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 Lewis P Stella A Grothey
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Phase III Randomized, Placebo-Controlled, Double-Blind Study of Intravenous Calcium/Magnesium to Prevent Oxaliplatin- Induced Sensory Neurotoxicity, N08CB.
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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 Lewis P Stella
A Grothey
• There are no relevant financial relationships to disclose
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
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
Patients to receive adj FOLFOXPatients to receive adj FOLFOX
RR
IV CaMgIV CaMg IV placeboIV placebo
% of grade 2+ sNT% 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
CP1347589-6
Primary endpoint Grade 2+ sNT (CTCAE Scale)
Neurotoxicity Grade CaMgN=50
PlaceboN=52
P
Grade 2+ 22% 41% 0.038
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20
Time to Grade 2+ sNT (CTC scale)
CP1347589-7
Placebo
P=0.05
Ca/Mg
Weeks
% Free 2+ sNT
Background
• Current trial designed to provide a definitive answer
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
Total Accrual: 362 Patients
Cancels: 6Ineligibles: 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 chemoBaseline: 116 patients
Primary endpoint: 110
Primary endpoint: 106
Primary endpoint: 110
Double-blinded
Neurotoxicity Evaluation- Chronic
• EORTC QLQ-CIPN20 sensory sub-scale
• Oxaliplatin-specific neuropathy instrument
• NCI-CTCAE-version 4.0
Neuropathy Evaluation-Acute
Neuropathy Evaluation-Acute
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
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
RESULTS
Pertinent patient characteristics
Plac/Plac CaMg/Plac CaMg/CaMg
Age (median) 56 57 57
Male 48% 48% 48%
Stage
•II
•III
•IV (NED)
19%
75%
6%
19%
76%
5%
19%
74%
8%
Pertinent patient characteristics
Plac/Plac CaMg/Plac CaMg/CaMg
Regimen
•FOLFOX 4
•mFOLFOX 68%
92%
7%
93%
6%
94%
Race
•White
•Black
•Other
88%
8%
4%
85%
13%
2%
81%
14%
5%
Adverse Events
• No substantial differences between CaMg and Placebo in any recorded adverse events