Intravenous Calcium and Magnesium (CaMg) Reduces Chronic, But Not Acute Neurotoxicity Associated With Oxaliplatin – Results From a Placebo- controlled Phase III Trial A. Grothey 1, D. A. Nikcevich 2, J. A. Sloan 1, J. W. Kugler 3, P. T. Silberstein 4, T. Dentchev 5, D. B. Wender 6, H. E. Windschilt 7, X. Zhao 1, C. L. Loprinzi 1 For the North Central Cancer Treatment Group

Background Oxaliplatin exhibits a characteristic toxicity profile with a very common, reversible acute, mainly cold-triggered sNT, muscle cramps during or immediately after oxaliplatin infusion, commonly understood as a symptom of acute sNT, a chronic, cumulative peripheral sNT which is the dose-limiting toxicity of oxaliplatin In a retrospective, non-randomized study, intravenous administration of calcium and magnesium (CaMg) was associated with reduced oxaliplatin-induced PSN (Gamelin 2004) N04C7 evaluated the activity of IV CaMg as a neuroprotectant against oxaliplatin-related sNT in a placebo-controlled phase III trial in adjuvant colon cancer Detailed patient-reported outcomes (PRO) measures were included to specifically analyze a potential protective effect of CaMg against acute and chronic sNT

N04C7 Cancer Control Phase III Trial – Study Design 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min immediately before and after oxaliplatin (placebo = 100 mL D5W) Neurotoxicity recorded in 3 different ways: NCI-CTC v3.0 (primary endpoint) Oxaliplatin-specific scale Patient questionnaires Pts to receive adj. FOLFOX IV CaMg % of Grade 2+ sNT R IV placebo

Key Inclusion Criteria Resected adenocarcinoma of the colon, stage II or III No evidence of residual disease Scheduled to receive 12 cycles of oxaliplatin-based adjuvant chemotherapy with 85 mg/m 2 oxaliplatin every 2 weeks (e.g. mFOLFOX6 or FOLFOX4) Age >18 years No pre-existing peripheral neuropathy of any grade No hypercalcemia No digitalis medication, no history of AV block

Statistics Primary endpoint Percentage of patients with Grade 2+ chronic PSN during or at end of therapy After discussions with NCI, CTC v3.0 “enhanced” by patient-reported outcomes (PRO) used With 150 patients per arm, 80% power to detect a 15% difference (25% vs 40%) in incidence of Grade 2+ PSN Stratification factors: Age ( 65), gender, regimen (FOLFOX4 vs mFOLFOX6)

Statistics Selected secondary endpoints Time-to-onset and duration of G2+ (and G3+) PSN Percentage of patients with acute neuropathic events Percentage of patients discontinuing adjuvant therapy Average cumulative oxaliplatin dose Duration of therapy Various QOL parameters (questionnaires) Pharmacogenomic analysis (e.g. GSTP1 polymorphism)

Neurotoxicity Evaluation GradeNCI-CTC 3.0 Oxaliplatin-specific scale I loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function sensory symptoms of short duration II objective sensory alteration or paresthesia, including tingling, interfering with function, but not interfering with activities of daily living sensory symptoms persisting between cycles III sensory alteration or paresthesia interfering with activities of daily living sensory symptoms causing functional impairment IV Permanent sensory losses that are disabling -

PRO-”Enhanced” NCI-CTC in N04C7 Do you have problems writing? Grade I “No, I might feel some tingling in my hands, but I have no problems writing” Grade II “It is a bit harder than before, but I can still write” Grade III“I have severe difficulties writing” or “I cannot write anymore” Grade IV“I haven’t been able to write for weeks”

Study Characteristics Study designed to randomize a total of 300 patients Accrual halted and study terminated prematurely in August 2007 when interim analysis of the palliative COncePT trial suggested that CaMg reduced activity of oxaliplatin-based therapy (Hochster et al. Letter to Editor, JCO 2007) At time of study closure, 104 patients randomized, 102 patients had started study medication (50 CaM, 52 PL) Presented analyses based on intention-to-treat analysis of these 102 patients Data cut-off after 127 days (4 months plus 1 week) due to premature study closure

Pertinent Patient characteristics % Patients CaMg (N=50) Placebo (N=52) Total (N=102) Age > Male Caucasian96 mFOLFOX

Adverse Events No difference between CaMg and Placebo in any recorded adverse events incl. Anemia Leuko-/neutropenia Thrombocytopenia Infection Diarrhea Dehydration Cardiac events Pain Myalgia Muscle weakness Hypersensitivity Taste abnormality Stomatitis Nausea/vomiting Hypercalcemia Incidence of any toxicity

Incidence of Grade 2+ sNT sNT Grade CaMg (N=50) Placebo (N=52) P NCI CTC scale Grade 0/178%59% Grade 2+22%41% Oxaliplatin scale Grade 0/172%49% Grade 2+28%51% Nikcevich et al. ASCO 2008, #4009

QOL Assessment At each visit, patients completed 3 questionnaires General QOL questionnaire Brief Fatigue Inventory Specific neurotoxicity evaluation form which tried to distinguish between acute vs chronic neuropathy “Symptoms immediately after last treatment” “Symptoms within last 2 week” Analysis of PRO-QOL items at distinct time points acute sNT Area between curves over sequential treatment cycles chronic sNT

Acute Symptoms on Day 2 of Cycle 1 Mean PRO-scores (SD) Symptom CaMg (N=45) Placebo (N=50) P Sensitivity to cold 17 (22)14 (21)0.41 Discomfort swallowing 13 (21)13 (23)0.81 Throat discomfort 5 (10)13 (27)0.19 Muscle cramps 2 (6)11 (23)0.002 Scale (0: no symptoms, 100: worst)

Chronic sNT (Examples) Numbness fingers/toesTingling fingers/toes p=0.02p=0.06 p-value for comparison of areas under the curves

Chronic sNT (Examples) Numbness fingers/toesTingling fingers/toes p=0.02p=0.06 p-value for comparison of areas under the curves Further significant effect of CaMg vs placebo on: impaired ability to button shirts (p=0.05), muscle cramps over the course of therapy (p=0.01)

Conclusions Analysis of specific PRO questionnaires in N04C7 demonstrated that CaMg was able to significantly reduce muscle cramps and chronic, cumulative sNT No effect was noted on phenomena associated with acute sNT. These data suggest that Acute sNT (mainly cold-triggered events) and muscle cramps have a different patho-physiologic origin Acute sNT and chronic, cumulative sNT are distinct neuropathologic phenomena CaMg can be recommended as neuroprotectant against oxaliplatin- related muscle cramps as well as chronic sNT, oxaliplatin's dose- limiting toxicity.