1 I4E-MC-JXBA and JXBB Phase 2 Study to Evaluate the PK and Drug-Drug Interaction of Cetuximab and Cisplatin (JXBA) Cetuximab and Cisplatin (JXBB)

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1 I4E-MC-JXBA and JXBB Phase 2 Study to Evaluate the PK and Drug-Drug Interaction of Cetuximab and Cisplatin (JXBA) Cetuximab and Cisplatin (JXBB)

2 Background Exhaustive PK data from 13 studies contributed to the initial clinical development program of cetuximab. Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion. Mean half-life of cetuximab is approximately 112 hours (range 63–230 hours). Pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer.

3 Why PK in These Studies (JXBA and JXBB) These studies are being conducted in response to a postsubmission request by the FDA to further characterize the PK of cetuximab and cisplatin/carboplatin when the two agents are coadministered, and to investigate the potential for drug-drug interactions. JXBA = Cetuximab and Cisplatin Interaction JXBB = Cetuximab and Carboplatin Interaction Identical protocols, one with Cisplatin & other with Carboplatin

4 Some PK Background Conventional PK Analysis Drug Concentration - Time Profile

5 Conventional PK Analysis (cont.) How much deviation in blood collection is allowed? Not much! Usually 5-10% i.e. less than 6 minutes for a 60 minute sample and less than 1 hr for a 10 hr sample

6 Important Points to Insure Quality Data for PK/PD Analyses Blood samples should be drawn as specified relative to the beiginning of infusion. Record the date and time of blood sample collection If a sample at a particular timepoint is accidentally missed please proceed to collect this sample but mark it the time it was actually drawn and not the time it should have been drawn

7 Example of Errors (From an Actual Study) Mean (95% CI) concentrations following a single dose Sparse sampling randomly collected from patients during a 6-week Phase II study

8 Pharmacokinetic Assessments (Cycle 1 and Cycle 2 Only) version 6 Group C: Blood for the determination of serum concentrations of cetuximab is to be drawn on Day 1 of Weeks 4 and 5 immediately prior to cetuximab infusion 1, 2, 4, 8, 24, 72, 120, and 168 hours after the start of the cetuximab infusion. A shift of 24 hours for the 120- hour time point to 96 hours is permissible. Group C: Blood for determination of plasma concentrations of Cisplatin/Carboplatin is to be drawn on Day 1 of Weeks 1 and 5 immediately prior to the Cisplatin/Carboplatin infusion. 1, 1:30, 2, 3, 5, 8, 24 and 72 hours after the start of the Cisplatin/Carboplatin infusion. A shift of 24 hours for the 72- hour time point to 48 hours is permissible. 8

9 Pharmacokinetic Assessments (Cycle 1 and Cycle 2 Only) Patients whose treatment deviates from the planned doses and timing during the first 4 weeks for Group A and B and 5 weeks for Group C must be replaced until a maximum of 15 patients have received the scheduled doses.