11-MULTI-12-OPI/CRAB (11-001) Ph. 1b/II Trial: Carfilzomib w/ Irinotecan in Small Cell LC Pts Who Progressed on prior plat. Chemo

Confidential - Lab for Confidential Human Clinical Trial - PI initiated Cross Reference: Dr. Arnold study MIS# 201309190702 Part of UK PI Initiated Study (1 of 4 contarcts - Membership Agreement with CRAB, Tri-Party Agreement wtih Onyx, CRAB and UKRF for funding, Site Agreement for UKRF and CRAB [MIS# 201309190702], and Lab Services [this account] SCOPE OF WORK Pharmacodynamics/Biomarkers (Phase-Ib and Phase-II): Correlative PD biomarkers will be collected from all Phase 1b subjects (up to 24) and the first 15 subjects from each stratum of the Phase 2 portion (30 Subjects total). The dose dependent proteasome inhibition on LMP7 and b5 proteasome subunits will be determined in purified PBMC. Carfilzomib mediated proteasome inhibition will be measured in purified PBMC using commercially available reagents. Irinotecan mediated DNA damage and the effect of carfilzomib in this process will be determined by time dependent changes in gamma-H2AX and Topoisomerase-I expression in purified PBMC. Testing to be completed: „h Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity) in all subjects in phase Ib and in 15 subjects in each cohort from phase II study. „h Expression of gamma-H2AX and Topoisomerase-I in PBMC in all subjects in all subjects in phase Ib and in 15 subjects in each cohort from phase II study. The expression of Topoisomerase-I using immunohistochemistry will be determined in all subjects with available banked tissues to determine if response to irinotecan correlates with Topo-I expression (Up to 112 subjects total). Testing to be completed: „h Expression of Topoisomerase-I IHC in banked tissues in all subjects. Reports of the Tests shall include Subject Sample Data and all other related data and results. Reports are to include, but are not limited to: „h Subject ID „h Subject results for each timepoint tested for Carfilzomib proteasome chymotrypsin-like activity in PBMC (LMP7 and b5 activity) Timepoints: Day 1 Pre-dose of irinotecan, 90 min, 2 hr 5.5 hr Post-irinotecan dose; Day 2 Pre-dose of Carfilzomib „h Subject results for each timepoint tested for expression of gamma-H2AX and Topoisomerase-I in PBMC Timepoints: Day 1 Pre-dose of irinotecan, 90 min, 2 hr 5.5 hr Post-irinotecan dose; Day 2 Pre-dose of Carfilzomib „h Subject results for expression of Topoisomerase-I IHC „h Any data interpretation and/or summary statements regarding results A correlative study report will be provided at the end of the study summarizing the study results for Phase 1b and Phase 2 to be included in the Clinical Study report Samples are to be shipped on Monday, Tuesday or Wednesday only. Notification of shipment will be sent via email to Dr. Leggas on the day of shipment.