3582 Background: AVE1642, a humanized mAb, binds the human IGF1R specifically and with high affinity (Kd<1nM). It delays growth of cancer cells in vitro and of human tumors xenografted to nude mice. Materiel and Methods: this study aims to select the dose of AVE1642 to be combined with docetaxel 75 mg/m2 (D). AVE1642 was administered as single agent at cycle(cy)1 and then in combination with D from cy2, q3w. Sequential tumor biopsies were performed in a subset of pts. Main eligibility criteria: ≥ 18y.o; measurable or evaluable advanced ST; PS ≤2; HbA1c≤7.5% or FPG≤160mg/dL. PK/PD: blood was collected at d1, d2, d8, d15 and d22 cy1 and cy2 and at d22 of each subsequent cy. Selection of the dose is based on safety (<33% pts with DLT) and on PK, PD parameters. Results: as of 20-Dec-07, 14 pts (4 at 3mg/kg; 4 at 6mg/kg; 4 at 12mg/kg; 2 at 18mg/kg) received 49cy, including 35cy with T. Safety: No DLT/related SAE were reported so far. Gr1/2 related AEs: hyperglycemia(1), hypersensitivity reactions (2), asthenia(2), anemia(1), nail disorder(1), paresthesia(1), pruritus(1). No anti-drug antibodies detected. Activity: 1 pt with breast cancer has had reduction in skin nodules and is on study cy6. In addition, 4 SD confirmed at cy4 are reported (small cell oesophagus, colon, melanoma, epithelioid sarcoma). Preliminary PK/PD data (mean, [CV%], (n)). AVE1642 concentrations increased dose-proportionally. Elimination t½ was ≈ 9 days. No PK interaction was observed. At all dose levels, mean IGF1 levels increased up to 6-fold from baseline, plateauing from 14–21d. Conclusion: AVE1642 is well tolerated as single agent and in combination with D. PK/PD data suggest a substantial and maintained biological effect from dose level 3mg/kg. Dose (mg/kg) AVE1642 IGF1 Cmax (μg/mL) t½(day) CL (L/day) maxEffect (ng/mL) tmax (day) 3 76.4 [12.7] (5) 9.31[17.9] (5) 0.471 [67.9] (5) 558 (3) 63 (3) 6 158 [22.1] (8) 8.60[14] (8) 0.265 [48.4] (8) 589 (3) 63 (3) 12 249 [25.1] (3) 9.01[12.7] (3) 0.281 [23.1] (3) 633 (2) 14 (2) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis

3048 Background: E7820 is a first-in-class oral antiangiogenic sulfonamide that inhibits alpha-2 integrin expression, endothelial cell proliferation and is active against human breast and pancreatic cancer xenografts. Methods: The objectives of the study were to evaluate the safety, tolerability, to determine the maximum tolerated dose (MTD) to characterize the PK behavior, to assess PD markers and to explore the antitumor activity. Results: Thirty pts (18 male/12 female; age range 40–83) received E7820 at doses ranging from 10 to 200 mg daily continuously, in a 28 day cycle. A total of 93 cycles were administered (range 1–15); 4 pts underwent intrapatient dose escalation. Dose-limiting toxicities (DLT) at 100 mg/day included grade (gr) 3 elevated liver enzymes and gr 3 hemoptysis. At the 200 mg dose level, 2 pts experienced hematological toxicity, including gr 4 thrombocytopenia and neutropenia. One of these patients with cervical cancer and a vaginal fistula had gr 4 thrombocytopenia, neutropenia and gr 3 anemia with a fatal bleed from her pelvic tumor. Other gr 3/4 adverse events included: nausea, vomiting, fatigue, hypoxia, chest pain, abdominal pain, ileus, anemia, neutropenia, hypoalbuminemia, elevated transaminases and alkaline phosphatases. Disease stabilization beyond cycle 4 was observed in 6 pts, with 3 lasting for 6+ months. Tmax ranged from 1.3–5.3 hr and the t1/2 is 5.7 to 11.9 hr. Cmax and AUC increased dose proportionaly up to 70 mg, however accumulation was seen at 200 mg. At higher doses (70–200 mg) plasma concentrations exceed levels active in preclinical models in vivo. Preliminary analysis of alpha-2 integrin expression showed marked (∼50%) and sustained decreases beyond day 28 in 3 of 4 pts at 200 mg, while moderate (<30%) and less consistent decreases were observed in 2/3 and 3/6 pts at 70 mg and 100 mg dose levels, respectively. No changes in integrin levels were observed at E7820 doses < 40 mg. Conclusions: Up to 100 mg/day E7820 has a good safety profile in pts with solid malignancies. MTD was established at 100 mg/day. Patient treatment and PD analyses are ongoing. [Table: see text]

