Oxaliplatin Neuropathie - Prophylaxe und Therapie

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1 Oxaliplatin Neuropathie - Prophylaxe und Therapie Dr. med. Tanja Trarbach Innere Klinik (Tumorforschung) Universitätsklinikum Essen Direktor: Prof. Martin Schuler WTZ

2 Möglicher Pathomechanismus Na + Einflusshemmung Chelatbildung von Oxalat mit Ca 2+ EXTRA Oxaliplatin Membran Na + INTRA ATP Oxalat ATP Ca 2+ Dach-Pt

3 MOSAIC: Long-term Safety Second cancer (% patients) FOLFOX 5.3 LV5FU2 5.7 Peripheral Sensory Neuropathy Grade 1 Grade 2 Grade 3 Evaluable patients n=811 Grade 84.3% 3 Grade 1 12.% Grade 2 2.8% 2 Grade 3.7% 1 During Tx 6 months 1-year 2-year 3-year 4-year De Gramont, ASCO 27, # 47

4 Neuromodulatorische Substanzen Therapie Substanz kontrollierte Autor Studie Nortriptyline ja Hammack, Gabapentin ja Rao Lamotrigine ja Rao

5 Neuromodulatorische Substanzen Prävention Substanz kontrollierte Autor Studie Ca + Mg + Infusion ja Grothey Xaliproden ja Cassidy Vitamin E ja Pace Glutathion ja Cascinu Glutamin ja Wang Carbamazepin nein Eckel

6 Neuromodulatorische Substanzen Prävention Substanz kontrollierte Autor Studie Ca + Mg + Infusion ja Grothey Xaliproden ja Cassidy STOP and GO? Vitamin E ja Pace Glutathion ja Cascinu Glutamin ja Wang Carbamazepin nein Eckel

7 OPTIMOX 1 FOLFOX4 R 623 Pat 6x FOLFOX7-12x slv5fu2-6x FOLFOX7 Kum. Oxali (%) FOLFOX4 FOLFOX7 RR PFS OS Tournigand et al., JCO 26

8 CONcePT Trial Primary endpoint: TTF for CO vs IO schedule First-line mcrc, 532 patients Primary endpoint: time to failure (TTF) Randomization (2x2): mfolfox7 + bevacizumab CO until Treatment Failure R +/- IV CaMg mfolfox7 + bevacizumab Intermittent oxaliplatin CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 3 min pre- and post-oxaliplatin Grothey et al., ASCO 28, # 41

9 CONcePT Trial Primary endpoint: TTF for CO vs IO schedule First-line mcrc, 532 patients Primary endpoint: time to failure (TTF) Randomization (2x2): 27 pts mfolfox7 + bevacizumab CO until Treatment Failure R +/- IV CaMg mfolfox7 + bevacizumab Intermittent oxaliplatin No randomization to placebo after protocol amendment CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 3 min pre- and post-oxaliplatin Grothey et al., ASCO 28, # 41

10 Sequentially confirmed response rates (RECIST Independent review) Hochster ASCO GI 28 Best response PR SD PD RR, % 95% CI CO Placebo CaMg (n=28) (n=31) IO Placebo (n=31) CaMg (n=28) Odds ratio 95% CI p-value IO / CO CaMg / Placebo Grothey et al., ASCO 28, # 41

11 Kaplan-Meier estimate of TTF for IO vs CO TTF (mos) 95% CI CO Proportion of patients 1..9 IO CO IO.8 Censored data Unstratified (IO relative to CO), p=.2 a Stratified by CaMg (IO relative to CO), p=.3 a a log rank test N at risk CO: IO: TTF months Grothey et al., ASCO 28, #

12 Kaplan-Meier estimate of PFS for IO vs CO PFS (mos) 95% CI Proportion of patients 1..9 CO NE IO NE CO IO.8 Censored data Unstratified (IO relative to CO), p=.44 a Stratified by Ca/Mg (IO relative to CO), p=.3 a N at risk CO: IO: PFS months a log rank test Grothey et al., ASCO 28, # 41

13 n (%) Grade 3/4 Adverse Events a Placebo (n=33) CO CaMg (n=35) Placebo (n=36) IO CaMg (n=35) Total (n=139) Neurotoxicity 8 (24) 8 (23) 3 (8) 4 (11) 23 (17) Neutropenia 4 (12) 8 (23) 5 (14) 3 (9) 2 (14) Leukopenia 1 (3) 1 (3) 1 (3) 3 (2) Thrombocytopenia Nausea Vomiting 2 (6) 1 (3) 2 (6) 2 (6) 2 (6) 16 (24) 7 (1) 2 (6) 1 (3) 3 (9) 1 (3) 4 (11) 2 (6) 4 (3) 1 (7) 8 (6) Fatigue 2 (6) 2 (6) 1 (3) 4 (11) 9 (7) Diarrhea 1 (3) 2 (6) 3 (9) 2 (6) 8 (6) Dehydration 2 (6) 2 (6) 3 (9) 7 (5) Hypertension 1 (3) 2 (6) 1 (3) 2 (6) 6 (4) Small intestinal obstr. 1 (3) 3 (8) 1 (3) 5 (4) Hyperglycemia 2 (6) 1 (3) 2 (6) 5 (4) Hand Foot syndrome 3 (9) 3 (2) a Occurring in >2% patients for hematologic events and >3% patients for non-hematologic events Grothey et al., ASCO 28, # 41

14 Neurotoxicity Events (NTE) leading to dose reduction, discontinuation, or delay N pts (%) with >1 NTE leading to Placebo (n=33) CO (n=68) CaMg (n=35) Placebo (n=36) IO (n=71) CaMg (n=35) 8 (24) 7 (2) 3 (8) 4 (11) Discontinuation 15 (22) 7 (1) Delay 1 (3) 1 (3) Dose reduction 7 (21) 6 (17) 2 (6) 2 (6) Delay and dose reduction Delay or dose reduction 1 (3) 1 (3) 1 (3) 8 (24) 7 (2) 3 (8) 3 (9) 15 (22) 6 (8)

