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XENOX

J. CASSIDY, G.A. BJARNASON, T. HICKISH, C. TOPHAM, M. PROVENCIO, G. BODOKY, L. LANDHERR, P. KORALEWSKI, G. LOPEZ-VIVANCO, G. SAID

BEATSON ONCOLOGY CENTER (UK), TORONTO SUNNYBROOK REGIONAL CANCER CENTER, (CANADA), POOLE AND BOURNEMOUTH HOSPITALS (UK), ROYAL SURREY COUNTY HOSPITAL (UK), CLINICA PUERTA DE HIERRO (SPAIN), ST LASZLO HOSPITAL (HUNGARY), UZSOKI STREET HOSPITAL (HUNGARY), RYDYGIER MEMORIAL HOSPITAL (POLAND), HOSPITAL DE CRUCES (SPAIN), HÔPITAL De BICÊTRE (FRANCE).

Randomized double blind (DB) placebo (Plcb) controlled Phase III study assessing the efficacy of xaliproden (X)

in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in 1st line treatment of

patients (pts) with metastatic colorectal cancer (MCRC).

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XaliprodenXaliproden

Orally active non-peptide neurotrophic and neuroprotective agent:

Increases the expression of neurotrophins (NGF, BDNF, NT3), endogenous proteins acting on the development and repair of neurons

Increases neuronal survival and differentiation Minimizes experimentally-induced neuronal

lesions, including oxaliplatin-induced lesions 5HT1A –receptor agonist

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Study Design

Stratification factors: number of metastatic organs (1 vs 2), LDH ( vs >1.5 x ULN), WHO PS (2 vs 0-1), study site

Treatment with study drug (xaliproden or placebo) started the day of first oxaliplatin infusion and discontinued 15 days following the last oxaliplatin infusion

R

FOLFOX4 +Xaliproden 1 mg po qd

FOLFOX4 + Placebo 1mg po qd

PatientsWith

MCRC

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Main Inclusion Criteria

Patient with proven MCRC No prior chemotherapy for metastatic disease No prior treatment with oxaliplatin Measurable disease (RECIST) No peripheral neuropathy

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Primary Endpoints

Two co-primary endpoints:

• Reduction in the risk of occurrence of Grade 3-4 peripheral sensory neuropathy (PSN) relative to the cumulative dose of oxaliplatin Specific Neurologic Toxicity Scale for Oxaliplatin

Dose Adjustment, administered every 2 weeks Kaplan Meier analysis

• Non-inferiority in Response Rate (RR) Response Evaluation Criteria in Solid Tumors

(RECIST) criteria, performed every 8 weeks

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Statistical Approach• Powered (80%) to demonstrate a 45% reduction in the

probability of experiencing Grade 3-4 PSN relative to the cumulative dose of oxaliplatin

2-sided logrank test with = 0.05 Assumption: 18% Grade 3 PSN for a cumulative dose of

1000 mg/m² in the control arm

• Powered (80%) to demonstrate non-inferiority in RR

Non-inferiority: lower bound of the 2-sided 95.2 % CI of the ratio of the RRs is at least 0.80

Assumption: 49% RR in the control arm

310 patients per treatment group needed

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Secondary Endpoints

Incidence, dose to onset of PSN, oxaliplatin dose reduction/delays, discontinuation due to PSN

Change in nerve conduction study (NCS)

Change in Modified Norris Scale score

Time to recovery from Grade 3-4 PSN

Progression free survival (PFS), overall survival (OS)

Safety

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Baseline Characteristics (ITT)

% of patients Placebon = 324

Xaliproden n = 325

Gender, male 61.7 57.2

Median age (years) 60.0 63.0

WHO PS 0-1 2

94.15.9

94.85.2

ColonRectumOther

62.737.00.3

65.234.50.3

2 organs involved 62.3 60.6

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Exposure to Oxaliplatin

Placebon = 324

Xaliprodenn = 325

Total number of cycles 3401 3550

No. of cycles Median 12.0 12.0

Mean 10.6 11.0

Cumulative dose (mg/m²)

Median 894.7 912.2

Mean 848.2 875.8

Duration (weeks) Median 25.9 25.0

RDI (%) Median 83.8 85.2

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Probability of First Onset of Grade 3 PSN Relative to Cumulative

Dose of Oxaliplatin (ITT)

Logrank test, p = 0.0203HR [95% CI] = 0.61 [0.40, 0.93]

Placebo

Xaliproden

0 200 400 600 800 1000 1200 1400 1600 1800 2000Oxaliplatin cumulative dose (mg/m²)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y

PlaceboXaliproden

Patients at risk:

Placebo 324 303 275 240 199 104 34 23 6 3 1

Xaliproden 325 308 281 248 200 119 50 23 16 5 2

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Probability of First Onset of Grade 3 PSN Relative to Cumulative Dose of

Oxaliplatin (ITT)

Placebon = 324

Xaliprodenn = 325

CD750 4 3

CD 1000 19 13

CD 1250 38 25

CD 1500 44 27

Logrank test, p-value 0.0203

Hazard ratio [95% CI] 0.61 [ 0.40; 0.93 ]

Probability of grade 3 PSN relative to cumulative dose (CD) of oxaliplatin , %

CD: mg/m²

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Nerve Conduction Studies, Sensory Action Potential

Percentage of change of SAP (median) by PSN grade Sural Nerve RIGHT

-90

-80-70

-60

-50-40

-30

-20-10

0

PSN Grade at time of 2nd NCS

Med

ian

Perc

enta

ge o

f ch

ange

of S

AP v

s ba

selin

e

Placebo Xaliproden

0 321

Percentage of change of SAP (median) by PSN grade Sural Nerve LEFT

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

PSN Grade at time of 2nd NCS

Media

n Perc

entag

e of c

hang

e of

SAP v

s bas

eline

Placebo Xaliproden

0 1 2 3

Relationship between the sensory action potential (SAP) and PSN Grade at the time of the second NCS

