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

Disclosures

• Honorarium: Roche

• Research support: Genentech, Bayer, Amgen, Sanofi-Aventis, BMS

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

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)

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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)

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)

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)

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+)

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

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

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

BACKUP

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

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

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)

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