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. 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

Colorectal Cancer 2 nd 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

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

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

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

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

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

Study Schema RANDOMISERANDOMISE STRATIFY Age (>65y vs <65y) PS (0,1 vs 2) Capecitabine dose (2000 vs 2500 mg/m 2 /d) Institution ARM C: CAPECITABINE + BEVACIZUMAB + MITOMYCIN C ARM B: CAPECITABINE + BEVACIZUMAB ARM A: CAPECITABINE PROGRESSION FREE SURVIVAL TREATMENT PRIMARY ENDPOINT

Recruitment First patient recruited on 14 th July 2005 Last patient recruited on 10 th July 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

Baseline Demographics Cap (n=156)Cap/Bev (n=157) Cap/Bev/ MMC (n=158) Median age (years, range)69 (37-86)67 (32-85)67 (33-84) Male/Female %63/3765/3560/40 PS 0-1 (%) Cap dose 2000mg/m2/day (%)6667 Liver metastases (%) Nodal metastases (%) Pulmonary metastases (%) Peritoneal metastases (%) Prior adjuvant treatment (%)222716

Cap (n=156)Cap/Bev (n=157)Cap/Bev/MMC (n=158) Diarrhoea62 (11)62 (15)68 (14) Hand-foot syndrome65 (15)75 (25)78 (26) Stomatitis27 (3)47 (2)54 (4) Vomiting29 (5)34 (5)35 (3) Nausea52 (5)64 (5)68 (5) Fatigue76 (9)79 (10)84 (13) Febrile neutropenia(2) (3) Infection with neutropenia24 (5)33 (9)32 (9) Neutropenia9 (1)10 (0)20 (2) Thrombocytopenia9 (0)13 (0)42 (3) Transaminitis28 (1)32 (3)35 (1) Bilirubin(2)(1) General toxicities % all grades (grade 3/4/5)

Events of special interest Cap (n=156)Cap/Bev (n=157)Cap/Bev/MMC (n=158) Proteinuria13 (<1)31 (3)43 (7) Hypertension13 (<1%)25 (3)23 (5) VTE(8) (10) Cardiac ischemia1 (0)4 (3)3 (1) CNS ischemia(0) (3) Epistaxis4 (0)29 (0)26 (0) Haemorrhage(3)(1)(4) GI perforation (n=)130 Haemolytic uraemic syndrome (n=) 002 % all grades (grade 3/4/5)

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.

Contact Dr Tim Price Senior Consulting Medical Oncologist Oncology Dept Queen Elizabeth Hospital Woodville Rd Woodville South SA 5011 Tel: Fax: