190 Friday 9 November 2012 Poster Session – Phase 0, I and II

criteria was applied for all patients (QTc <450ms), 13.8% of the patientswould have been considered a screening failure for Phase 1 trials.Conclusion: We identified a high variability in the QTc inclusion/exclusioncriteria in different Phase 1 protocols. A small group of patients could havebeen excluded due to QTc prolongation related to multiple clinical factors.

616 POSTERPimasertib (MSC1936369B/AS703026), a Selective Oral MEK1/2

Inhibitor, Shows Clinical Activity in Melanoma

J.P. Delord1, N. Houede2, A. Awada3, C. Lebbe4, T. Lesimple5,J.H.M. Schellens6, S. Rottey7, R. Kefford8, N. Rejeb9, E. Raymond10.1Centre Claudius Regaud, Clinical Research Unit, Toulouse, France;2Institut Bergonie, Bordeaux, France; 3Jules Bordet Institute, Brussels,Belgium; 4APHP Hopital Saint-Louis, Paris, France; 5Centre EugeneMarquis, Rennes, France; 6The Netherlands Cancer Institute, Amsterdam,The Netherlands; 7 Heymans Institute of Pharmacology Ghent UniversityHospital, Ghent, Belgium; 8Westmead Hospital and Melanoma Institute,University of Sydney, Sydney NSW, Australia; 9Merck Serono S.A. −Geneva, Geneva, Switzerland; 10Beaujon University Hospital, Clichy,France

Background: Pimasertib is a selective, uncompetitive MEK1/2 inhibitorwith potent activity in melanoma cell lines and xenografts with mutationsin the MAPK pathway (mainly BRAF and NRAS). The clinical activityof pimasertib in melanoma is reported based on tumor molecularcharacteristics.Materials and Methods: Phase I dose-escalation trial (3+3 design)of pimasertib administered according to four dosing schedules (S)(Table) in patients (pts) with advanced solid tumors (ClinicalTrials.gov,NCT00982865). Following activity signals in the dose-escalation part of S1and S2, the study population was restricted to pts with advanced/metastaticmelanoma and continuous dosing (S3 and S4) was investigated to optimizetreatment.Results: A total of 89 pts with metastatic melanoma (76 cutaneous,13 uveal) were treated at doses showing inhibition of the target (ERKphosphorylation, pERK) in peripheral blood mononuclear cells (dose range28–255mg) (Table). Median age was 59.5 yrs (range 30−83); 63% weremale and the ECOG performance status of all pts was 0−1. Tumormolecular characteristics: 23 were BRAF mutant (mt), 17 NRAS mt, 1 dualBRAF/NRAS mt, 28 BRAF/NRAS wild-type (wt), with unknown mutationstatus for the remaining pts. The median time on treatment was 10 weeks(wks) (range 0.1−98 wks), with 38 (43%) pts on treatment for >12 wks and12 (14%) pts on treatment for >24 wks. Efficacy: in NRAS mt melanoma,4/17 pts (24%) achieved either a complete response (CR, 1 pt) or a partialresponse (PR, 3 pts). In BRAF mt melanoma, 5/23 pts (22%) had a PR.Two additional PRs were reported in BRAF/NRAS wt cutaneous and uvealmelanomas. Five of the 11 responses were observed with S4 twice-daily(bid) dosing at doses of 45−75mg bid. The other 6 occurred with interruptedS2 at doses of 68–195mg once-daily (qd) and continuous dosing S3 at adose of 90mg qd. Nine additional patients remained on treatment for >24wks (25−98 wks), 7 with >10% tumor shrinkage. Five out of 9 pts had aBRAF mutation (3 pts) or NRAS mutation (2 pts) reported.Conclusions: Pimasertib shows clinical activity at doses associated withtarget inhibition. Sustained responses were observed mostly in BRAF- orNRAS-mutated melanoma. A phase II study is ongoing.

Schedule S1 S2 S3 S4

No. of pts 5 35 15 34Dose levels, mg 28–120 qd 28–255 qd 60−90 qd 45−75 bidDays on treatment (21-day dosing cycles) 1−5, 8−12, 15−19 1−15 1−21 1−21Median no. of cycles (range) 6 (2−30) 4 (1−14) 5 (1−12) 2 (1−15)Maximum Tolerated Dose (MTD), mg 120 qd 195 qd 90 qd 75 bidRecommended Phase II Dose (RP2D), mg 60 bid

617 POSTERPharmacokinetic Study of Enzastaurin in Cancer Patients with

Varying Degrees of Hepatic Dysfunction

J. Sarantopoulos1, E.G. Chiorean2, J. Stephenson3, H. Burris4,D. Mahalingam1, A. Younger2, M. Ayan-Oshodi5, J. Baldwin5, J.R. Infante4.1Institute for Drug Development Cancer Therapy and Research Center atUniversity of Texas Health Science Center San Antonio, Medical Oncology,San Antonio TX, USA; 2Indiana University Simon Cancer Center, MedicalOncology, Indianapolis IN, USA; 3Cancer Centers of the Carolinas,Medical Oncology, Greenville SC, USA; 4Sarah Cannon ResearchInstitute Tennessee Oncology PLLC, Medical Oncology, Nashville TN,USA; 5Eli Lilly and Company, Medical Oncology, Indianapolis IN, USA

