intermittent oxaliplatin administration improves time-to-treatment failure in metastatic colorectal...
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Intermittent oxaliplatin administration improves time-to-treatment failure in metastatic colorectal cancer: Final
results of the phase III CONcePT trial
Grothey A1, Hart L2, Rowland K3, Ansari R4, Alberts SR1, Chowan N5, Shpilsky A6, Hochster HS7
1Mayo Clinic, Rochester, MN; 2Florida Cancer Specialists, Fort Myers, FL; 3Carle Clinic Association, Urbana, IL; 4Northern Indiana Cancer Research Consortium, South Bend, IN; 5Cancer Care Center, Inc., New Albany, NY; 6sanofi-aventis, Bridgewater,
NJ; 7NYU School of Medicine, New York, NY
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Disclosures
• Honorarium: Roche
• Research support: Genentech, Bayer, Amgen, Sanofi-Aventis, BMS
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Introduction
• Oxaliplatin–fluoropyrimidine combinations are widely used in the first-line treatment of metastatic colorectal cancer
• Addition of bevacizumab to oxaliplatin-based therapy further improves efficacy
• In all recent phase III trials, most patients discontinued oxaliplatin-based therapy for reasons other than PD– Detailed analysis of N9741 identified neurotoxicity and
myelosuppression as most common reasons for treatment discontinuation (Green et al, ASCO GI 2005)
• Oxaliplatin-induced peripheral sensory neurotoxicity (PSN)– Reversible, acute PSN (e.g. cold-triggered dysethesias, muscle cramps)
– Chronic, cumulative PSN = DLT
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CONcePT: Combined Oxaliplatin Neurotoxicity Prevention Trial
• Study objective
– Optimizing FOLFOX + Bevacizumab by reducing the reasons for premature discontinuation of therapy, i.e. d/c before progression
• Reducing PSN by
– Intermittent oxaliplatin (OPTIMOX1-like strategy) and
– Use of IV calcium/ magnesium (CaMg) as neuroprotectant
• Reducing myelosuppression (mFOLFOX7 = no 5-FU bolus)
• Primary hypothesis
• Intermittent oxaliplatin (IO) will allow patients to remain on therapy longer compared with conventional schedule (continuous oxaliplatin; CO)
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CONcePT: Statistical Design
• Primary endpoint
– Time-to-Treatment Failure (TTF)
• Time from randomization to withdrawal from study due to:
– adverse event,
– progressive disease / insufficient therapeutic response,
– failure to return, refused treatment / did not cooperate / withdrew consent,
– started a new treatment,
– or death,
whichever comes first
– To demonstrate prolonged TTF (7 to 9.2 months, HR 1.306) with IO compared with CO (80% power, = 0.05) 532 patients needed
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CONcePT: Statistical Design
• Secondary endpoints
• Impact of CaMg infusion on incidence and severity of neurotoxicity in patients receiving either IO or CO
• RR, PFS, OS, Time of Tumor Control
• Adverse events
• Neurotoxicity assessment via QOL questionnaires and physical exam
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Eligibility criteria
• Inclusion• Histologically or cytologically documented, inoperable mCRC
with ≥1 measurable lesion
• Age ≥18 years
• ECOG PS 0–1
• No prior therapies for metastatic or recurrent CRC
• Adequate organ function
• Life expectancy >3 months and no other serious concomitant disease
• Exclusion• Prior treatment with oxaliplatin or bevacizumab
• Peripheral neuropathy grade >1
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CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin
Study design Primary endpoint: TTF for CO vs IO schedule
No randomization to placebo after protocol amendment
First-line mCRC, 532 patientsPrimary endpoint: time to failure (TTF)Randomization (2x2):
mFOLFOX7 + bevacizumabCO until Treatment Failure
mFOLFOX7 + bevacizumabIntermittent oxaliplatin
+/- IV CaMgR
270 pts
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CONcePT study: IO armCONcePT study: IO arm
2400
x 8
Cumulative oxaliplatin
680 mg/m2
Months
42400
x 8
8680 mg/m2
2400
200855
2005
200855
x 8 1360 mg/m2 12
etc.