15 N4C7 Cancer Control Phase III Trial Study Design IV CaMg Pts to receive adj. FOLFOX R IV placebo % of Grade 2+ snt N = 3 1g Ca-gluconate and 1g Mg-sulfate in 1 ml D5W over 3 min immediately before and after oxaliplatin (placebo = 1 ml D5W) Neurotoxicity recorded in 3 different ways: NCI-CTC v3. (primary endpoint) Grad 2+ PNP Oxaliplatin-specific scale Patient questionnaires Grothey et al., ASCO 29, # 425

16 Incidence of Grade 2+ snt snt Grade CaMg (N=5) Placebo (N=52) P NCI CTC scale Grade /1 78% 59% Grade 2+ 22% 41%.38 Oxaliplatin scale Grade /1 72% 49% Grade 2+ 28% 51%.18 Grothey et al. ASCO 29, # 425

17 Acute Symptoms on Day 2 of Cycle 1 Mean PRO-scores (SD) Symptom CaMg (N=45) Placebo (N=5) P Sensitivity to cold Discomfort swallowing Throat discomfort 17 (22) 14 (21) (21) 13 (23).81 5 (1) 13 (27).19 Muscle cramps 2 (6) 11 (23).2 Scale -1 (: no symptoms, 1: worst) Grothey et al., ASCO 29, # 425

18 Chronic snt (Examples) Numbness fingers/toes Tingling fingers/toes p=.2 p=.6 p-value for comparison of areas under the curves Grothey et al., ASCO 29, # 425

19 Chronic snt (Examples) Numbness fingers/toes Tingling fingers/toes Keine Effektivitätsdaten p=.2 p=.6 p-value for comparison of areas under the curves Grothey et al., ASCO 29, # 425

20 Xaliproden (SR57746A): Pharmacology CF 3 N Orale neurotrophische und neuroprotektive Substanz: Erhöhung der Expression von Neurotrophinen (NGF, BDNF, NT3), endogenen Proteinen die bei der Entwicklung und Reparatur von Neuronen eine wichtige Rolle spielen Erhöhung von neuronalem Überleben und Differenzierung Minimierung experimentell-induzierten neuronalen Läsionen, inklusive Oxaliplatin-induzierter Schäden 5HT1A Receptor Agonist (Hauptmechanismus der Nebenwirkungen: Schlaflosigkeit, Schwindel, Diarrhoen,...)

21 XENOX Study Design Patients mit mcrc R FOLFOX4 + Xaliproden 1 mg po QD FOLFOX4 + Placebo 1 mg po QD Behandlung mit Studienmedikament (Xaliproden oder Placebo) beginnt am d1 der Oxaliplatininfusion und ended 15 Tage nach der letzten Oxaliplatininfusion Primärer Endpunkt: Wahrscheinlichkeit Beginn Grad 3 PSN relativ zur kumulativen Oxaliplatindosis Cassidy et al., ASCO GI 26, # 229

22 Probability WTZ XENOX study results Logrank test, p =.23 HR [95% CI] =.61 [.4,.93] Placebo Xaliproden Placebo Xaliproden Oxaliplatin cumulative dose (mg/m²) Patients at risk: Cassidy et al., ASCO GI 26, # 229 Placebo

23 Incidence PSN (ITT) % of Pts Placebo Xaliproden n = 324 n = 325 All grades Grade Grade Grade Grade 4 Cassidy et al., ASCO GI 26, # 229

24 Probability WTZ XENOX: overall survival Placebo Xaliproden Nb of events Median OS Placebo N= (61.1%) 18.9 Xaliproden N= (59.1%) Time (months) Placebo Xaliproden Cassidy et al., ASCO GI 26, # 229

25 XENOX: all-grade adverse Placebo % of patients events n = 321 2% higher incidence in Xaliproden vs Placebo Xaliproden n = 324 All Grade Gr 3-4 All Grade Gr 3-4 Diarrhea * Alopecia 15.6 NA 2.4 NA Insomnia * Headache Dizziness * Peripheral edema * Hand foot syndrome Back pain Anxiety * Weight decrease Chest pain Tinnitus * Pulmonary embolism Vertigo *.9 3.1

26 EFC555 Study design - First-line colorectal cancer patients Modified FOLFOX6 + xaliproden 1 mg qd Modified FOLFOX6 + Placebo E nd O XA Xaliproden 1 mg qd R PSN >1 N = 883 Double blind Placebo -Stratification factors: number of metastatic organs involved (1, 2), oxaliplatin (yes, no), bevacizumab (yes, no) Primary endpoint : probability of occurrence of grade 3+ PSN, in relation with cumulative dose of oxaliplatin Objective: confirm XENOX study and explore continuing treatment with Xaliproden after oxaliplatin discontinuation

27 XENON: Curative study XENON Patients with PSN grade 1 after completion of adjuvant oxaliplatin- based CT R Xaliproden 1 mg po daily for 6 months Placebo Primary Endpoint: Rate of complete resolution of PSN at 6 months Secondary Endpoint: Health Related QoL Rate of least partial recovery of grade > 2 PSN at 6 months Time to complete recovery from PSN To evaluate the safety profile of xaliproden

28 Zusammenfassung Medikamentöse Therapie der PSN enttäuschend STOP and GO Strategien in den Alltag integrieren In der adjuvanten Situation Hinweise auf protektive Ca/Mg Infusionen, aber Effektivitätsdaten fehlen

29 Vielen Dank für Ihre Aufmerksamkeit!