Poster Session – Molecular-targeted therapies − clinical trials Thursday, 18 November 2010 131 more than 6 months, out of 18 evaluable patients. The patient with ovarian Inhibition of VEGF signaling at the ligand and receptor level has the cancer had progressive disease on liposomal doxorubicin and now on this potential for enhanced antitumor efficacy. This hypothesis was tested trial had a 30% drop in her CA125. The patient with neuroblastoma had in a NCI-sponsored phase 2 trial of sorafenib (inhibitor of VEGFR and resolution of her lesions on PET/CT. Patients received a median number of RAS/RAF/MEK/ERK) and bevacizumab in pts with advanced melanoma. 2 (1−10) treatment cycles. H3 and H4 histone acetylation will be correlated Methods: Pts with measurable advanced melanoma, adequate organ with HDAC2 expression, panobinostat dose, and plasma concentrations. function, PS 0−2,  2 prior therapies in the advanced setting were eligible; Conclusions: A sequence-specific combination of panobinostat and pts with active brain metastases were excluded. S at 200 mg BID days 1−5 epirubicin is tolerable and shows early activity. A dose expansion to include q 7 days and B at 5 mg/kg q 14 days on a 28 day cycle. Dose reduction mandatory biopsies is being explored at the panobinostat dose of 50 mg. of S permitted, but no dose reduction of B. The primary objective of the study was to determine clinical biological activity (defined as CR + PR+ 412 POSTER SD >16 wks). Secondary objectives included safety, tolerability, median BMS-754807, an oral dual IGF-1R/insulin receptor (IR) inhibitor: time to progression (TTP). Pharmacodynamic (PD) studies analyzing initial results from a Phase 1 dose- and schedule-finding study in S-100b protein, circulating melanoma cells (CMC), endothelial cells (CEC), combination with carboplatin/paclitaxel in subjects with solid tumors vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) levels of serum and plasma at Q.S. Chu1 , S.W. Kim2 , P.M. Ellis3 , L. Mileshkin4 , R.H. de Boer5 , baseline, C1D15 and C2D1 were measured using standard ELISA. J.S. Park6 , T. Pellas6 , F. Huang6 , F. Graf Finckenstein6 , A. Dhar6 . Results: Final ITT Stage 1 analysis, 14 patients with metastatic melanoma 1 Cross Cancer Institute University of Alberta, Department of Oncology, treated (median age 61 years [43−77]; 64% male). No RECIST responses Edmonton, USA; 2 Asan Medical Center University of Ulsan College were observed, although 6 (42.9%) patients had SD for more than >16 weeks, 3 of these pts had SD  1 year, 5 (35.7%) had PD at or of Medicine, Department of Oncology, Seoul, Korea; 3 Juravinski prior to 16 weeks (3/2), 3 unevaluable for tumor response. Median TTP Cancer Center McMaster University, Department of Oncology and Clinical was 18.6 months (95% CI 4.7–32.7 mo). The most frequently reported Epidemiology & Biostatistics, Hamilton, Canada; 4 Peter MacCallum drug-related adverse events (AEs) were hand-foot skin reaction (HFS) Cancer Center, Division of Haematology and Medical Oncology, 57.1%, rash 14.2%; fatigue 57.1%, anorexia 28.6%; hypertension (HTN) East Melbourne, Australia; 5 Royal Melbourne Hospital, Department of 64.3%; proteinuria 35.7%; nausea 14.2%, diarrhea 21.4%; bleeding 14.2%. Medical Oncology, Melbourne, Australia; 6 Bristol-Myers Squibb Company, Grade 3/4 drug-related AEs were HTN 14.2%, HFS 7%, proteinuria 7% and Research and Development, Princeton, USA thrombocytopenia 7%. Dose reduction of S required in 6 (42.9%) patients (4 due to grade 2/3 HFS, 1 each for HTN and proteinuria). Updated PD Background: BMS-754807 is a potent reversible inhibitor of IGF-1R/IR analysis and its correlation with clinical activity will be presented. kinase family (IGF-1R, IR; Ki1/2 (9−13h), BMS-754807’s effects on normal Conclusions: Combined VEGF/VEGFR blockade employing S in combi- tissues and tumor cell cycle