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The IPC solutions exhibit phase transformation in vivo. and demonstrate no evidence of toxicity. The pharmacological effects observed from the of release of 3A2-ATG-psODNs suggest that the formulation can entrap, protect, and sustain the delivery of macromolecules. .

The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)-insulin and FITC-albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, alpha-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations > 30% w/v IPC were required to form the gel, however, those mixtures containing > 60% w/v IPC could not be easily injected via 18-22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, alpha-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.

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.

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