C Loprinzi P Atherton R Qin D Seisler S Dakhil R Qamar

1. Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium to Prevent Oxaliplatin-Induced Sensory Neurotoxicity, N08CB An Alliance for Clinical Trials in Oncology Study C Loprinzi P Atherton R Qin D Seisler S Dakhil R Qamar L Fehrenbacher G LewisP Stella A Grothey

2. There are no relevant financial relationships to disclose

3. Background • Neurologic symptoms are a major oxaliplatin-induced toxicity • Acute neuropathy • Chronic peripheral neurotoxicity-dose limiting • Improves after drug cessation in many • Prominent chronic neurotoxicity in some • Treatment options are limited

4. Background • Finding an effective and safe way to prevent the neuropathy…. • In a retrospective, non-randomized study, intravenous administration of CaMg was associated with reduced oxaliplatin-induced neuropathy (Gamelin, Clin Cancer Res 2004) • Subsequent randomized trials • Prematurely stopped due to an errant DMC report • Revealed mixed results

5. IV CaMg IV placebo N04C7 Cancer Control Phase III Trial – Study Design Patients to receive adj FOLFOX R % of grade 2+ sNT Grothey et al; J Clin Oncol 2011; 29(4):421-7 CP1347589-5

6. Primary endpoint Grade 2+ sNT (CTCAE Scale) CP1347589-6

7. Time to Grade 2+ sNT (CTC scale) Ca/Mg % Free 2+ sNT Placebo P=0.05 Weeks CP1347589-7

8. Background Current trial designed to provide a definitive answer

9. Key Inclusion Criteria • Age >18 years • Resected adenocarcinoma of the colon • No evidence of residual disease • Scheduled to receive 12 cycles of oxaliplatin-based adjuvant chemotherapy with 85 mg/m2 oxaliplatin every 2 weeks • No pre-existing peripheral neuropathy of any grade or neurotoxic chemotherapy

10. Total Accrual: 362 Patients Cancels: 6 Ineligibles: 3 Arm A: CaMg before and after chemo Baseline: 118 patients Arm B: Placebo before and after chemo Baseline: 119 patients Arm C: CaMg before chemo and placebo after chemo Baseline: 116 patients Primary endpoint: 110 Primary endpoint: 106 Primary endpoint: 110 Double-blinded

11. Neurotoxicity Evaluation- Chronic • EORTC QLQ-CIPN20 sensory sub-scale • Oxaliplatin-specific neuropathy instrument • NCI-CTCAE-version 4.0

12. Neuropathy Evaluation-Acute

13. Neuropathy Evaluation-Acute

14. Statistics Primary endpoint • The area under the curve (AUC) of CIPN20 sensory scale during the 12 cycles of chemotherapy • Wilcoxon rank-sum test was used • Bonferroni adjustment for two comparisons

15. Statistics • A sample size of 107 patients, per arm provided 80% power • To detect a difference in incidence of grade 2+ neuropathic toxicity from • 40% in the placebo arm to • 20% in either schedule of the CaMg infusion arms

16. Results

17. Pertinent patient characteristics

18. Pertinent patient characteristics

19. Adverse Events • No substantial differences between CaMg and Placebo in any recorded adverse events

20. Chronic Neuropathy

21. Sensory Neuropathy by Treatment Arm Mean score (0-100 scale) Cycle n= CaMg/CaMg 114 108 103 103 97 88 89 84 76 73 58 46 Placebo/Placebo 111 105 104 104 95 92 82 81 71 66 52 40 CaMg/Placebo 112 105 109 105 95 99 94 85 80 71 59 51

22. Time to Grade 2 Neuropathy 100 90 80 70 60 50 40 30 20 10 0 Without Grade 2 neuropathy (% of patients) P=0.3383 0 1 2 3 4 5 6 7 8 9 10 11 12 Cycle n= CaMg/CaMg 109 109 106 100 95 85 77 68 63 60 54 47 26 Placebo/Placebo 105 104 103 94 90 81 75 67 59 54 49 46 22 CaMg/Placebo 108 107 101 96 93 87 77 72 69 62 58 53 29

23. Time to Grade 2 Oxaliplatin — Induced Neuropathy 100 90 80 70 60 50 40 30 20 10 0 Without Grade 2 neuropathy (% of patients) P=0.9721 0 1 2 3 4 5 6 7 8 9 10 11 12 Cycle n= CaMg/CaMg 110 110 107 99 90 76 67 58 47 43 39 35 19 Placebo/Placebo 107 106 103 93 84 78 70 63 56 48 41 37 18 CaMg/Placebo 111 108 101 94 89 77 65 61 55 46 40 36 13

24. Acute Neuropathy

25. Sensitivity to Touching Cold Items 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.7978 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11 Cycle 12 Days n= CaMg/CaMg 112 106 99 97 92 89 85 79 72 69 54 41 Placebo/Placebo 109 100 100 96 92 87 82 69 68 65 45 40 CaMg/Placebo 110 103 100 99 93 95 89 82 77 64 60 49

26. Discomfort Swallowing Cold Liquids 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.4274 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11 Cycle 12 Days n= CaMg/CaMg 112 104 97 97 91 87 84 77 71 68 52 40 Placebo/Placebo 109 99 99 95 90 86 81 68 67 64 44 39 CaMg/Placebo 110 103 100 98 93 95 88 82 77 64 60 49

27. Throat Discomfort 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.0366 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11 Cycle 12 Days n= CaMg/CaMg 112 106 99 97 92 89 85 79 73 69 54 41 Placebo/Placebo 109 99 101 96 93 88 82 70 69 65 46 40 CaMg/Placebo 110 103 101 99 93 96 89 82 77 64 60 49

28. Muscle Cramps 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.5501 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11 Cycle 12 Days n= CaMg/CaMg 112 106 99 97 92 89 85 79 73 69 54 41 Placebo/Placebo 109 100 101 96 93 86 82 70 69 63 46 40 CaMg/Placebo 110 103 101 99 93 96 89 82 77 64 60 49

29. Effect on Oxaliplatin Doses

30. Oxaliplatin Use Based on Rx Arm Patients receiving Oxaliplatin (%) P=0.62 Cycle

31. % of Patients Receiving Full Dose of Oxaliplatin by Rx Arm Receiving full dose (% of patients) P=0.25 Cycle

32. Average Oxaliplatin Dose (mg/m2) by Rx Arm Oxaliplatin dose (mg/m2) P=0.11 Cycle

33. Conclusion • The data from this well-powered clinical trial did not support the use of intravenous CaMg use for preventing Oxaliplatin-induced neuropathy