are expected to be different from effects nation with B was safe and tolerable. Although objective responses were of continuous inhibition by anti-IGF-1R antibodies. This allows exploring not observed, 43% of the patients with advanced melanoma had clinical continuous and intermittent schedules in chemotherapy combinations for biological activity. improved safety and efficacy. Methods: CA191005 is an open-label ascending dose study of BMS- 414 POSTER 754807 combined with carboplatin (C)/paclitaxel (P) in subjects with Clinical pharmacokinetics and pharmacodynamics of CX-4945, a advanced or metastatic solid tumors. C (AUC = 6 mg/ml min) and novel inhibitor of protein kinase CK2: Interim report from the phase 1 P (200 mg/m2 ) are given on day (D) 1 of 3 week cycles. BMS- clinical trial 754807 is administered orally continuously (D2−21) or in an intermittent schedule. Subjects completing 4 cycles of combination therapy can C.S. Padgett1 , J.K.C. Lim1 , R.F. Marschke2 , D.W. Northfelt3 , opt for BMS-754807 monotherapy. Pharmacodynamic (PD) assessments E. Andreopoulou4 , D.D. Von Hoff5 , K. Anderes6 , D.M. Ryckman7 , include plasma glucose, insulin, C-peptide and IGF-1 levels. 3 -deoxy-3 - T.K. Chen8 , S.E. O’Brien6 . 1 Cylene Pharmaceuticals Inc., Clinical, San [18 F]fluorothymidine (FLT)-PET imaging is performed at baseline, D13−15 Diego CA, USA; 2 Front Range Cancer Specialists, Medical Oncology, and D19−21 in cycle 1 to assess anti-tumor activity and explore Fort Collins CO, USA; 3 Mayo Clinic Arizona, Medical Oncology, dependence of anti-proliferative effects on treatment schedule. Scottsdale AZ, USA; 4 M. D. Anderson Cancer Center, Medical Oncology, Results: To date, 11 subjects have been treated with 3-weekly C/P and Houston TX, USA; 5 Cylene Pharmaceuticals, Clinical, San Diego CA, BMS-754807 at doses of 4, 10, 20 and 30 mg on the continuous schedule. USA; 6 Cylene Pharmaceuticals, Biology, San Diego CA, USA; 7 Cylene Treatment durations were 21 to 151 days. No dose-limiting toxicity has been observed and dose escalation is ongoing. All subjects had treatment- Pharmaceuticals, CMC, San Diego CA, USA; 8 Cylene Pharmaceuticals, related AEs, the majority consistent with chemotherapy administration. The Pharmacokinetics, San Diego CA, USA most frequent treatment-related Grade 3/4 AE was neutropenia. No AE of fasting hyperglycemia was noted, though subjects experienced post- Background: CX-4945 is a potent and selective, first-in-class oral inhibitor prandial hyperglycemia most frequently between D2−5, possibly due to of the CK2 protein kinase. CK2 is an essential non-oncogene molecular steroid use during chemotherapy. Insulin increases 2 hours post dose target that promotes the survival of many cancers. CK2 modulates the indicate PD effects on IR, consistent with observations in a monotherapy PI3K/Akt pathway via phosphorylation of several proteins (Akt and p21), trial. One subject (small cell lung cancer, chemotherapy failure) had PR which we have validated as mechanistic biomarkers for CX-4945 activity. after 2 cycles of combination therapy. Data from additional dose levels and In certain tumors CK2 mediates the release of IL-6 and IL-8, and these updated safety, efficacy, PD and imaging results will be presented. proteins were evaluated as tumor-based biomarkers for CX-4945 activity. Conclusion: BMS-754807 can be administered safely in combination with Two different oral dosing schedules have been assessed in a phase C/P at doses that resulted in exposures exceeding preclinical efficacious 1 clinical trial in order to characterize the pharmacokinetic (PK) and exposures in a monotherapy trial. Analysis of PD and FLT-PET responses pharmacodynamic (PD) relationships of CX-4945 in humans. is expected to provide a rational basis for selection of an optimal dose and Materials & Methods: Eligible patients having