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

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

Adverse events pazopanib

Hutson J Clin Oncol. 2010

Reasons for adverse events?

Deng Xenobiotica. 2013Waterbeemd Nature Reviews Drug Discovery 2003

Bioavailability of ca 21 %

Low solubility in aqueous media

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

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.

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)

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

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

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

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)

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

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

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

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%)

Discussion

- Lower GI–toxicity than in previous research?

- Extrapolation to other breakfasts?

- Cost reduction of €10.800,- per patient

Conclusion

A simple food intervention can reduce pazopanib dose. It does not change GI-toxicity, but improves patients

satisfaction

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