3014 Background: Survivin is one of the family of inhibitor of apoptosis proteins (IAP) that suppresses apoptosis through inhibition of caspases and procaspases. Survivin is selectively expressed in most solid tumors but not normal tissues. In a PC-3 cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferative activity in preclinical models including tumor regressions. Methods: The objectives were to determine the maximum tolerated dose (MTD) of 168 hour continuous infusion of YM155 every 3 weeks, to evaluate toxicity, characterize the pharmacokinetics and observe anti-tumor activity. Standard 3+3 dose escalation scheme was utilized. Additional pts were added to fully characterize toxicities at the MTD. Pharmacokinetic sampling was performed during cycles 1 and 2. Results: 41 pts (M/F: 31/10, median age 61, range 28–78) with performance status of 0–2 were enrolled into 4 dose cohorts [1.8 mg/m2/day (N = 8), 3.6 (6), 6.0 (2) and 4.8 (25)]. Most common tumor types were prostate (9), NHL (5), and colorectal (5). 2/2 pts experienced DLTs at 6.0 (renal tubular necrosis with grade 3 mucositis and increased serum creatinine), thus the MTD was 4.8 mg/m2/day. The most frequent AEs were: pyrexia, arthralgia, nausea, fatigue and diarrhea. The most common grade 3 or 4 drug related AEs were: mucosal inflammation (N = 2, 4.9%) and increased INR (N = 2, 4.9%). At MTD, the median clearance was 47 L/hr with a median steady state concentration of 7.5 ng/mL and a median terminal half-life of 22 hours. Two pts with chemotherapy refractory intermediate grade NHL had marked reduction of lymph nodes including one that was durable (PR reviewed independently). This pt went onto BMT and was in remission at the time of this submission. Two HRPC pts exhibited PSA response (> 50% reduction). Conclusions: YM 155, the first survivin inhibitor, was well tolerated, had a MTD of 4.8 mg/m2/day × 7 days and exhibited provocative anti-tumor activity in 4 pts that warrant broad phase II evaluation. No significant financial relationships to disclose.

Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR. Accordingly, MC1R is a major determinant of susceptibility to melanoma. Despite extensive phenotypic heterogeneity and high mutation loads, the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood. Mutations of intracellular effectors of receptor tyrosine kinase (RTK) signalling, notably NRAS and BRAF, are major driver events more frequent than mutations in RTKs. Nevertheless, melanomas often display aberrant signalling from RTKs such as KIT, ERRB1-4, FGFR, MET and PDGFR, which contribute to disease progression and resistance to targeted therapies. Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche. However, key aspects of the melanoma-stroma interplay, such as the molecular determinants of dormancy, remain poorly understood.

The bacterial peroxiredoxin AhpC, a cysteine-dependent peroxidase, can be converted through a single amino acid insertion to a disulfide reductase, AhpC∗, active in the glutathione and glutaredoxin pathway. Here we show that, whereas AhpC∗ is inactive as a peroxidase, other point mutants in AhpC can confer the in vivo disulfide reductase activity without abrogating peroxidase activity. Moreover, AhpC∗ and several point mutants tested in vitro exhibit an enhanced reductase activity toward mixed disulfides between glutathione and glutaredoxin (Grx-S-SG), consistent with the in vivo requirements for these components. Remarkably, this Grx-S-SG reductase activity relies not on the peroxidatic cysteine but rather on the resolving cysteine that plays only a secondary role in the peroxidase mechanism. Furthermore, putative conformational changes, which impart this unusual Grx-S-SG reductase activity, are transmissible across subunits. Thus, AhpC and potentially other peroxiredoxins in this widespread family can elaborate a new reductase function that alleviates disulfide stress.