advanced solid tumors schedule for BMS-754807 in combination with chemotherapy. with progressive disease, or having no available approved therapies, were administered CX-4945 in successive dose escalation cohorts using a standard 3+3 design. Oral doses were administered twice daily (BID) or 413 POSTER four times daily (QID) for twenty-one consecutive days of a four week Phase II study evaluating the efficacy, safety and pharmacodynamic cycle. Plasma samples were evaluated for PK analysis and for IL-6 and correlative study of dual anti-angiogenic inhibition using IL-8, while peripheral blood mononuclear cells (PBMC) were isolated for Bevacizumab (B) in combination with Sorafenib (S) in patients (pts) PD biomarkers. with advanced malignant melanoma Results: Twenty-three patients from six dose cohorts have received BID D. Mahalingam1 , M. Beeram1 , J. Rodon1 , K. Sankhala1 , A. Mita1 , doses, and six patients from two dose cohorts have received QID doses of CX-4945 to date. CX-4945 has been well tolerated, with no dose D. Benjamin1 , J. Michalek2 , A. Tolcher1 , J. Wright3 , J. Sarantopoulos1 . 1 limiting toxicities observed to date. Plasma exposures at steady state were University of Texas Health Science Center San Antonio, Institute of significantly increased by QID dosing when compared with BID dosing. Drug Development-Cancer Therapy and Research Center, Texas, USA; Evidence of inhibition of CK2 and the Akt pathway, manifested as reduced 2 University of Texas Health Science Center San Antonio, Department of phosphorylation of Akt (S129) and p21 (T145) in PBMC, was observed in a Epidemiology and Biostatistics, Texas, USA; 3 Investigational Drug Branch drug exposure related manner. Stable disease is evident in 26% of patients Cancer Therapy Evaluation Program, Division of Cancer Treatment and (6/23) at the time of first evaluation, and in a further 17% of patients (4/23) Diagnosis NCI, Texas, USA for at least 6 months, including two patients on treatment for more than 9 months. Background: Melanomas are highly vascular tumors and are known Conclusions: CX-4945 has been well tolerated on BID and QID dosing to have high incidence of B-Raf mutations driving tumor proliferation. schedules. QID dosing provides for substantial increases in plasma 132 Thursday, 18 November 2010 Poster Session – Molecular-targeted therapies − clinical trials exposures when compared with BID dosing. Moreover, mechanistic and 70 and 170 nM. Primary cells from patients with relapsed/refractory tumor biomarker analyses in patients demonstrates that CX-4945 inhibits AML were significantly more sensitive to SB939 than those of newly CK2 activity. This phase I trial will continue to seek the maximum tolerated diagnosed patients with IC50 of 0.70±0.36 mM (n = 8) versus 1.28±0.47 mM dose of CX-4945 while preparing for additional clinical trials as a single (n = 8), respectively. SB939 was highly efficacious in the xenograft models: agent and in combination with other targeted agents as well as conventional MV4−11 (116% TGI) and HEL92.1.7 (55% TGI) after dosing at 50 mg/kg chemotherapy. q.d. and 125 q.o.d. respectively. In the HL-60 leukemia model white blood counts were reduced by 73% and the onset of severe paralysis or death was delayed for at least 18 days. Maximal acH3 levels were measured 3 h 415 POSTER after dosing in tissues as well as patient PBMCs. AcH3 values in normal A phase I study evaluating the safety profile and pharmacokinetics tissues decreased after 15 days, but increased in diseased tissues, showing of CS-1008 (Tigatuzumab), humanized monoclonal antibody targeting a selectivity of SB939 for diseased tissues. Levels of several cytokines death receptor 5 (DR5), in Japanese patients with advanced solid important in AML (VEGF, TNFa, PDGF AA and MCP-1), were significantly tumours reduced in AML cell lines after treatment with SB939. H. Nokihara1 , N. Yamamoto1 , Y. Yamada1 , H. Asahina1 , T. Shibata1 , Conclusion: SB939 is highly efficacious on AML cell lines in vitro and Y. Seki1 , Y. Tamura1 , K. Honda1 , S. Misawa1 , T. Tamura1 . 