Improving the tolerability of the oral targeted anticancer drug pazopanib by...
Transcript of Improving the tolerability of the oral targeted anticancer drug pazopanib by...
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Improving the tolerability of the oral targeted
anticancer drug pazopanib by food intake
DIET-study
Floor J E Lubberman, Hans Gelderblom, Paul Hamberg, Walter L Vervenne, Sasja F Mulder,
Frank G A Jansman, Angela Colbers, Winette T A van der Graaf, David M Burger, Saskia
Luelmo, Dirk Jan A R Moes, Carla M L van Herpen, Nielka P van Erp
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Pazopanib
Registered for mRCC and STS
Oral TKI targeting- VEGFR-1, -2, -3- PDGFR –α and –β- c-KIT
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi5kbmy15zeAhUGZVAKHbxeCwIQjRx6BAgBEAU&url=https://en.wikipedia.org/wiki/Pazopanib&psig=AOvVaw1FAOAKWkgmjVoC_hY0t_4K&ust=1540388206963313
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Adverse events pazopanib
Hutson J Clin Oncol. 2010
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Reasons for adverse events?
Deng Xenobiotica. 2013Waterbeemd Nature Reviews Drug Discovery 2003
Bioavailability of ca 21 %
Low solubility in aqueous media
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Food effect – on bioavailability
Heath Clin Pharmacol Ther. 2010
Treatment sequence ratio
AUC(0-72h) µg.h/ml High fat 2.34
Low fat 1.92
Cmax µg/ml High fat 2.08
Low fat 2.10
http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjsjdLQnPDMAhWC1xQKHXaZA-gQjRwIBw&url=http://www.telegraph.co.uk/news/health/news/7540732/A-high-fat-breakfast-of-bacon-and-eggs-may-be-the-healthiest-start-to-the-day-report-shows.html&bvm=bv.122448493,d.bGg&psig=AFQjCNGouGP1YFEUDj8bfklt6y0vNVB9Bw&ust=1464093781314703
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DIET study
Phase 1:Determine the equivalent dose of pazopanib when taken with a continental breakfast compared to 800 mg in fasted state.
Phase 2:To monitor the occurrence of diarrhea and/or nausea of pazopanib with and without food and measure patient preference.
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MethodPhase 1 → open-label, cross-over, multi center, bio-equivalence study
Phase 2 → open-label, randomized, cross-over multi-centre phase 3 trial
Eligible : - Use of 800mg pazopanib OD- ECOG 0-2
Excluded: - Patients with gastro-intestinal abnormalities- Use of interacting drugs (PPI use was allowed)
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Example continental breakfast
http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiszb-tnfDMAhWJXBQKHW1HBUUQjRwIBw&url=http://www.lekkerensimpel.com/zelfgemaakte-cruesli/&bvm=bv.122448493,d.bGg&psig=AFQjCNF8J-lXmMpHaQJdxw-1ztjLAqVz-Q&ust=1464094005125557http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwit68OAnfDMAhXCuRQKHaX3CCMQjRwIBw&url=http://www.nrc.nl/nieuws/2014/06/05/kaas-verkopen-maar-dan-in-de-supermarkt&bvm=bv.122448493,d.bGg&psig=AFQjCNEuJ4nL-XiDBA6fmnWzgaZ8VMfQRw&ust=1464093912214109http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiU0PWUnfDMAhXKvxQKHa92BWAQjRwIBw&url=http://kuifjeindekeuken.nl/koninklijke-hagelslagfabrikant-onderzoekt-onze-broodgewoonten/&bvm=bv.122448493,d.bGg&psig=AFQjCNFfICLMo79KVdqJOWc6FMhHqxorUA&ust=1464093955514132
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t28t15t14t0
Phase 1
Patients take 800 mg pazopanib in a fasted state
PK curve is taken
Patients take 600 mg pazopanib with continental breakfast
PK curve is taken
25% dose reduction
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Phase 2
Patients take 800 mg pazopanib in a fasted state
Patients take 600 mg pazopanib with continental breakfast
- GI-toxicity through patient diary
- CTSQ- Ctrough level monitoring
-GI toxicity through patient diary
- Patient preference- CTSQ - Ctrough level monitoring- PFS data
Patients take 800 mg pazopanib in a fasted state
Patients take 600 mg pazopanib with continental breakfast
t28t0 t29 t56
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Results Phase 1Characteristics at baseline
No. %
Patients, n 16 100
Age, median (range) 58 (35-77)
SexFemaleMale
88
5050
BMI, kg/m2 median(range)
24 (21-30)
ECOG performance status01
115
6931
Primairy tumorRenal cell carcinomaSoft tissue sarcoma
10 6
6238
800 mg fasted 600 mg fed
AUC0-24h, mg·h/l (CV%) 821 (36) 895 (38)
Cmax, mg/l (CV%) 44.8 (33) 50.2 (39)
Ctrough, mg/l (CV%) 26.7 (42) 29.0 (42)
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Eligible n=77
Arm A n= 36 Arm B n=41
Per protocol treatment n=27
Per protocol treatment n=33
Never started n=2 Progression n=2Hepatotoxicity n=2Dose reduction n=1GI toxicity n=1Other n=1
Hepatotoxicity n=1Withdrew consent n=1GI toxicity n=1Other n=5
Results phase 2
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Characteristics at baseline No. %
Patients, n 60
Age, median (range) 62 (28-85)
SexFemaleMale
1644
2773
BMI, kg/m2 median (range) 26 (19-52)
ECOG performance status012
unknown
223215
375328
Primairy tumorRenal cell carcinomaSoft tissue sarcomaOther
47 121
78202
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800 mg fasted 600 mg fed
Number of stools per day, mean (SD) 1.72 (0.81) 1.60 (0.64)
Times vomited per day, mean (SD) 0.02 (0.04) 0.02 (0.05)
Nausea, mean (SD) 0.15 (0.29) 0.13 (0.27)
GI-toxicity
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Treatment satisfaction
CTSQ 800 mg fasted 600 mg fed P-value
Expectations of therapy, mean (SD) 53.7 (15.7) 52.2 (16.8) 0.71
Feelings about side effects, mean (SD) 67.4 (19.7) 73.1 (15.7) 0.03
Satisfaction with therapy, mean (SD) 81.7 (12.0) 84.9 (12.0) 0.02
Preferred intake regime 800 mg fasted 600 mg fed
No preferred
intake
15 (25%) 41 (68%) 4 (7%)
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Discussion
- Lower GI–toxicity than in previous research?
- Extrapolation to other breakfasts?
- Cost reduction of €10.800,- per patient
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Conclusion
A simple food intervention can reduce pazopanib dose. It does not change GI-toxicity, but improves patients
satisfaction
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AcknowlegementPatients and their families
RadboudumcNielka van ErpCarla van HerpenSasja MulderWinette van der GraafDavid BurgerAngela ColbersMarlies KuiperijWilleke RuttenAnita Smits-vander CampHeidi Zweers
Betaalbaar beter (VGZ)
LUMCHans GelderblomSaskia LuelmoDirk Jan MoesMargret den Hollander
Franciscus GasthuisPaul HambergSuraya van Broekhoven
Deventer ZiekenhuisWalter VervenneFrank JansmanErica ten BergeMarianne PapaEliane Veurink