C. Mita’s research while affiliated with Brooke Army Medical Center and other places

3512 Background: The combination of S and T is hypothesized to maximize pathway inhibition by concurrently targeting parallel signaling mechanisms and will abrogate potential resistance mechanisms directed towards the MAPK pathway through increased signaling via the survival pathway involving PI3K/Akt. Methods: Eligible patients (pts) were treated with escalating continuous oral doses of S (200 and 400 mg BID) and weekly T IV (15 mg, 25 mg). S began on day 8 of course 1 to permit PK evaluations of T. PD studies in PBMCs were performed serially in pts. Results: To date, 24 evaluable pts have received 85 courses [median 3;range1–12] in the following S/T dose cohorts; cohort 1: 200 mg/15 mg (n=6), cohort 2: 400 mg/15 mg (n=11), cohort 3: 400 mg/25 mg (n=6), and cohort 4: 200 mg/25 mg (n=1). Patients demographics were males/female 11/13, median age 54.5 [range 27–71] and PS of 0/1/2 : n=9/13/2. Dose limiting toxicities (DLT) were grade 3 typhlitis in 1/6 pts in cohort 1, and mucositis in 1/6 pts in cohort 2. Expansion of cohort 2 to 11 patients resulted in 4 additional DLTs (hand foot syndrome (HFS) x 2 pts, thrombycytopenia/rash x 1 pt, creatinine elevation x 1 pt). 3 of 6 pts in cohort 3 experienced DLT (HFS x 2 pts, thrombocytopenia x 1 pt). PK analyses show no evidence of S effect on T kinetics while C ss,min values of S are consistent with those reported in single-agent studies (S 200mg BID median C ss,min 4.42 μg/mL [SD 3.05], S 400 mg BID median C ss,min 5.11 μg/mL [SD 4.35]). Apparent downregulation of 4E-BP1 and activated forms of p70S6 kinase and ERK was observed in some patients following treatment. Partial responses have occurred in NHL (1 pt) and papillary thyroid cancer (1 pt) and prolonged SD (> 12 mo) has been observed in RCC (1 pt). Conclusions: The combination of S and T demonstrate significant mucocutaneous toxicity at full doses of S, however preliminary PK analyses show no evidence of drug-drug interactions. Characterization of an intermediate dose of S 200 mg BID/T 25 mg IV is ongoing. [Table: see text]

2523 Background: MDX-214 is a recombinant fusion protein between human EGF and the Fab′ fragment of a fully human anti-CD89 (IgA FcR) MAb. MDX-214 is designed to block EGFR and activate neutrophils via CD89 stimulation, and promotes EGFR+ cell killing in vitro by both mechanisms. Methods: The objectives of this study were to evaluate the safety and tolerability, to determine the maximum tolerated dose (MTD), to characterize the PK, to assess PD markers and to explore the antitumor activity of MDX-214 administered intravenously weekly for 4 weeksin EGFR+ malignancies. PD studies included monitoring immune cell trafficking to tumors by paired In ¹¹¹ WBC scans at the final dose level, MDX-214 saturation of CD89+ neutrophils in blood, as well as EGFR signaling in skin. Pts were permitted only 1 course of therapy. Results: To date, 18 pts (median age 61, range 48–83, 10 M/8 F) have been treated over 4 dose levels at 0.4, 1, 4 and 10 mg/m ² , respectively. Tumor types included renal (4), colorectal (2), pancreatic (2), head/neck (2), tracheal, parotid, esophageal, breast, anal, thyroid, hepatocellular, and skin carcinomas. DLT was encountered at 10 mg/m ² with one grade 3 reversible infusion reaction of rigors, erythema and transient hypoxemia. In the 6 pts treated at this dose level, 2 additional pts experienced grade 2 infusion reactions despite premedication, and one grade 2 hypotension. The MTD was therefore 4 mg/m ² . Other grade 1–2 toxicities included nausea/vomiting (9), diarrhea (2), fatigue (4), headache (4). There were 7 pts with stable disease at 6 weeks. The serum half-life was < 30 min but neutrophil-bound MDX-214 was detectable for 24 h. In ¹¹¹ WBC scans are under analysis. Conclusion: Weekly administration of MDX-214, a novel immune mediated therapeutic strategy targeting EGFR is feasible with an MTD of 4 mg/m ² . This dose results in neutrophil labeling with MDX-214 for over 24 hours, and may permit activated neutrophil localization at tumor sites. Accrual at the MTD is ongoing. [Table: see text]

Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic micropar- ticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of adminis- tering AI-850 as a <30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacoki- netics of paclitaxel in this new formulation, and seek evidence of anticancer activity. Experimental Design: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concen- trations were measured by liquid chromatography-tandem mass spectrometry. Results: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m 2 . Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m 2 AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Phar- macokinetics of free and total paclitaxel showed biexponential plasma decay and dose propor- tionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas. Conclusions:The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m 2 . The potential of AI-850 as an alternative to other approved paclitaxel