1 National also on primary cells from AML patients, with higher activity in vitro on Cancer Center Hospital, Division of Internal Medicine, Tokyo, Japan cells from patients with relapsed/refractory AML compared to cells from newly diagnosed patients. SB939 was highly efficacious in mouse models of AML, where target efficacy was confirmed by detection of increased Background: CS-1008 (Tigatuzumab) is an IgG1 agonistic humanized acH3 levels in diseased tissue. Target efficacy was also demonstrated monoclonal antibody targeting the human death receptor 5 (DR5). CS-1008 in PBMCs from patients. The influence of HDACi on cytokines may be triggers apoptosis after binding to DR5 resulting in death of targeted tumor an additionally benefit during AML treatment. These findings indicate a cells. This is a phase I, open-label, dose-escalating study evaluating the therapeutic potential of SB939 for treating relapsed/refractory AML. safety profile and pharmacokinetics (PK) of CS-1008 in Japanese patients (pts) with advanced solid tumors. In addition, evaluation of anti-CS-1008 antibody (HAHA), preliminary anti-tumor effects, DR5 protein expression, 417 POSTER and potential CS-1008 biomarker activity were performed. Human biotransformation of olaparib (AZD2281) an oral Methods: Pts with advanced solid tumors having no available standard poly(ADP-ribose) polymerase (PARP) inhibitor therapy were enrolled. CS-1008 is administered over 30 minutes intra- venously once every week at doses of 2 mg/kg (level 1), 4 mg/kg (level 2), J. Clarkson-Jones1 , C. Page1 , S. Sarda1 , H. Swaisland1 . 1 AstraZeneca, and 6 mg/kg (level 3); once every 2 weeks at a dose of 8 mg/kg (level 4); Alderley Park, Macclesfield, United Kingdom and once every 3 weeks at a dose of 10 mg/kg (level 5). Results: Three pts were enrolled in each level (total 15 pts); median age Background: Olaparib (AZD2281) has demonstrated activity and accept- was 57 years. Pts had pancreatic cancer (4), esophageal carcinoma (3), able toxicity as an oral monotherapy in patients with advanced breast or sarcoma (3), thymic carcinoma (2), breast cancer (1), non-small cell ovarian cancer who are BRCA mutation carriers, and acceptable toxicity lung cancer (NSCLC) (1), intrahepatic cholangiocarcinoma (1). There as monotherapy in patients with advanced solid tumours. was no dose-limiting toxicity observed. The most frequent (6 patients) Material and Methods: A single oral radiolabelled dose of olaparib adverse events (AEs) were AST increase, serum albumin decrease and (100 mg; 120 mCi of 14 C-labelled drug) was administered to patients fever. Grade 3/4 drug-related AEs were not observed. Two pts had (n = 6) with advanced or metastatic solid tumours in an open-label, non- serious AE (fever and esophagostenosis), but all of them related to the randomized, single-centre study. A single radiolabelled dose of olaparib disease progression. Neither infusion reaction nor HAHA was observed. PK was also administered to male and female Han Wistar rats (15 mg/kg, results demonstrated a half-life of 166±10 hr (mean±SD) to 237±38 hr. 200 mCi/kg) to provide samples which could be used to compare the At level 1, 2, 3, 4 and 5, the exposures (level 1, 2, 3: AUC168, level biotransformation between humans and the toxicology species. Samples 4: AUC336, level 5: AUC504 ) were 4031±376 mg·hr/mL (mean±SD), of plasma, urine and faeces were obtained for metabolite identification 6317±1702 mg·hr/mL, 14085±3702 mg·hr/mL, 26577±8134 mg·hr/mL, and purposes from both studies. Metabolite profiles of samples were generated 40041±10579 mg·hr/mL, respectively. PK was similar to those in the study by high performance