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Incidence PSN (ITT)

% of patients Placebon = 324

Xaliprodenn = 325

All Grades 73.5 73.2

Grade 1 38.0 38.5

Grade 2 18.8 23.7

Grade 3 16.7 11.1

Grade 4 0 0

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Acute Symptoms of PSN Acute Symptoms of PSN (ITT(ITT))

% of patients Placebon = 324

Xaliproden n = 325

Any acute symptoms 82.7 81.2Cold related dysesthesia 80.9 79.7

Pharyngolaryngeal dysesthesia

16.4 17.8

Jaw pain 9.6 10.5Muscle cramps 9.0 8.6

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Grade 2/3 PSN Recovery (ITT)Placebo

N = 114

Xaliproden

N = 113

Partial Recovery% of patients

Median time (Mos), 95% CI

75.4

4.83 [3.25 ; 5.78]

77.8

4.63 [3.68 ; 5.75]

Total Recovery% of patients

Median time (Mos), 95% CI

47.4

12.98 [9.53 ; 20.57]

48.7

14.65 [10.84 ; 17.97]

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Response Rate (ITT)

% of patients PlaceboN = 324

XaliprodenN=325

RR [95% CI] 42.6[37.1; 48.2]

44.9 [39.4; 50.6]

Stable disease 41.7 42.2Progressive disease 7.7 5.8

Not evaluable 8.0 7.1

RR ratio [2-sided 95.2% CI] = 1.055 [0.88; 1.26]

17 Placebo 324 315 296 270 231 194 129 77 50 28 8 3 0

Xaliproden 325 311 299 280 238 202 140 96 61 34 17 1 0

Overall survival

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y

PlaceboXaliproden

20.1

192 (59.1%)

XaliprodenN=325

18.9Median OS

198 (61.1%)Nb of events

PlaceboN=324

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Safety Overview

% of patients Placebon = 321

Xaliproden n = 324

Any AE 99.4 98.8

At least 1 AE Grade 3 59.8 59.9

Discontinuation for AE (including PSN)

35.5 32.3

Discontinuation due to PSN

17.3 13.5

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All-Grade Adverse Events with 2% Higher Incidence in Xaliproden vs PlaceboTreated Group

% of patients Placebon = 321

Xaliproden n = 324

All Grade Gr 3-4 All Grade Gr 3-4

Diarrhea * 56.1 10.9 62.3 13.0

Alopecia 15.6 NA 20.4 NAInsomnia * 12.8 0 18.5 0Headache 10.9 0.3 14.2 0.6Dizziness * 8.7 0.6 13.3 0.9Peripheral edema * 5.0 0 9.9 0Hand foot syndrome 6.2 0.6 8.3 0Back pain 5.3 0.3 8.0 0.9Anxiety * 3.4 0.3 6.8 0.3Weight decrease 3.4 0.3 6.5 0.6Chest pain 2.8 0 4.9 0Tinnitus * 0.6 0 3.7 0Pulmonary embolism 0.9 0.9 3.1 3.1Vertigo * 0.9 0 3.1 0

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Conclusions (I)In patients with MCRC treated with 1st line FOLFOX4:

• Xaliproden decreases the risk of occurrence of Grade 3 oxaliplatin-induced PSN by 39% (p = 0.0203).

• Absence of negative impact of xaliproden on the FOLFOX4 outcome – non-inferiority in Response Rate: 42.6% vs 44.9 in the xaliproden

arm

– similar median Overall Survival: 18.9 months vs 20.1 months in the xaliproden arm

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Conclusions (II)In patients with MCRC treated with 1st line FOLFOX4:

• Reported safety figures mostly reflect the 5-HT1A –receptor agonist properties of xaliproden

• No effect reported on acute symptoms.

• No effect reported on recovery but xaliproden discontinued at the end of treatment with oxaliplatin

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Next Step, Study EF5505,Next Step, Study EF5505,

• Stratification factors: number of metastatic organs involved (1, 2), oxaliplatin (yes, no), bevacizumab (yes, no)

Modified FOLFOX6 +xaliproden 1 mg qd

Modified FOLFOX6 +Placebo

End

OXA

Xaliproden 1 mg qd

Placebo

R PSN >1

Double blind

-Confirm XENOX study-Explore continuing treatment with Xaliproden after oxaliplatin discontinuation

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Acknowledgments

Sponsored by Sanofi-Aventis

Investigators:Australia: Slancar M, Abdi E, Grygiel J, Burns IBelgium: Van Cutsem E, Peeters M, Humblet Y, Bols A, Honhon BCanada: Bjarnason G, Fields A, Latreille J, Panasci L France: Ychou M, François E, Metges JP, Viret F, Legoux JL, Rotarski M, Joly JPHungary: Bodoky G, Nagykalnai T, Moskovits K, Izso J, Thurzo L, Baki M, Boer KItaly: Bonetti A, Pinotti G, Zaniboni A, Villa E, Siena SPoland: Koralewski P, Filipczyk-Cisarz E, Szczylik C, Utracka-Hutka B, Załuski JSouth Africa: Ruff P, Rapoport BL, Slabber CF/Lombard J, Hacking D, Geddes C, Robertson BMSpain: Tabernero JM, Salgado M, Lopez G, Provencio M, Benavides M, Oaknin A, Rifa J, Cervantes A, Alvarez SUK: Cassidy J, Corrie P, Valle J, Topham C, Samuel L, Hickish T