1. A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities CTOS 2014 Rick Haas Department of Radiotherapy, The Netherlands Cancer Institute Amsterdam

2. Co-authors

3. Disclosure Investigator Initiated Research Grant GSK, but GSK had no part in the design nor the conduct of my studies

4. Introduction

5. Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT

6. Introduction Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT The timing of RT in ESTS is under debate.

7. Introduction Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT The timing of RT in ESTS is under debate. Epithelial tumors (carcinomas) => conventional chemotherapy and/or targeted agents + RT => an increased local control (increased overall survival) => at the cost of usually temporary acute side effects.

8. Introduction Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT The timing of RT in ESTS is under debate. Epithelial tumors (carcinomas) => conventional chemotherapy and/or targeted agents + RT => an increased local control (increased overall survival) => at the cost of usually temporary acute side effects. Myxoid liposarcomas (crow feet vasculature) respond rapidly to pre-op RT

9. Introduction Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT The timing of RT in ESTS is under debate. Epithelial tumors (carcinomas) => conventional chemotherapy and/or targeted agents + RT => an increased local control (increased overall survival) => at the cost of usually temporary acute side effects. Myxoid liposarcomas (crow feet vasculature) respond rapidly to pre-op RT

10. Introduction Local control in the majority of extremity soft tissue sarcomas (ESTS) is achieved by a combination of radical surgery and (neo-) adjuvant RT The timing of RT in ESTS is under debate. Epithelial tumors (carcinomas) => conventional chemotherapy and/or targeted agents + RT => an increased local control (increased overall survival) => at the cost of usually temporary acute side effects. Myxoid liposarcomas (crow feet vasculature) respond rapidly to pre-op RT This prospective phase I clinical trial aimed to establish 1 safety 2 toxicity profile 3 recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) amenable to treatment with curative intent.

11. Patients and Methods

12. Patients with intermediate or high grade deep seated ESTS, ≥ 5 cm in maximal dimension Once daily pazopanib (dose escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks Preoperative RT (25 x 2 Gy) starting on day 8 of pazopanib. Surgery was performed five to seven weeks later. Toxicity was scored according to CTC criteria 4.0. 6 wk Pazopanib 5 wk RT5 wk rest surgery 3 wk observation

13. Toxicity definitions DLT Itoxicities during and immediately after the induction treatment period, directly related to chemoradiation Note:systemic toxicities (like RR, hepatotoxicity etc.) could be reasons for drug interruption, but were not designated as DLT

14. Toxicity definitions DLT Itoxicities during and immediately after the induction treatment period, directly related to chemoradiation Note:systemic toxicities (like RR, hepatotoxicity etc.) could be reasons for drug interruption, but were not designated as DLT DLT IItoxicities in the perioperative phase

15. Results

16. Results; patients 12 patients were enrolled 3 nonevaluable 1 never started (“second thoughts refusal”) 2 due to hepatotoxicity (day 17 and 24 respectively) 9 evaluable

17. Results; patients Sex:2 females and 7 males Age:median age 49 years (range 24-74 years) Size:median size 9 cm (range 5-15 cm) Location:extremities Pathology:variety grade II / III conform inclusion criteria FU:Median FU 17 months (range 6-39 months).

18. Toxicity profile in the induction phase: DLT I 6 wk Pazopanib 5 wk RT5 wk rest surgery 3 wk observation

19. Toxicity profile in the induction phase: DLT I No increased toxicities within the radiation portals; mild skin erythema Other toxicities like fatigue, hair discoloration, hypertension and diarrhea were all mild (grade I) and transient

20. “Systemic” toxicity profile Grade III transaminase elevations (without hyperbilirubinemia) in 3 cases => leading to stopping of pazopanib => incompliance rate 27% (3/11) All returned to normal values < 3 weeks

21. Toxicity profile in the perioperative phase: DLT II 6 wk Pazopanib 5 wk RT5 wk rest surgery 3 wk observation

22. Toxicity profile in the perioperative phase: DLT II 9 evaluable patients 1 refused surgery (progressive on induction management) 8 underwent surgery

23. Toxicity profile in the perioperative phase: DLT II 9 evaluable patients 1 refused surgery (progressive on induction management) 8 underwent surgery 6 uncomplicated wound healing uncomplicated perioperative phase 2delayed wound healing

24. Toxicity profile in the perioperative phase: DLT II Case Ihealthy male 49 years UPS III, lateral side calf 400 mg cohort Case IImale 67 years, heavy smoker pretibial myxofibrosarcoma 600 mg cohort

25. Response: volume No significant volume reduction at date of surgery

26. Response: pathology ≥ 50% necrosis88% (7 / 8 resection specimens) ≥ 95% necrosis(near) complete pathological response 50% (4 / 8 resection specimens) (near) complete responses with replacement of the sarcoma by a fibro-inflammatory tissue.

27. Response: pathology 400 mg 800 mg 600 mg 800 mg 600 mg

28. Response: pathology 400 mg 800 mg 600 mg 800 mg 600 mg

29. Oncological outcome Median follow-up17 months, range 6-39 months, 1 local recurrence 8 months after surgery with a pathological complete response. he was salvaged by surgery; now NED for 25 months. 1 case wide spread pulmonary metastatic disease 14 months after surgery and he died 7 months later. Otherwise no sarcoma related events have been seen up to now.

30. Conclusions Pazopanib based preoperative chemoradiation 800 mg once daily Pazopanib and 50 Gy / 5 weeks RT 1Is feasible 2Does lead to a 27% incompliance rate due to hepatotoxicity 3Does not lead to increased toxicity within the RT portals 4Does not lead to increased or delayed wound healing 5Does not lead to significant volume reductions 6Does induce pathological (near) CR in 50%

31. Conclusions Pazopanib based preoperative chemoradiation 800 mg once daily Pazopanib and 50 Gy / 5 weeks RT 1Is feasible 2Does lead to a 27% incompliance rate due to hepatotoxicity 3Does not lead to increased toxicity within the RT portals 4Does not lead to increased or delayed wound healing 5Does not lead to significant volume reductions 6Does induce pathological (near) CR in 50% And therefore, further studies to better understand the biology, imaging and pathological characteristics, efficacy and long term toxicity appear warranted.

32. thanks for your attention and CTOS: thanks for the invitation Rick Haas Department of Radiotherapy, The Netherlands Cancer Institute Amsterdam