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

6. CP1347589-6 Primary endpoint Grade 2+ sNT (CTCAE Scale) Neurotoxicity GradeCaMg N=50 Placebo N=52 P Grade 2+22%41%0.038

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

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

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 Plac/PlacCaMg/PlacCaMg/CaMg Age (median)5657 Male48% Stage II III IV (NED) 19% 75% 6% 19% 76% 5% 19% 74% 8%

18. Pertinent patient characteristics Plac/PlacCaMg/PlacCaMg/CaMg Regimen FOLFOX 4 mFOLFOX 6 8% 92% 7% 93% 6% 94% Race White Black Other 88% 8% 4% 85% 13% 2% 81% 14% 5%

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

20. Chronic Neuropathy

21. Mean score (0-100 scale) Sensory Neuropathy by Treatment Arm n= CaMg/CaMg1141081031039788898476735846 Placebo/Placebo1111051041049592828171665240 CaMg/Placebo1121051091059599948580715951 Cycle

22. Without Grade 2 neuropathy (% of patients) Time to Grade 2 Neuropathy n= CaMg/CaMg109109106100958577686360544726 Placebo/Placebo10510410394908175675954494622 CaMg/Placebo10810710196938777726962585329 Cycle 100 90 80 70 60 50 40 30 20 10 0 0123456789101112 P=0.3383

23. Time to Grade 2 Oxaliplatin — Induced Neuropathy n= CaMg/CaMg11011010799907667584743393519 Placebo/Placebo10710610393847870635648413718 CaMg/Placebo11110810194897765615546403613 Cycle P=0.9721 100 90 80 70 60 50 40 30 20 10 0 0123456789101112 Without Grade 2 neuropathy (% of patients)

24. Acute Neuropathy

25. n= CaMg/CaMg11210699979289857972695441 Placebo/Placebo109100100969287826968654540 CaMg/Placebo110103100999395898277646049 Days 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.7978 Cycle 1Cycle 2Cycle 3Cycle 4Cycle 5Cycle 6Cycle 7Cycle 8Cycle 9Cycle 10Cycle 11Cycle 12 Sensitivity to Touching Cold Items

26. n= CaMg/CaMg11210497979187847771685240 Placebo/Placebo1099999959086816867644439 CaMg/Placebo110103100989395888277646049 Days Cycle 1Cycle 2Cycle 3Cycle 4Cycle 5Cycle 6Cycle 7Cycle 8Cycle 9Cycle 10Cycle 11Cycle 12 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.4274 Discomfort Swallowing Cold Liquids

27. n= CaMg/CaMg11210699979289857973695441 Placebo/Placebo10999101969388827069654640 CaMg/Placebo110103101999396898277646049 Days Cycle 1Cycle 2Cycle 3Cycle 4Cycle 5Cycle 6Cycle 7Cycle 8Cycle 9Cycle 10Cycle 11Cycle 12 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.0366 Throat Discomfort

28. n= CaMg/CaMg11210699979289857973695441 Placebo/Placebo109100101969386827069634640 CaMg/Placebo110103101999396898277646049 Days Cycle 1Cycle 2Cycle 3Cycle 4Cycle 5Cycle 6Cycle 7Cycle 8Cycle 9Cycle 10Cycle 11Cycle 12 10 9 8 7 6 5 4 3 2 1 0 Mean score (0-10 scale) P=0.5501 Muscle Cramps

29. Effect on Oxaliplatin Doses

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

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

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

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