Abstract 2749: MP-470, a dual inhibitor of mutant kinases (c-KIT and PDGFRα) and DNA repair protein Rad 51. Final results from a first-in-man single agent study

Abstract

Background: MP-470 is an orally bioavailable multi-targeted tyrosine kinase inhibitor specifically designed to be a potent inhibitor of mutant c-Kit and PDGFRα. MP-470 is also active as an inhibitor of DNA repair protein Rad51 following chemotherapy. MP-470 has shown synergistic activity with DNA damaging chemotherapy in several xenograft models and in a phase Ib combination study. Presented herein are final results from a MP-470 single agent first-in-man study. Methods: Adult pts with unresectable or metastatic solid tumor cancer refractory to standard therapies or for which no standard therapy exists, adequate bone marrow, renal and hepatic function, and KPS 70 were eligible. The study followed an Accelerated Titration Design. Starting dose was 100 mg/day and dose escalation was based on the modified Fibonacci sequence. Objectives of the study include evaluating the safety profile of MP-470, estimating the therapeutic response rate, and characterizing its pharmacokinetic (PK) profile. Results: Twenty-two pts with a median age of 56 yrs (range, 18-86); 13 M/9 F were enrolled and received MP-470 100-1500 mg/day of the dry powder (DP) formulation for 1-6 (median, 2) 28-day cycles. Median number of prior chemotherapies was 3 (range, 0-11). A positive FDG-PET response was observed on Day 15 in a GIST pt (900 mg/day) who previously failed imatinib and sunitinib. Notably, the percent change in SUVmax from baseline in the pelvis, retrocrural and left lower lobe was reported at 32% (21.3 vs 14.5), 32% (10.5 vs 7.1), and 14% (7.8 vs 6.7), respectively. Related G1/G2 AEs included nausea, vomiting, abdominal distension, diarrhea, dysgeusia, dyspnea, anorexia, hyperkalemia, fatigue, anxiety, heartburn, and alopecia. Related G3/4 AEs included hyponatremia and anxiety. The highest dose reached was 500 mg TID with no DLTs observed. PK evaluation using non-compartmental analysis revealed lower Cmax and AUC with increasing dose. As a result, a lipid suspension (LP) formulation was developed and compared to the existing DP formulation in a single dose randomized, two-way cross-over study in HV. The objective of the study was to determine the relative bioavailability and safety of these two formulations. The LP formulation demonstrated a 6- and 2-fold increase in Cmax and AUC, respectively as compared to the DP formulation (AACR-NCI-EORTC, B209, 2009). Both formulations were well tolerated. Conclusions: The MP-470 DP formulation was well tolerated at doses up to 500 mg TID. A transient response in a highly refractory GIST patient was observed and as such warrants further investigation as a single agent in refractory GIST tumors. A phase 1b study is ongoing in combination with chemotherapy as an inhibitor of DNA repair protein Rad51. An LP formulation in a tocopherol-based vehicle provided improved overall exposure and will be further evaluated in future MP-470 clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2749.

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

“…Molecular modeling of the mutant c-KIT and AXL failed to show IM binding but displayed efficient binding to amuvatinib. In the first-in-human phase I trial of amuvatinib in 22 patients with solid malignancies, the initial formulation did not show consistent pharmacokinetic properties [63]. The plasma levels of the drug were generally low and highly variable.…”

Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers

“…Amuvatinib has been studied in a single-agent, openlabel, dose-escalation, Phase 1, Wrst-in-human clinical trial in 22 patients with solid malignancies [10]. This Phase 1 study used amuvatinib dry-powder capsules (DPC); dosages from 100 to 1,500 mg/day were administered in 28-day cycles (continuous dosing) with patients who derived clinical beneWt receiving up to six cycles.…”

“…A new amuvatinib LSC was developed to increase the systemic exposure levels observed with the amuvatinib DPC [10][11][12]. This article summarizes the results from the three clinical pharmacology studies undertaken in healthy adult subjects to evaluate the systemic exposure of amuvatinib after oral administration of amuvatinib DPC and amuvatinib LSC: a food-eVect study using amuvatinib DPC (Study A [13]), a single-dose study comparing amuvatinib DPC to amuvatinib LSC (Study B [10,14]), and a multipleascending-dose study using amuvatinib LSC (Study C).…”