1. Effect of intravenous calcium and magnesium versus placebo on response to FOLFOX+bevacizumab in the CONcePT trial
Hochster HS,1 Grothey A,2 Shpilsky A3, Childs BH3
1NYU School of Medicine, New York, NY; 2Mayo Clinic, Rochester, MN; 3sanofi-aventis, Bridgewater, NJ

2. Introduction
Oxaliplatin–fluoropyrimidine combinations are widely used in the 1st line treatment of metastatic colorectal cancer (mCRC)1-3
Addition of bevacizumab to oxaliplatin-based therapy further improves efficacy4,5
Oxaliplatin-based therapy is associated with cumulative peripheral sensory neuropathy (PSN):
10–15% of pts experience PSN after a cumulative oxaliplatin dose of 780–850 mg/m2,6
Common cause of treatment discontinuation prior to disease progression7
Strategies to reduce PSN:
Intermittent oxaliplatin dosing (OPTIMOX)
Prophylactic calcium and magnesium salts (Ca2+/Mg2+)
1. J Clin Oncol 2000;18:2938–47; 2. Proc ASCO 2002;21(Abstr 512); 3. J Clin Oncol 2000;18:136–47; 4. J Clin Oncol 2007;25:1539–44; 5. J Clin Oncol 2006;24(Suppl):3510; 6. Semin Oncol :21–33; 7. J Clin Oncol 2004;24:23–30

3. CONcePT trial
CONcePT: Combined Oxaliplatin Neurotoxicity Prevention Trial
Conducted to test the primary hypothesis:
Intermittent oxaliplatin (IO) schedule (using mFOLFOX7+bev) would allow patients to remain on therapy longer compared with conventional schedule (continuous oxaliplatin; CO)
Additionally, to evaluate:
The impact of Ca2+Mg2+ infusions on the incidence and severity of neurotoxicity in patients receiving either the IO or CO treatment schedules as first-line treatment for mCRC

4. Study background Opened February 2005 and terminated June 2007
Per recommendation of independent data-monitoring committee (IDMC)
IDMC letter stated:
“These recommendations are based on the interim data provided by the CRO which we used to conduct an unplanned interim analysis comparing confirmed response (CR/PR) on treatment arms A and C (no Ca/Mg) versus response on treatment arms B and D (Ca/Mg). The response rates were 32.9% and 17.3% for (A and C) and (B and D), respectively (2-sided Fisher’s exact test p=0.028) indicating superiority in terms of confirmed response for the treatment arms without Ca/Mg.”
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

5. Eligibility criteria Inclusion: Exclusion:
Histologically or cytologically documented, inoperable mCRC with ≥1 measurable lesion
Age ≥18 years
ECOG performance status (PS) score 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, bevacizumab, or both
Peripheral neuropathy grade >1

6. Study design Primary endpoint: TTF for CO vs IO schedule
mFOLFOX7+bev + placebo
BEV LV
CI 5FU
Continuous oxaliplatin OX
‘treat to failure’
mFOLFOX7+bev + Ca2+/Mg2+ Ra OX
BEV LV
CI 5FU
X 8 cycles
mFOLFOX7+bev + placebo
Intermittent oxaliplatin
aNo randomization to placebo after protocol amendment
BEV, bevacizumab; CI, continuous infusion; LV, leucovorin; OX, oxaliplatin; 5-FU, 5-fluorouracil
mFOLFOX7+bev = OX 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr and 5-FU 2400 mg/m2 over 46 hr plus bev 5 mg/kg over 30–90 minutes, on Day 1 once every 2 weeks
Ca2+/Mg2+ = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin

7. Assessments Tumor assessments q 8 weeks
Neurotoxicity evaluation q 2 weeks
PE including calibrated tuning fork, patient questionnaire
Follow-up: q 3 months from end of treatment  3 years from randomization
After study closure, an Independent Radiology Review Committee (IRRC) was formed to conduct a retrospective analysis of CT/MRI tumor images
Radiologists read all images blinded to response assessment from the site
Two radiologists independently reviewed each patient
Adjudication required if the two primary radiologists had discordant findings

8. Radiologic assessment
Sequentially confirmed response:
Response confirmed by RECIST criteria and based on two sequential assessments
Subsequently confirmed response:
Response confirmed by any subsequent scan, allowing:
multiple intervening integrated responses as unevaluable, partial response, stable disease or progressive disease* for complete response determination AND
multiple intervening integrated responses as unevaluable, stable disease, or progressive disease* for partial response determination
Unconfirmed response:
Response without subsequent or sequential confirmatory assessment
*minor progression by RECIST criteria from max response allowed during maintenance by study definitions

9. Results: patient disposition and baseline characteristics
Randomized: n=180
Original 2x2 design: n=140
After amendment (all pts received Ca2+/Mg2+): n=40
Data are presented for original 2x2 design (139/140 pts treated)
21 pts were unevaluable:
No baseline (n=5) or post-baseline (n=8) scans
Uninterpretable scans (n=4)
Unavailable scans (n=2)
Insufficient treatment duration (n=2)
Evaluable subset: n=118

