oxaliplatin neuropathie - prophylaxe und therapie 1/2_supportive... · universitätsklinikum essen...

Westdeutsches Tumorzentrum WTZ UK EssenWTZ Westdeutsches Tumorzentrum WTZ UK Essen

WTZ

Dr. med. Tanja Trarbach

Innere Klinik (Tumorforschung)

Universitätsklinikum Essen

Direktor: Prof. Martin Schuler

Oxaliplatin Neuropathie -

Prophylaxe und Therapie

Westdeutsches Tumorzentrum WTZ UK EssenWTZ

Möglicher Pathomechanismus Na+

Einflusshemmung –Chelatbildung von

Oxalat mit Ca2+

ATP ATP

EXTRA

Membran

INTRA

Ca2+

Oxalat

Dach-Pt

Na+

Oxaliplatin

MOSAIC: Long-term Safety

(% patients)

FOLFOX

5.3

LV5FU2

5.7

0

10

20

30

40

50

60

During

Tx

6

months

1-year 2-year 3-year 4-year

Grade 1

Grade 2

Grade 3

Second cancer

Peripheral

Sensory

Neuropathy

Evaluable

patients n=811

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

De Gramont, ASCO 2007, # 4007

Substanz kontrollierte AutorStudie

Nortriptyline ja Hammack,

Gabapentin ja Rao

Lamotrigine ja Rao

Neuromodulatorische Substanzen

Therapie


Ca+Mg+ Infusion ja Grothey

Xaliproden ja Cassidy

Vitamin E ja Pace

Glutathion ja Cascinu

Glutamin ja Wang

Carbamazepin nein Eckel


Prävention


Ca+Mg+ Infusion ja Grothey

Xaliproden ja Cassidy

Vitamin E ja Pace

Glutathion ja Cascinu

Glutamin ja Wang

Carbamazepin nein Eckel


Prävention

STOP and GO ?

OPTIMOX 1

Tournigand et al., JCO 2006

6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7

FOLFOX4

623 Pat

R

Kum. Oxali 780 1560

(%) FOLFOX4 FOLFOX7

RR 58.5 58.3

PFS 9.0 9.2

OS 20.0 21.6

CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin

CONcePT TrialPrimary 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


Intermittent oxaliplatin

+/- IV CaMgR

Grothey et al., ASCO 2008, # 4010

CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin

CONcePT TrialPrimary endpoint: TTF for CO vs IO schedule

No randomization to placebo after protocol amendment

First-line mCRC, 532 patients

Primary endpoint: time to failure (TTF)

Randomization (2x2):


CO until Treatment Failure


Intermittent oxaliplatin

+/- IV CaMgR

270 pts


Sequentially confirmed response rates (RECIST

– Independent review) – Hochster ASCO GI 2008

Best response

CO IO

Placebo (n=28)

CaMg(n=31)

Placebo (n=31)

CaMg(n=28)

PRSDPD

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


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

Proportion

of 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

CO

IO

Censored data

N at risk

CO:

IO:

1 3 5 7 9 11 13 15

68

71

58

61

36

52

20

32

6

21

4

12

2

10

1

4

0

1

63

65

46

56

28

43

11

28

4

18

4

12

2

7

1

1

TTF (mos)

95% CI

CO 4.2 3.7 - 5.5

IO 5.6 4.7 - 7.0


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

Proportion

of 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

CO

IO

Censored data

N at risk

CO:

IO:

1 3 5 7 9 11 13 15

68

71

46

55

29

43

13

27

3

18

3

10

0

8

0

2

0

1

64

64

39

51

24

38

7

24

3

15

1

9

0

3

0

1

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)

Discontinuation

8 (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 anddose reduction

0 1 (3) 1 (3) 1 (3)

Delay ordose reduction

8 (24) 7 (20) 3 (8) 3 (9)

15 (22) 6 (8)


N04C7 Cancer Control Phase III Trial – Study Design

• 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min

immediately before and after oxaliplatin (placebo = 100 mL D5W)

