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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
Chronic Neuropathy
Meanscore (0-100scale)
Sensory Neuropathy by Treatment Arm
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 40CaMg/Placebo 112 105 109 105 95 99 94 85 80 71 59 51
Cycle
WithoutGrade 2
neuropathy(% of
patients)
Time to Grade 2 Neuropathy
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 22CaMg/Placebo 108 107 101 96 93 87 77 72 69 62 58 53 29
Cycle
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6 7 8 9 10 11 12
P=0.3383
Time to Grade 2 Oxaliplatin — Induced Neuropathy
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 18CaMg/Placebo 111 108 101 94 89 77 65 61 55 46 40 36 13
Cycle
P=0.9721
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6 7 8 9 10 11 12
WithoutGrade 2
neuropathy(% of
patients)
Acute Neuropathy
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 40CaMg/Placebo 110 103 100 99 93 95 89 82 77 64 60 49
Days
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 11Cycle 12
Sensitivity to Touching Cold Items
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 39CaMg/Placebo 110 103 100 98 93 95 88 82 77 64 60 49
Days
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 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
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 40CaMg/Placebo 110 103 101 99 93 96 89 82 77 64 60 49
Days
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11Cycle 12
10
9
8
7
6
5
4
3
2
1
0
Mean score(0-10 scale)
P=0.0366
Throat Discomfort
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 40CaMg/Placebo 110 103 101 99 93 96 89 82 77 64 60 49
Days
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle 10 Cycle 11Cycle 12
10
9
8
7
6
5
4
3
2
1
0
Mean score(0-10 scale)
P=0.5501
Muscle Cramps
Effect on Oxaliplatin Doses
Patients receiving
Oxaliplatin(%)
Cycle
Oxaliplatin Use Based on Rx Arm
P=0.62
Receiving full dose
(% of patients)
% of Patients Receiving Full Dose of Oxaliplatin by Rx Arm
Cycle
P=0.25
Oxaliplatin dose
(mg/m2)
Average Oxaliplatin Dose (mg/m2) by Rx Arm
Cycle
P=0.11
Conclusion
• The data from this well-powered clinical trial did not support the use of intravenous CaMg use for preventing Oxaliplatin-induced neuropathy