LVOXBEV
5-FU
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CONcePT study: IO armCONcePT study: IO arm
2400
x 8
Cumulative oxaliplatin
680 mg/m2
Months
42400
x 8
8680 mg/m2
2400
200855
2005
200855
x 8 1360 mg/m2 12
etc.
LVOXBEV
5-FU
OPTIMOX1-like design with• mFOLFOX7 with 85mg/m2 oxaliplatin q2w• Planned reintroduction of oxaliplatin after 16 weeks• Provision for earlier reintroduction of oxaliplatin
if tumor progression >50% in maintenance phase
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Study background - Hochster ASCO GI 2008
• Opened February 2005 and terminated June 2007 • Per recommendation of IDMC
• Basis of IDMC recommendation• Unplanned interim analysis• Confirmed response (CR/PR) on treatment arms A and C (no CaMg)
32.9% versus arms B and D (CaMg) 17.3%. • 2-sided Fisher’s exact test (p=0.028) — superiority without CaMg
• Data provided by CRO• Response rates based on tumor measurements from local
radiology reports of patients with confirmatory scans• No investigator-determined response rates• No review of images
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Sequentially confirmed response rates (RECIST – Independent review) – Hochster ASCO GI 2008
Best response, n
CO IO
Placebo (n=28)
CaMg(n=31)
Placebo (n=31)
CaMg(n=28)
PR SD PD
6139
11155
14152
12115
RR, %95% CI
218.3– 41.0
3619.2– 54.6
4527.3– 64.0
4324.5– 62.8
Odds ratio 95% CI p-value
IO / CO 1.96 0.86–4.54 0.089
CaMg / Placebo 1.29 0.57–2.98 0.565
Exact logistic regression with effect of treatment schedule and CaMg on RR
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Sequentially confirmed response rates (RECIST – Independent review) – Hochster ASCO GI 2008
Best response, n
CO IO
Placebo (n=28)
CaMg(n=31)
Placebo (n=31)
CaMg(n=28)
PR SD PD
6139
11155
14152
12115
RR, %95% CI
218.3– 41.0
3619.2– 54.6
4527.3– 64.0
4324.5– 62.8
Odds ratio 95% CI p-value
IO / CO 1.96 0.86–4.54 0.089
CaMg / Placebo 1.29 0.57–2.98 0.565
Exact logistic regression with effect of treatment schedule and CaMg on RR
CaMg did NOT interfere with activity of FOLFOX + BEV per independent radiologic review
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Study cohorts
• Randomized: n=180
• Original 2x2 design: n=140 (Cohort 1)
• After amendment (all pts to receive CaMg) 40 pts randomized (Cohort 2)
• Due to early study closure, collection of data was stopped on July 12, 2007 (date of Last Patient Last Visit)
• Data are presented for original 2x2 design = Cohort 1 (139/140 pts treated)
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Patient and disease characteristics at baseline
N Patients
CO (n=68) IO (n=71)
Total(n=139)
Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Mean age (years) 61 63 62 67 63
Age ≥65 yrs 14 15 15 24 68
Male 16 24 18 18 76
ECOG PS 0/1 19/13 17/17 22/14 16/19 74/63
Stage IV at dx 19 22 25 21 87
Primary tumor Colon Rectum CRC, NOS
2553
2761
3123
2861
11119 8
Prior treatment Radiation Chemotherapy
49
56
38
47
1630
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Time to Treatment Failure (TTF) Primary Endpoint
CO (n=68) IO (n=71)Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Pts with event 97% 100% 86% 97%
Median TTF (mos)95% CI
4.03.3–5.5
4.63.6–6.0
6.95.6–8.9
4.63.6–6.9
4.2 5.6
Cox regression modelHazard
ratio95% CI p-value