liquid chromatography coupled to radiochemical conducted in the United States. Three pts (pancreatic cancer, NSCLC, detection (HPLC-RAD) and metabolite characterization was performed on intrahepatic cholangiocarcinoma) had stable disease, and 12 pts had selected samples by HPLC with mass spectrometry (HPLC-MSn ). progressive disease. Results: In plasma, olaparib accounted for 70% of the radioactivity present Conclusions: CS-1008 is well tolerated up to 10 mg/kg in Japanese pts in human plasma, and 70% or 100% in male and female rats, respectively. with advanced solid tumors. Clinical trials of CS-1008 in combination Olaparib was also the major component in human excreta, accounting for with chemotherapy for the treatment of DR5 positive tumors have been ca. 21% of the dosed radioactivity; comprising ~15% in the urine and ~6% implemented. in the faeces. In addition to the parent compound, 36 metabolites were identified in human excreta, the major ones accounting for up to 11% of the dosed radioactivity. Of the 36 metabolites observed in human excreta, 416 POSTER 17 were specific to urine. All of these urine specific metabolites were of The oral HDAC inhibitor SB939 shows activity in in vitro and in vivo low abundance; six of which accounted for slightly more than 1% of the models of acute myeloid leukemia dose whilst the remainder accounted for less than 1% of the dose (or were detectable by HPLC-MS only). Metabolites observed in human samples V. Diermayr1 , L.C. Ong1 , Y.K. Loh1 , A. Cheong1 , S. Hart1 , K.C. Goh1 , were present in similar proportions to those in rat. Only three metabolites H.H. Hentze1 , H. Wang2 , K.E. Ethirajulu3 , J.M. Wood1 . 1 SBIO Pte Ltd, were identified in human that were not identified in rat samples, these non- Biology, Singapore, Singapore; 2 SBIO Pte Ltd, Chemistry, Singapore, rat metabolites each accounted for less than 1% of the dosed radioactivity. Singapore; 3 SBIO Pte Ltd, Preclinical, Singapore, Singapore The main site of metabolism was the piperazine carboxycyclopropyl moiety, although, to a lesser extent, both the fluorophenyl and the phthalazinone Background: SB939 is an orally active HDAC inhibitor with a very favorable ring systems were subject to metabolism. The majority of the metabolism pharmacological, pharmacokinetic, pharmacodynamic and safety profile can be attributed to two main pathways, dehydrogenation and oxidation. that is currently in phase Ib clinical trials in AML and MDS. There were a number of components that were further metabolized by the Methods: Blasts from primary AML cells (obtained from AllCells; glucuronide or sulphate conjugation. Emeryville, CA) were expanded using a StemSpan® medium and a Conclusions: The metabolic fate of olaparib is similar in the toxicology cytokine cocktail (FLT3 ligand, SCF, IL-3 and IL-6) as recommended species and humans, with metabolism and urinary excretion being by the manufacturer (StemCell Technologies). Effects of SB939 on cell important clearance pathways. proliferation were assessed in leukemic cell lines as well as in primary AML cells. The anti-tumor activity was tested against MV4−11 or HEL92.1.7 tumors grown s.c. in nude mice, and against HL-60-induced leukemia, induced after i.v. injection into SCID mice. Mice were dosed with SB939 either with 25−50 mg/kg q.d. or 75 or 125 mg/kg q.o.d or three times per week in the different animal models. Tissues from the AML in vivo model or PBMCs from phase I patients were analyzed for target efficacy by using a validated Western blot assay to measure acetylated histone H3 (acH3) levels. Cytokines from AML cell lines or AML patients treated with SB939 were measured using the Milliplex® cytokine multiplex assay (Millipore). Results: Leukemia cell lines were the most sensitive cell lines towards SB939 amongst 30 liquid and solid cell lines tested, with IC50 between