translational phase I, dose escalation and pharmacokinetic (PK) trial to determine the maximum tolerated dose (MTD) of this agent when used in combination with Epirubicin. Methods: Eligibility: advanced Ca without anthracycline exposure, adequate organ function and performance status. Treatment:Up to 6 cycles of E (75mg/m2) + escalating dose S. (0, 200, 400, 600, 800mg, no intra-patient escalation). S was administered orally 2 hours prior to each E administration. PK analysis was carried out following 1st and 3rd cycles. Results: A total of 17 pts (breast 8, lung 3, colon 2, melanoma 1, renal 1, unknown primary 2; prior CRx 15) were enrolled between 5/2001–6/2003. Eight pts received 6 cycles, 14 pts >/=3 cycles. Dose limiting toxicity was observed in 2 pts at S800 (1-increased creatinine; 1-fatal haemorrhage). Another patient died from neutropenic sepsis at S 400. PK analysis is ongoing. Partial response (11 month) was seen in one patient (melanoma). A second patient with platinum/taxotere pre-treated evaluable NSCLung Ca had PR of 9 month duration Conclusions:The MTD of this combination was identified as S 600mg, and this is the recommended dose for phase II studies. We are studying this combination in melanoma, and will conduct a phase I with pGP and MRP-1 inhibition. No significant financial relationships to disclose.