IO / CO 0.58 0.41–0.83 0.0025CaMg / placebo 1.32 0.93–1.86 0.12
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Kaplan-Meier estimate of TTF for IO vs CO
a log rank test
Unstratified (IO relative to CO), p=0.002a
Stratified by CaMg (IO relative to CO), p=0.003a
Proportionof patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16 17
TTF months
COIO
Censored data
N at riskCO:IO:
1 3 5 7 9 11 13 15
6871
5861
3652
2032
621
412
210
14
01
6365
4656
2843
1128
418
412
27
11
TTF (mos)
95% CI
CO 4.2 3.7 - 5.5
IO 5.6 4.7 - 7.0
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Progression-Free Survival (PFS)
CO (n=68) IO (n=71)
Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Pts with event 46% 26% 25% 34%
Median (mos)95% CI
3.92.3–NE
10.97.3–10.9
NE8.2–NE
9.65.6–13.9
7.3 12.0
Cox regression modelHazard
ratio95% CI p-value
IO / CO 0.53 0.29–0.99 0.048
CaMg / Placebo 0.99 0.55–1.79 0.976
NE, not estimable
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Kaplan-Meier estimate of PFS for IO vs CO
a log rank test
Unstratified (IO relative to CO), p=0.044a
Stratified by Ca/Mg (IO relative to CO), p=0.030a
Proportionof patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16 17
PFS months
COIO
Censored data
N at riskCO:IO:
1 3 5 7 9 11 13 15
6871
4655
2943
1327
318
310
08
02
01
6464
3951
2438
724
315
19
03
01
PFS (mos)
95% CI
CO 7.3 6.9 - NE
IO 12.0 8.2 - NE
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Grade 3/4 Adverse Eventsa
n (%)
CO IO
Total(n=139)
Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Neurotoxicity
Neutropenia
Leukopenia
Thrombocytopenia
Nausea
Vomiting
Fatigue
Diarrhea
Dehydration
Hypertension
Small intestinal obstr.
Hyperglycemia
Hand–Foot syndrome
8 (24)
4 (12)
1 (3)
2 (6)
2 (6)
2 (6)
2 (6)
1 (3)
2 (6)
1 (3)
0
2 (6)
0
8 (23)
8 (23)
1 (3)
1 (3)
2 (6)
1 (3)
2 (6)
2 (6)
2 (6)
2 (6)
1 (3)
1 (3)
0
3 (8)
5 (14)
0
0
2 (6)
3 (9)
1 (3)
3 (9)
0
1 (3)
3 (8)
2 (6)
0
4 (11)
3 (9)
1 (3)
1 (3)
4 (11)
2 (6)
4 (11)
2 (6)
3 (9)
2 (6)
1 (3)
0
3 (9)
23 (17)
20 (14)
3 (2)
4 (3)
10 (7)
8 (6)
9 (7)
8 (6)
7 (5)
6 (4)
5 (4)
5 (4)
3 (2)a Occurring in >2% patients for hematologic events and >3% patients for non-hematologic events
16 (24) 7 (10)
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Neurotoxicity Events (NTE) leading to dose reduction, discontinuation, or delay
N pts (%) with >1 NTE leading to
CO (n=68)
IO(n=71)
Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Discontinuation8 (24) 7 (20) 3 (8) 4 (11)
15 (22) 7 (10)
Delay 1 (3) 0 1 (3) 0
Dose reduction 7 (21) 6 (17) 2 (6) 2 (6)
Delay and dose reduction 0 1 (3) 1 (3) 1 (3)
Delay or dose reduction
8 (24) 7 (20) 3 (8) 3 (9)
15 (22) 6 (8)
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Neurotoxicity assessment — Patient Neurotoxicity Questionnaire (PNQ)
• Qualitative assessment of PSN (none, mild, moderate, moderate to severe, or severe PSN)
• Quantitative comparison of neurotoxicity effects in CO vs IO and placebo vs CaMg
• Answers to 2 items assessed:• Item 1 — sense of touch in hands/fingers, or feet/toes
or mouth area (chronic PSN)• Item 2 — difficulty in swallowing, breathing, drinking
or chewing food, or muscle spasms (acute PSN)
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Mean PNQ by cycle
• Item 1 – chronic PSN
22
Mean assessment
4
3
2
1
00 4 8 12 16 21 25 26
Cycle
CO (placebo)CO (Ca2+/Mg2+)IO (placebo)IO (Ca2+/Mg2+)