10. Disposition and discontinuation data
Number of pts
CO Placebo CO
Ca2+Mg2+ IO
Placebo
Total
Randomized 34 35 36
140
Received treatment
139
Discontinued treatment
Adverse event
Death
Disease progression
Investigator/pt decision
Patient non-compliance
New anti-cancer treatment
Othera 16 9 8 1 13 5 14 2 10 12 11 49 30 43 3 7
a Early study closure by IDMC recommendation 10

11. Patient and disease characteristics at baseline (treated population)
Parameter
CO Placebo
(n=33) CO
Ca2+Mg2+
(n=35) IO
Placebo
(n=36)
Total
(n=139)
Mean age, years (SD)
61 (12)
63 (12)
62 (12)
67 (12)
Age, n
<65 years
≥65 years 19 14 20 15 21 11 24 71 68
Male/Female, n
16/17
24/11
18/18
18/17
76/63
ECOG PS, na 1 13 17 22 16 18 74 62
Stage, nb
I–III IV 12 10 25 48 87
Site of disease, nc
Colon
Rectum
Colorectal, NOS 5 3 27 6 31 2 28
111 8
Prior treatment, n
Radiotherapy
Surgery
Anticancer drugs 4 9 7 69 30
a Measurement not done for 3 pts; bData unknown for 4 pts; cData unknown for 1 pt 11

12. Duration of study treatment
Duration weeks CO
Placebo
(n=33)
CO Ca2+Mg2+
(n=35) IO
Placebo (n=36)
Ca2+Mg2+
Mean (SD)
18.7 (14.5)
18.4 (10.7)
29.7 (17.1)
22.2 (17.9)
Median (Range)
15.1 (0.1, 66.0)
17.1 (2.0, 54.3)
28.1 (0.1, 68.9)
18.1 (0.1, 60.6) 12

13. Response rate: sequentially confirmed response
Parameter CO IO
Placebo
Ca2+Mg2+
ITT
(n=34)
Eval (n=28)
(n=35)
Eval
(n=31)
(n=36)
Eval (n=31)
(n=28)
Best overall response, n CR PR SD PD
Uneval. 7 13 9 5 6 - 10 15 11 14 2 12
ORR, %
95% CI 21 29 36 39 45 34 43
Exact logistic regression model with treatment schedule and Ca2+Mg2+effects for evaluable pts
Odds ratio
95% CI
P-value
IO relative to CO
1.96
0.089
Ca2+Mg2+ relative to placebo
1.29
0.565 13

14. Response rate: unconfirmed response
Parameter CO IO
Placebo
Ca2+Mg2+
ITT
(n=34)
Eval (n=28)
(n=35)
Eval
(n=31)
(n=36)
Eval (n=31)
(n=28)
Best overall response, n CR PR SD PD
Uneval. 9 11 5 8 - 15 10 16 18 2 13 7
ORR, %
95% CI 27 29 43 52 50 58 37 46
Exact logistic regression model with treatment schedule and Ca2+Mg2+ effects for evaluable pts
Odds ratio
95% CI
P-value
IO relative to CO
1.62
0.203
Ca2+Mg2+ relative to placebo
1.26
0.581 14

15. Statistical Analyses Response rate
Two-factor logistic regression exploratory model of IRRC response data showed
no significant relationship with respect to treatment schedule (IO vs CO) or use of Ca2+/Mg2+ for
Sequentially confirmed response
Subsequently confirmed response (data not shown)
Unconfirmed response 15

16. Sequentially confirmed Subsequently confirmed
Ca2+Mg2+ effect on response rate (evaluable pts)
Parameter
Sequentially confirmed
Subsequently confirmed
Unconfirmed
Placebo (n=59)
Ca2+Mg2+ (n=59)
Ca2+Mg2+
(n=59)
Pts with response, n 20 23 21 24 26 29
ORR, %
95% CIa
P-valueb 34 - 39
0.702 36 41
0.705 44 49
0.712
No significant effect of Ca2+Mg2+ on response was observed, regardless of the criteria used for response rate determination
a2-sided exact confidence interval; bFisher’s exact test 16

17. Ca2+Mg2+ effect on time to first response
Placebo
(n=59)
Ca2+Mg2+
Patients with response, n 26 29
Time to first response
Median (weeks)
95% CI
25–75th percentile
32.7
16.3–NE
15.3–NE
24.0
9.3–NE
Unstratified analysis
Hazard ratio (vs placebo)a
p-valueb
1.356
0.796–2.310
0.261
Stratified by treatment schedule analysis
Hazard Ratio (vs placebo)a
1.347
0.788–2.304
0.275
aCox regression model with Ca2+Mg2+; bLog-rank test
NE, non-estimatable 17

18. Conclusions
Multiple data analyses based on an independent radiologic review of images in the CONcePT trial failed to demonstrate any deleterious effect of Ca2+Mg2+ on response to FOLFOX plus bevacizumab in pts with mCRC
Some limitations of this analysis:
Trial not primarily intended or designed to evaluate effects of Ca2+Mg2+ on tumor response to FOLFOX/bev
Small sample size
Missing scans
Data on neuroprophylaxis are pending
Additional results from this study will be reported 18