1. Axi-STS: an NCRI Sarcoma Clinical Studies Group phase II trial of the VEGFR inhibitor axitinib in advanced soft tissue sarcoma (STS) Penella Woll, Piers Gaunt, Ian Judson, Michelle Scurr, Sandra Strauss, Beatrice Seddon, Michael Leahy, Maria Marples, Ana Hughes, Baljit Kaur, Cindy Billingham

2. Disclosures Support or research funding from Amgen Ariad AstraZeneca Boehringer GSK Immunogen Pfizer Pharmamar Novartis Virttu

3. Rationale Raised levels of sVEGF and bFGF in STS correlate with disease extent and risk of recurrence. Angiosarcomas are tumours of blood vessels expressing endothelial markers. Evidence of activity for VEGFR inhibitors in STS. Objectives to evaluate the therapeutic activity, safety and tolerability of axitinib in patients with advanced STS unsuitable for or relapsed after standard chemotherapy. to assess its therapeutic activity separately in angio-, synovial, leiomyo- and other sarcomas. to identify angiogenic pathways in these tumours.

4. Trial design Open-label, multi-centre, stratified phase II trial in 4 strata. Simon’s 2-stage design is applied separately for each stratum (Interim N=18, Final N=33): p0=20%, p1=40%, α=0.05, power=80% Axitinib 5mg bd po taken in 4-week cycles Patients monitored weekly on cycle 1, then 4 weekly. CT scan every 12 weeks. Synovial sarcoma Leiomyo sarcoma Other sarcoma Angio sarcoma This report is restricted to the first two cohorts

5. Study endpoints Primary Progression-free survival rate at 12 weeks, according to RECIST criteria. Success = SD or PR at 12 weeks. Secondary Tumour response rate (using RECIST & Choi criteria). Progression-free interval & progression-free survival. Overall survival time. Changes in performance status. Toxicity. Biomarkers of angiogenesis in blood and tumour samples.

6. Patient population Age ≥ 16. Pathologically confirmed soft tissue sarcoma. Locally advanced or metastatic disease. Measurable disease according to RECIST criteria. Objective evidence of disease progression in the past 6 months. Ineligible for chemotherapy or ≤ 2 prior chemo regimens. WHO performance status 0, 1 or 2. No uncontrolled or poorly controlled hypertension. No thromboembolic events within the past 12 months. No patients with cavitating lung metastases or any metastasis abutting or invading a major pulmonary blood vessel. No history of blood clots, or streaky haemoptysis that was persistent (> 2 weeks) or recurrent (> 3 episodes) within the previous 6 months.

7. Patient characteristics Leiomyosarc (n=37)Other STS (n=34) Age Median (range)59 (29-79)50 (21-80) Sex Male Female 11 (30%) 26 (70%) 21 (62%) 13 (38%) WHO PS 0 1 2 Not known 10 (27%) 23 (62%) 3 (8%) 1 (3%) 7 (21%) 24 (71%) 2 (6%) 1 (3%) Trojani Grade1 2 3 Not known 2 (5%) 13 (35%) 15 (41%) 7 (19%) 2 (6%) 6 (18%) 16 (47%) 10 (29%) Other STS included: 6 solitary fibrous tumour, 5 pleomorphic STS, 4 spindle cell STS, 4 alveolar soft part sarcoma, 3 liposarcoma, 3 myxoid liposarcoma, 2 endometrial stromal sarcoma, 1 desmoplastic small round cell, 1 fibrosarcoma, 1 haemangioendothelioma, 1 neurofibro-sarcoma, 1 phylloides tumour

8. Results – primary endpoint PFS rate at 12 weeks Patients were only considered assessable if they had at least 4 weeks of treatment. Success in 40% or more is considered worthwhile for further study, whereas success in 20% or less is considered unacceptable. The confidence intervals for both groups exclude the lower bound of 20% and include the upper bound of 40%. Trial StratumPFS Rate at 12 weeksN alive and progression-free Leiomyosarcoma47% (90% CI; 34, 61)16/34 Other STS38% (90% CI; 25, 55)10/26

9. Results – secondary endpoints Outcome MeasureLeiomyosarcoma (N=34)Other STS (N=26) RECIST Resp Rate0% (0/34)4% (1/26) Median PFS,* months3.0 (95% CI; 2.6, 5.6) 3.0 (95% CI; 2.6, 5.5) Median OS, months11.6 (95% CI; 8.8, 13.0) 10.7 (95% CI; 7.4, **) *PFI results are identical to PFS **There is no upper confidence limit for overall survival for the Other STS group. This is because the upper confidence interval does not drop below the median proportion of 50%.

10. Results – toxicities Common grade 1/2 events were diarrhoea, mucositis, nausea, hypertension, anorexia, pain and fatigue One episode of G4 hypercalcaemia in a leiomyosarcoma patient in cycle 1 who continued treatment and had SD at 12 weeks Leiomyosarcoma N = 34 Other STS N = 26 Total N G3/4 toxicities5542 G3 Fatigue, n/N pts10 / 69 / 6 G3 Hypertension, n/N pts16 / 59 / 2 G3 Diarrhoea, n/N pts2 / 24 / 4 G3 Arthralgia, n/N pts6 / 20

11. Results – serious adverse events Leiomyosarcoma N = 34 Other STS N = 26 SAE reports, n/N pts14 / 915 / 11 Study drug related Study drug unrelated 5959 3 11 SUSAR1* * Fatal pneumothorax & pulmonary haemorrhage

12. Conclusion The VEGFR inhibitor axitinib has activity in patients with advanced/metastatic Leiomyosarcoma and Other sarcoma. The 12 week PFS rates observed for the Leiomyosarcoma and Other STS stratum are comparable to those in another phase II trial of a TKI (pazopanib). The drug is well tolerated and merits further investigation in a phase III setting for this patient population. Axi-STS studyPazopanib study Leiomysarcoma47% (16/34)44% (18/41) Other STS38% (10/26)39% (16/41)

13. Work in progress Angiosarcoma (n=25) and synovial sarcoma (n=26) strata are still recruiting. Central histopathology review. iTRAQ to identify predictive biomarkers in patient serum. Sequencing for PTPRB and PLCG1 mutations in angiosarcoma (Sanger Institute, Cambridge).

14. Acknowledgements Patients, clinicians & nurses at each centre Funding: Cancer Research UK, Pfizer Sponsor: Sheffield Teaching Hospitals Cancer Research UK Clinical Trials Unit at the University of Birmingham