2 6 10 14 19 233 7 11 15 20 241 5 9 13 18
3153
32343432
19272821
13172616
89156
72136
3153
1142
1142
28273027
17233020
11162211
34157
3193
3163
24262722
17232717
814228
43
174
3154
2153
28282827
21252821
11132513
66158
32115
17
27293028
No at risk
CO (placebo)CO (Ca2+/Mg2+)
IO (placebo)IO (Ca2+/Mg2+)
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Mean PNQ by cycle
• Item 2 – acute PSN
4
3
2
1
0
Cycle
CO (placebo)CO (Ca2+/Mg2+)IO (placebo)IO (Ca2+/Mg2+)
220 4 8 12 16 21 25 262 6 10 14 19 233 7 11 15 20 241 5 9 13 18
3152
32343432
18272921
13172616
87156
42136
3153
1142
1142
27273027
17232920
11162211
34157
3193
3163
24252722
16232517
814228
43
173
3154
2153
28282827
20252821
11132313
66157
32115
17
27293029
CO (placebo)CO (Ca2+/Mg2+)
IO (Ca2+/Mg2+)IO (placebo)
No at risk
Mean assessment
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Effect of treatment schedule and CaMg on change in PNQ (Cycle ≥ 8)
PNQ ComparisonPoint estimate of difference
Difference 95% CI p-value
Item 1 CO / IO -0.28 -0.55, -0.01 0.04
Placebo / CaMg -0.31 -0.58, -0.04 0.02
Item 2 CO / IO -0.39 -0.64, -0.14 0.002
Placebo/CaMg -0.11 -0.36, +0.15 0.42
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Conclusions• Several limitations of this analysis
• Trial not primarily intended to evaluate effects of CaMg on RR• Small sample size• Early discontinuation of trial
• Activity of FOLFOX + BEV unaffected by CaMg
• Suggestion of neuroprotection by CaMg
• IO is associated with significant improvement of TTF compared with CO – without compromising PFS
• CO leads to higher number of discontinuations from the study due to PSN compared with IO
• IO = OPTIMOX1-like strategy should be considered standard of care for first-line oxaliplatin-based therapy
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BACKUP
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Assessments
• Tumor assessments q 8 weeks
• Neurotoxicity evaluation q 2 weeks• PE including patient neurotoxicity questionnaire (PNQ)
• Follow-up: q 3 months from end of treatment 3 years from randomization
• After study closure, an Independent Radiology Review Committee (IRRC) conducted a retrospective analysis of CT/MRI scans
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Disposition and discontinuation data
Number of pts
CO
n=69
IO
n=71 Total
Placebo CaMg Placebo CaMg
Randomized 34 35 36 35 140
Received treatment 34 34 36 35 139
Discontinued treatment
Adverse event
Disease progression
Investigator/pt decision/non-compliance
Other
16
9
8
1
12
5
15
2
8
8
12
8
12
8
11
4
48
30
46
15
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Exposure to Oxaliplatin
CO IO
Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Duration of study treatment (months)
Median (Range)
3.5 (0–15.1)
3.9 (0.5–12.5)
6.4 (0–15.8)
4.2 (0–13.9)
Cumulative dose per patient (mg/m2)
Median(Range)
680(88–2624)
745(169–2262)
706(85–1412)
682(79–1752)
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CaMg effect on categorized measures of neurotoxicity in PNQ Item 1 (as-treated population)
Neurotoxicity N pts (%)Placebo
(n=69)CaMg (n=70)
A - None 7 (11) 13 (20)
B - Mild 19 (29) 26 (39)
(A or B) 26 (40) 30 (59)
C - Moderate 26 (40) 17 (26)
D - Moderate to severe 13 (20) 5 (8)
E - Severe 0 5 (8)
(C or D or E) 39 (60) 27 (41)
p-value 0.036