• Neurotoxicity recorded in 3 different ways:

• NCI-CTC v3.0 (primary endpoint) Grad 2+ PNP

• Oxaliplatin-specific scale

• Patient questionnaires

Pts to receiveadj. FOLFOX

IV CaMg

% of Grade 2+ sNTR

IV placebo


N = 300


Incidence of Grade 2+ sNT

sNT GradeCaMg

(N=50)

Placebo

(N=52)P

NCI CTC scale

Grade 0/1 78% 59%

0.038

Grade 2+ 22% 41%

Oxaliplatin scale

Grade 0/1 72% 49%

0.018

Grade 2+ 28% 51%

Grothey et al. ASCO 2009, # 4025


Acute Symptoms on Day 2 of Cycle 1

Mean PRO-scores (SD)

SymptomCaMg

(N=45)

Placebo

(N=50)P

Sensitivity to

cold17 (22) 14 (21) 0.41

Discomfort

swallowing13 (21) 13 (23) 0.81

Throat

discomfort5 (10) 13 (27) 0.19

Muscle cramps 2 (6) 11 (23) 0.002

Scale 0-100 (0: no symptoms, 100: worst)



Chronic sNT (Examples)Numbness fingers/toes Tingling fingers/toes

p=0.02 p=0.06

p-value for comparison of areas under the curvesGrothey et al., ASCO 2009, # 4025


Chronic sNT (Examples)Numbness fingers/toes Tingling fingers/toes

p=0.02 p=0.06

p-value for comparison of areas under the curvesGrothey et al., ASCO 2009, # 4025

Keine

Effektivitätsdaten


Xaliproden (SR57746A): Pharmacology

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, ...)

NCF3


XENOX Study Design

• 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

R

FOLFOX4 +

Xaliproden 1 mg po QD

FOLFOX4 +

Placebo 1 mg po QD

Patients

mit

mCRC

Cassidy et al., ASCO GI 2006, # 229


0 200 400 600 800 1000 1200 1400 1600 1800 2000

Oxaliplatin 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

ba

bil

ity

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

Logrank test, p = 0.0203

HR [95% CI] = 0.61 [0.40, 0.93]

Placebo

Xaliproden

XENOX study results



% of Pts Placebo Xaliproden

n = 324 n = 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

Incidence PSN (ITT)



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

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

ba

bil

ity

PlaceboXaliproden

20.1

192 (59.1%)

Xaliproden

N=325

18.9Median OS

198 (61.1%)Nb of events

Placebo

N=324

XENOX: overall survival



XENOX: all-Grade adverse events 2% higher incidence in Xaliproden vs Placebo

% of patientsPlacebon = 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 NA

Insomnia * 12.8 0 18.5 0

Headache 10.9 0.3 14.2 0.6

Dizziness * 8.7 0.6 13.3 0.9

Peripheral edema * 5.0 0 9.9 0

Hand foot syndrome 6.2 0.6 8.3 0

Back pain 5.3 0.3 8.0 0.9

Anxiety * 3.4 0.3 6.8 0.3

Weight decrease 3.4 0.3 6.5 0.6

Chest pain 2.8 0 4.9 0

Tinnitus * 0.6 0 3.7 0

Pulmonary embolism 0.9 0.9 3.1 3.1

Vertigo * 0.9 0 3.1 0


EFC5505 – Study design

Modified FOLFOX6 +

xaliproden 1 mg qd

Modified FOLFOX6 +

Placebo

End

OXA

Xaliproden 1 mg qd

Placebo

R PSN >1

Double blind

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

(yes, no)

- First-line colorectal cancer patients

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

N = 883


XENON: “Curative study”

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

R

Xaliproden1 mg po daily for

6 months

Placebo

Patients with

PSN grade ≥1 after

completion of adjuvant

oxaliplatin- based CT

XENON


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

Zusammenfassung


Vielen Dank für Ihre

Aufmerksamkeit !

oxaliplatin neuropathie - prophylaxe und therapie 1/2_supportive... · universitätsklinikum essen...

Documents