Background: Enzastaurin monohydrochloride (E) is an oral serine/threonine kinase inhibitor that targets the protein kinase C (PKC) and

phosphoinositide 3-kinase (PI3K)/AKT pathways to inhibit tumor cellproliferation, induce tumor cell apoptosis, and suppress tumor-inducedangiogenesis. E inhibits PKCb as well as other PKC isoforms at nanomolarconcentrations. It is a small molecule targeted therapy hepaticallymetabolized primarily by CYP3A4 forming active metabolites, includingLSN326020 and LSN485912 via LSN2406799. We conducted a phase Istudy to characterize the pharmacokinetics (PK) of E and 3 of its activemetabolites following a single dose in patients (pts) with hepatic dysfunction(HD), and to evaluate the safety and tolerability of E in pts with HD followingmultiple E doses.Methods: Pts with advanced solid tumors or lymphoma, ECOG �2,adequate renal and bone marrow function, received oral E. Pts stratifiedinto 3 HD groups: A − mild, B − moderate, C − severe, using NationalCancer Institute Criteria. Planned at least 6 pts in each group. Dataalso collected for Child-Pugh classification (CPC). 2 part study. Part 1single dose 500mg E (d1) followed by 6-day washout d2−7 (Period1) then continued with 22-day multiple dosing d8-d29 (Period 2). Part2 safety extension phase after Part 1. Study completers defined aspts who completed Part 1. Groups dosed in parallel. E and metaboliteconcentrations in plasma determined using a validated LC/MS/MS assay.Study objectives included characterizing PK following a single dose, andsafety and tolerability following multiple dosing.Results: 23 pts in total received E starting at 500mg (4×125mg tablets).Median age 58 (25−74), male 48%, ECOG 0/1 100%. CRC 39%. Groups:mild-6, moderate-8, severe-9 pts. 12 completers (6,4,2), 7 in Part 2 (4,2,1).The most common related AEs were fatigue 13%, hyperbilirubinemia 8.7%,anorexia 8.7%, and nausea 8.7%, No study drug related DLTs, SAEs orQTc changes. D1 PK on all 23 pts. E and metabolites Cmax and AUCdecreased with increasing HD. Comparable t1/2 for mild and moderateHD. Slight tendency of increased CL and t1/2 with severe HD. Cycle 1Day 1 E Mild Group: Cmax 1120 nmol/L, AUC 35300 nmol/L·h, t1/2 16.6 h,CL/F 27.4 L/h. Severe Group: Cmax 584 nmol/L, AUC 15300 nmol/L·h,t1/2 25.0 h, CL/F 63.2 L/h.Conclusions: E and metabolites exposure decreased with increasing HD.

618 POSTERIntegrated Analysis of Pharmacokinetics and Exposure–

Adverse Event Relationship of the Investigational Agent MLN0128 to

Guide Dose and Schedule Selection for Further Clinical Investigation

C. Patel1, P.J. Lipman1, K. Venkatakrishnan1. 1MillenniumPharmaceuticals Inc., Cambridge, USA

Background: MLN0128 (INK128) is a small molecule dual mammaliantarget of rapamycin (mTOR) inhibitor, that is in clinical investigation. TheINK128–001 phase 1 dose-escalation study is evaluating the safety, tolera-bility, and pharmacokinetics (PK) of single-agent MLN0128 at various dosesand schedules: 2−7mg once-daily (QD); 6−20mg 3 days/week; 7−13mg 5days/week; and 7−40mg once-weekly. Mucositis was the key dose-limitingtoxicity, consistent with that observed with other mTOR inhibitors. To identifya dose and schedule for further clinical investigation, it was importantto understand the dose–exposure (area under the curve [AUC]) andexposure–adverse event (AE) relationships of MLN0128, and to determinewhether dosing schedule was a clinically meaningful driver of mucositis.Materials and Methods: Non-compartmental analysis (WinNonLin version5.3) was used to estimate MLN0128 PK parameters. Power modelregression analysis (SigmaPlot 11.0) was conducted to evaluate dose-proportionality, and logistic regression analyses (using R) were conductedto study the exposure–AE relationship of MLN0128 on the preliminarycycle 1 PK and AE data from 71 patients across the various dosesand schedules. The base model assumed a lack of a schedule effect,with total calculated cycle 1 AUC as the only predictor of incidence ofmucositis. Subsequent models evaluated the effect of dosing scheduleswhile controlling for cycle 1 AUC.Results: MLN0128 exhibited dose-linear PK with a plasma half-life of ~8hours, and did not display accumulation following QD dosing; the mostfrequent regimen explored. Exposure–AE analyses suggest the odds ofdeveloping grade �2 mucositis were largely dependent on total cycle AUCof MLN0128, and were not influenced by dosing schedule. At the QDmaximum tolerated dose (MTD) of 6mg, the model-predicted probabilityof grade �2 mucositis was 15.1% (95%CI: 8.1–26.5%). None of thedosing schedules significantly influenced the odds of mucositis at any givenplasma exposure value.Conclusions: Emerging data suggests that the risk of developing grade�2mucositis is primarily dependent on drug exposure and not on dosingschedule. This finding is favorable and provides flexibility when selectingdose and schedule of MLN0128 (based on the anticipated level of risk ofdeveloping mucositis), and should be complemented with other relevantinformation (e.g., PK determinants of efficacy in preclinical xenograftmodels) for the selection of dose and schedule for further clinicalinvestigation. Non-clinical model-based analyses confirm an acceptableincidence of grade �2 mucositis at the current MLN0128 QD MTD of 6mg.