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LBA7501 Background: Mapatumumab, a fully human agonist monoclonal antibody, targets and activates the death receptor TRAIL-R1. We conducted this randomized, controlled phase II trial to evaluate mapatumumab in combination with carboplatin and paclitaxel as first-line therapy in advanced non-small call lung cancer (NSCLC). Methods: Patients were required to have histologically or cytologically confirmed Stage IIIB or IV advanced primary NSCLC with measurable disease by RECIST. Patients were randomly assigned to Arm A, paclitaxel 200 mg/m2 + carboplatin AUC 6.0 (PC); Arm B, PC + mapatumumab 10 mg/kg; or Arm C, PC + mapatumumab 30 mg/kg. Cycles were repeated every 21 days; patients completed up to 6 cycles in the absence of evidence of disease progression or unacceptable toxicity. Patients in Arms B and C could receive additional cycles of mapatumumab in the absence of disease progression. The co-primary endpoints were response rate (RR; complete response + partial response) and progression-free survival (PFS). Images were read by independent radiologists blinded to treatment group assignment, as well as locally. Results: 111 patients were enrolled at 22 sites in 4 countries. Addition of mapatumumab to PC did not improve RR or PFS. RR and PFS, based on the independent read, and overall survival results are summarized below. The results based on local reading also showed no benefit from the addition of mapatumumab to PC. Adverse events were generally balanced across treatment groups; there was no evidence that mapatumumab exacerbated toxicities associated with PC. Conclusions: The results do not support further evaluation of mapatumumab in combination with PC in patients with advanced NSCLC. Additional trials of mapatumumab in other indications are ongoing. [Table: see text] [Table: see text]

2612 Background: The IGF pathway is believed to play a key role in the pathogenesis of several tumors. BIIB022 is a human, nonglycosylated IgG4 monoclonal antibody that binds to IGF-1R and blocks I...

3564 Background: OSI-930 is an oral TKI with potent activity against Kit, VEGFR2, and PDGFR. Preclinical studies demonstrate tumor regression with long-term remissions across multiple xenograft models. Methods: Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930 to determine the maximum tolerated dose (MTD) and to evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. An expansion cohort was enrolled for detailed PD analysis including sVEGFR2 plasma levels, PET imaging in GIST pts or DCE-MRI in selected pts. Results: A total of 58 pts were treated (20M/38F; median 60 years (range 19–83)). OSI-930 was dosed up to 1600 mg QD without reaching MTD. 46 pts received BID dosing [mg(# pts treated)]; 400(7), 500 (31) and 600(8). DLT's were seen in 3/8 pts at 600 mg BID; G3 rash (2 pts) and G4 GGT; and 3/31 at 500 mg BID; G3 myalgia, G3 fatigue and G3 lipase. G3 hypertension was noted in 3/46 pts but not dose-limiting. Common G1/2 toxicities were fatigue (37%), diarrhea (27%), nausea (31%), and rash (24%). Objective (CA125) responses were seen in platinum-resistant ovarian cancer (2 PR/8) while in heavily pretreated GIST (median 4 prior therapies including imatinib/sunitinib), 8/18 pts achieved SD ≥12 w. Median therapy duration in the BID arm was 9 w and 18/46 pts with SD ≥12 w. PK indicated that Css were achieved after ∼7d with BID dosing. PET scans showed reduction in glycolytic activity in 4/9 pts and DCE-MRI response was seen in 4/6 pts. A trend in decreased sVEGFR levels was seen at higher doses. Conclusions: At the MTD level of 500 mg BID OSI-930 is an active, well-tolerated compound with clinically relevant antitumor activity and exposure levels consistent with antitumor activity in preclinical models. PD data indicate mechanistic proof of concept for OSI-930. OSI-930/erlotinib combination phase I study is currently enrolling. [Table: see text]

3553 Background: OSI-930 is a potent TKI with nanomolar activity against Kit, KDR and PDGFR. Regression and long-term remissions were seen in a broad range of xenograft models. Methods: A phase I s...

3535 Background: AZD6244 is a potent, selective, uncompetitive inhibitor of MEK1/2 being tested in phase II clinical trials for a number of solid tumors. To date, clinical trials have studied a fre...

2048 Background: Enzastaurin (ENZ), an oral inhibitor of protein kinase C (PKC), affects signal transduction associated with angiogenesis, proliferation, and survival. The combination of ENZ and capecitabine (CAPE) has the potential for additive or synergistic anticancer effects without excessive toxicity. Methods: Patients (pts) with advanced, refractory, solid tumors received lead-in treatment with ENZ for 7–14 days (cycle 1), to achieve steady-state exposures. In subsequent 21-day cycles, ENZ was given once daily, orally, on days 1–21 and CAPE twice daily (bid), orally, on days 1–14 in 3 dose levels (L): L 1 = ENZ 350 mg + CAPE 750 mg/m2; L 2 = ENZ 350 mg + CAPE 1000 mg/m2; L 3 = ENZ 525 mg (some pts received 500 mg tablets) + CAPE 1000 mg/m2. PK for ENZ was assessed on day 1–3 and 7 in cycle 1 and day 8 in cycle 2 and for CAPE on day 1, 8 in cycle 2. Therapy continued until disease progression or unacceptable toxicity occurred. Results: 27 pts (13 males; 14 females, ECOG ≤1) with a median age of 58 yrs (range: 38–74 yrs), received a median number of 3 cycles (range: 2–14 cycles). High interpatient PK variability was noted for total ENZ analytes. Ratio of geometric mean AUC (90% CI) of ENZ with CAPE versus ENZ alone at 500/525 mg was 0.65 (0.38–1.11, n=6) and of Cmax was 0.66 (0.42–1.10, n=4). PK parameters of CAPE in the presence of ENZ were similar to those previously reported for CAPE alone. No grade (Gr) 4 toxicities occurred. Gr 3 toxicities were anemia (1 pt), headache (1 pt), intestinal perforation (1 pt with gastric carcinoma), fatigue (1 pt), hand-foot syndrome (2 pts), and cardiac ischemia (1 pt). PBMCs demonstrated PKC inhibition following exposure to ENZ. Plasma VEGF and bFGF levels did not reflect any significant changes. No objective tumor responses were seen. Five pts had stable disease (lung, breast, pancreas, head/neck, and hemangiopericytoma) for ≥ 6 months (range: 6–9.7 months). Conclusions: The recommended phase II dose is ENZ 500 mg, qd and Cape 1000 mg/m2 bid, days 1–14 every 21 days. This regimen was well tolerated, and exposures of ENZ and CAPE did not appear to be significantly altered when given in combination. [Table: see text]

9707 Background: Easily accessible human tissue with a high rate of cell proliferation would be of great utility in the study of antiproliferative agents. The buccal mucosal tissue offers an easily accessible region from which highly proliferating cells can be obtained. In order to investigate the utility of acquiring buccal tissue, we conducted a small feasibility study in healthy male subjects. Objectives were to establish a tolerable procedure, and to determine levels of cell proliferation in the biopsy samples. Methods: Ten subjects underwent the biopsy procedure. Following administration of a local anesthetic (2% lidocaine with adrenaline, AstraZeneca), single punch biopsies (3 mm Stiefel Biopsy Punch, Stiefel Laboratories Ltd, Bucks UK) were taken from the buccal mucosa of each subject and fixed immediately in 10% formal saline for embedding in paraffin. All biopsies were taken within the same 2-hour time window of the 24-hour clock. Results: Two subjects felt momentarily faint after the procedure -...