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3544 Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5 hr; AUC0-∞ 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses > 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for > 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues. [Table: see text]

5168 Background: Abiraterone acetate (A) is an oral compound with metabolites that selectively inhibit CYP 17(17OH/ 17,20 lyase), blocking adrenal androgen synthesis and exhibiting anti-tumor activity in castration resistant prostate cancer (CRPC). Methods: Patients were divided into fed or fasted groups, and treated at 1000mg/day as a single dose in either capsule or tablet formulation on day 1, then the opposite formulation one week later on day 8, and from day 15, continuous dosing of 1000mg of the tablet formulation. PK samples were taken pre-dose and 1, 2, 4, 6, 8, 24, 48 and 72 hr post dose on days 1 and 8. Statistical analysis employed a two- period crossover model, using non-compartmental analysis. Results: A was well tolerated and side effects readily managed by mineralocorticoid antagonists. Overall 31 patients were enrolled, with PK results from 19 patients presented here. Area under the curve (AUC), was not significantly different between the two formulations for either the fed (p=0.412) or th...

5072 Background: Recent studies have shown that CTCc predict OS in patients (pts) with CRPC. Methods: CTC were collected at baseline and after 1 and 2 cycles of treatment in CPRC pts starting a new...

5510 Background: AZD2281 is a novel, potent orally active PARP inhibitor. It induces cancer specific synthetic lethality in homologous recombination repair defective cells, including BRCA-deficient tumors. We previously reported a first-in-human Phase I trial, with dose escalation guided by toxicity, pharmacokinetic and pharmacodynamic (PD) data (Yap et al, ASCO 2007 Abstr 3529). Method: Initial dose escalation phase included patients (p) with a wide range of drug-resistant cancers. Once a PD active dose was identified, enrichment of the population with p with BRCA-deficient tumors was encouraged. Doses started from 10mg daily for 2 of 3 weeks, escalating to 600mg bd continuously. After the maximum tolerated dose (400mg bd) was identified, an expansion phase in BRCA-deficient ovarian cancer (BDOC) at 200mg bd was opened. Results: Of the total 92 p treated, 44 p had BDOC (includes 1 p with compelling family history). Doses received were 40mg daily (1 p), 100mg bd (3 p), 200mg bd (34 p), 400mg bd (5 p) and ...

Aim: To examine the evidence of benefit in initiating immediate chemotherapy in patients with newly diagnosed asymptomatic metastatic incurable cancer, compared with delaying chemotherapy until symptomatic progression. Methods: Through an extensive review of published reports, we examined the biological, clinical, psychological and ethical background of the issue and reported on the available clinical trial evidence in a variety of tumor types. Results: Only a limited number of clinical trials have directly examined the role of immediate versus delayed chemotherapy in patients with incurable asymptomatic metastatic cancer. Small studies in mesothelioma, colorectal cancer, breast cancer, myeloma, and low-grade lymphoma suggest no survival benefit for the immediate initiation of chemotherapy. However, there was no evidence in other tumor types. Conclusion: The appropriate timing of chemotherapy initiation in an asymptomatic patient with metastatic cancer remains a substantial question in oncology. Many factors are likely to impact on the decision. However, little if any evidence demonstrates a clear advantage in the immediate initiation of chemotherapy in this setting.