Abstract

Abstract 3879Poster Board III-815 IntroductionPreclinical and clinical studies have demonstrated the central importance of the PI3K/AKT axis in malignant cell survival and proliferation, yet few therapeutic options have been available. SF1126 is a conjugate comprised of the well-characterized PI3K inhibitor SF1101 (LY294002) attached to a vascular-targeting tetra-peptide (SF1174) designed to bind to RGD-recognizing integrin receptors expressed on endothelial and tumor cells resulting in angiogenesis inhibition and direct antitumor effect. SF1126 has recently demonstrated reversal of resistance mediated through the PI3K/PTEN pathway in trastuzumab-resistant HER2-over-expressing breast cancer cell lines. From the parallel solid tumor study (ASCO 2009), SF1126 was well tolerated, inhibited the PI3K pathway selectively in tumor tissue, and resulted in stable disease in a heavily pretreated population. The rationale for using SF1126 in myeloma is based upon a body of work from Durden et al. (ASH 2007) and David et al. (ASH 2008) demonstrating in vivo and in vitro activity in human myeloma cell lines and xenograft models. These studies demonstrated SF1126 has activity at 5-10uM and combines safely and with enhanced efficacy with dexamethasone, melphalan, and bortezomib. MethodsPatients were eligible if they had relapsed or refractory myeloma with at least 2 prior lines of therapy. Dose escalation using Bayesian methodology [Escalation With Overdose Control (EWOC)] incorporated information from the solid tumor trial along with information from this trial. In addition to standard measures of efficacy, a novel assay assessing in vivo PI3K inhibition was evaluated. Briefly, we have developed a protocol for multiparameter flow cytometry analysis of intracellular phosphoepitopes for monitoring pharmacodynamic (PD) molecular targets of SF1126 in study subject's myeloma cells. The aims are to determine: 1) constitutive activation of AKT (by comparing to ex vivo LY294002 treatment) 2) AKT activation in response to IGF-1 (a microenvironment stimulus) 3) inhibition of basal activation and/or inhibition of IGF-1 potentiated response following SF1126 treatment and 4) correlation of this analysis to SF1126 dose and patient response. Subjects undergo serial bone marrow (BM) sampling on day 0 and day 1 (4 hrs after dosing) of cycles 1 and 2. ResultsTo date, a total of 7 patients have been treated with escalating doses ranging from 90 to 1110 mg/m2. Most patients were male (6), median age was 63 (50-69) and median number of prior treatments was 8 (3-10). All had documented refractory disease with bone marrow aspirates showing plasma cell percentages of 30-90%. No grade 4 drug-related toxicities have been noted to date. Approximately one-third of patients experienced grade 2 nausea/vomiting. Constitutional symptoms included fatigue and loss of appetite. Although preclinical studies demonstrated a rise in blood glucose one hour post infusion, this was not seen in any patients receiving drug. The dose limiting toxicity is still undefined. Median number of cycles is 1 (0.4-2.5), with one patient achieving stable disease (urinary protein stabilized following rapid rise prior to study initiation). All patients were taken off study due to progression. In vivo inhibitory effects of SF1126 on the pathway were demonstrated in bone marrow samples. PK data demonstrates similar PK to what has been seen in the solid tumor trial: a) SF1126 is rapidly cleared post-infusion; b) PK of active hydrolysis product (LY294002/SF1101) shows t1/2 ∼1.1-1.5 hrs; c) dose proportional Cmax and AUC(0-t); d) AUC values at doses ≥ 140 mg/m2 exceed those found effective in mouse xenograft studies. ConclusionThe PI3K inhibitor SF1126 resulted in similar PK to that seen in solid tumor patients and in vivo studies demonstrated that PI3K activity in the plasma cell compartment of the bone marrow had suppression of this key pathway following SF1126. Completion of the study at the current dose (1110mg/m2) and planning for a future trial combining SF1126 with other active agents in myeloma is currently ongoing. Additional PK/PD and clinical data from this trial will be available. Disclosures:Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Garlich:Semafore Pharmaceuticals: Employment, Equity Ownership, Research Funding. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria.

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