Colorectal Cancer

1. T Price, V. Gebski, G. van Hazel, B. Robinson, A. Broad, V. Ganju, D. Cunningham, K. Wilson, V. Tunney, N. Tebbutt : on behalf of the Australasian GI Trials Group MAX: International multi-centre randomised phase II/III study of capecitabine (Cap), bevacizumab (Bev) and mitomycin C (MMC) as first-line treatment for metastatic colorectal cancer (mCRC): Final safety analysis of an AGITG trial.

2. Colorectal Cancer • 2nd most common cause of cancer death • Increasing age is a major risk factor for colorectal cancer • Older patients have greater chance of co-morbidities • Metastatic colorectal cancer is incurable • Palliative chemotherapy has an established role for patients with mCRC with prolonged survival and improved QoL

3. Current metastatic colorectal cancer treatments • Older patients usually have monotherapy such as capecitabine monotherapy • Younger patient usually have combination therapy such as FOLFOX or FOLFIRI

4. Background/Rationale • Capecitabine & bevacizumab+/-MMC • Good activity with minimal toxicity • Suitable for broad range of population • Young & fit • Older & less fit • Less data available on older less fit patients

5. Study Objectives Stage One – Phase II Primary objective: Relative toxicity of the three treatment arms Secondary objective : Tumour response rate Stage Two – Phase III Primary objective : Comparison of progression free survival Secondary objectives • Treatment related toxicity • Tumour response rates • Overall survival • Disease-related symptoms and Quality of Life • Cost effectiveness of bevacizumab

6. Inclusion and Exclusion Criteria • Histological diagnosis of colorectal cancer • Metastatic disease that is not resectable • Any patient for whom the investigator considers capecitabine monotherapy appropriate • ECOG performance status 0, 1 or 2. Patients with PS2 should have serum albumin >30 g/L • Adequate bone marrow, renal and hepatic function • No major surgical procedure within the last 28 days • No other malignant disease • Written informed consent

7. Inclusion and Exclusion Criteria • No prior chemotherapy except for adjuvant chemotherapy given in association with (ii) complete resection of primary colon or rectal cancer provided there is no clinical, radiological or biochemical evidence of relapse for at least 6 months after completion of adjuvant treatment and/or (ii) complete resection of limited colorectal metastases to liver and/or lung provided there is no clinical, radiological or biochemical evidence of relapse for at least 6 months after completion of adjuvant treatment

8. ARM A: CAPECITABINE ARM B: CAPECITABINE + BEVACIZUMAB ARM C: CAPECITABINE + BEVACIZUMAB + MITOMYCIN C Study Schema TREATMENTPRIMARY ENDPOINT STRATIFY Age (>65y vs <65y) PS (0,1 vs 2) Capecitabine dose (2000 vs 2500 mg/m2/d) Institution R A N D O M I S E PROGRESSION FREE SURVIVAL

9. Recruitment • First patient recruited on 14th July 2005 • Last patient recruited on 10th July 2007 • 471 patients were recruited from 43 sites. 38 sites in Australia 2 sites in New Zealand 3 sites in the United Kingdom • 13 patients were ineligible (10 < 6mths post adjuvant chemotherapy, 2 prior carcinoma, 1 hypoalbuminemia/PS 2) • 3 patients were randomised but did not commence study treatment

10. Baseline Demographics

11. General toxicities % all grades (grade 3/4/5)

12. Events of special interest % all grades (grade 3/4/5)

13. Conclusion • Treatment well tolerated in all 3 arms. • Addition of Bev or Bev and MMC to Cap was associated with little additional grade 3/4 toxicity, apart from higher rates of grade 3 HFS in Arms B and C. • Acceptable rates of grade 3/4 HT, VTE, haemorrhage & perforation was in the Bev arms.

14. Contact • Dr Tim Price Senior Consulting Medical OncologistOncology Dept Queen Elizabeth HospitalWoodville Rd Woodville South SA 5011 Tel: +61 8 8222 6000 Fax: +61 8222 7054