Intravenous calcium and magnesium prevents oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: Results of a phase III placebo-controlled, double-blind trial (N04C7) DA Nikcevich, A Grothey, JA Sloan, JW Kugler, PT Silberstein, T Dentchev, DB Wender, PJ Novotny, HE Windschitl, CL Loprinzi For the North Central Cancer Treatment Group

I have no relevant relationships to discuss.

Background Cumulative peripheral sensory neurotoxicity (PSN) is the dose-limiting toxicity of oxaliplatin PSN commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting In a retrospective, non-randomized study, intravenous administration of calcium and magnesium salts (CaMg) was associated with reduced oxaliplatin-induced PSN (Gamelin, Clin Cancer Res 2004). N04C7 prospectively evaluated the activity of IV CaMg as a neuroprotectant against cumulative oxaliplatin-related PSN in a placebo-controlled phase III trial

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

Primary Endpoint Grade 2+ sNT (CTC Scale) Neurotoxicity Grade CaMg (N=50) Placebo (N=52) P-value (Chi-Square) Missing Grade 0/178%59% Grade 2+22%41%

Time to Grade 2+ sNT (CTC scale)

Primary Endpoint Grade 2+ sNT (Oxaliplatin Scale) Neurotoxicity Grade CaMg (N=50) Placebo (N=52) P-value (Chi-Square) Missing Grade 0/172%49% Grade 2+28%51%

Time to Grade 2+ sNT (Oxaliplatin scale)

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 weeks” QOL analysis ongoing, presented results preliminary

QOL Assessment (Acute PSN) Swallowing discomfortMuscle cramps p=0.065p=0.012 p-value for comparison of areas under the curves

QOL Assessment (Chronic PSN) Numbness fingers/toesTingling fingers/toes p=0.021p=0.062 p-value for comparison of areas under the curves

Conclusions Results and conclusions are affected by early, premature discontinuation of study due to external reasons Despite early termination, our study demonstrates neuroprotective activity of CaMg against oxaliplatin- induced chronic PSN in adjuvant colon cancer in NCI-CTC assessment Oxaliplatin-specific scale Select QOL parameters Effect on acute neuropathy still indeterminate

Conclusions In view of its negligible toxicity, its low cost, and its demonstrated lack of interference with chemotherapy, CaMg could be considered as a standard component of oxaliplatin-based therapy Additional studies of CaMg as neuroprotectant with other neuropathic chemotherapy are contemplated