1 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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1
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
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