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

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

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 ObjectivesStage 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 cancerMetastatic disease that is not resectableAny patient for whom the investigator considers capecitabine monotherapy appropriateECOG 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 daysNo 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

RANDOMISE

STRATIFY

Age(>65y vs <65y)

PS (0,1 vs 2)

Capecitabine dose (2000 vs 2500 mg/m2/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 14th July 2005Last patient recruited on 10th July 2007

471 patients were recruited from 43 sites.38 sites in Australia2 sites in New Zealand3 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 % 63/37 65/35 60/40PS 0-1 (%) 96 92 93Cap dose 2000mg/m2/day (%)

66 67 67

Liver metastases (%) 72 75 77Nodal metastases (%) 44 50 44Pulmonary metastases (%) 39 40 39Peritoneal metastases (%) 21 13 19Prior adjuvant treatment (%) 22 27 16

Cap (n=156) Cap/Bev (n=157) Cap/Bev/MMC (n=158)

Diarrhoea 62 (11) 62 (15) 68 (14)

Hand-foot syndrome 65 (15) 75 (25) 78 (26)

Stomatitis 27 (3) 47 (2) 54 (4)

Vomiting 29 (5) 34 (5) 35 (3)

Nausea 52 (5) 64 (5) 68 (5)

Fatigue 76 (9) 79 (10) 84 (13)

Febrile neutropenia (2) (2) (3)

Infection with neutropenia

24 (5) 33 (9) 32 (9)

Neutropenia 9 (1) 10 (0) 20 (2)

Thrombocytopenia 9 (0) 13 (0) 42 (3)

Transaminitis 28 (1) 32 (3) 35 (1)

Bilirubin (2) (1) (1)

General toxicities

% all grades (grade 3/4/5)

Events of special interestCap (n=156) Cap/Bev (n=157) Cap/Bev/MMC

(n=158)

Proteinuria 13 (<1) 31 (3) 43 (7)

Hypertension 13 (<1%) 25 (3) 23 (5)

VTE (8) (8) (10)

Cardiac ischemia 1 (0) 4 (3) 3 (1)

CNS ischemia (0) (0) (3)

Epistaxis 4 (0) 29 (0) 26 (0)

Haemorrhage (3) (1) (4)

GI perforation (n=)

1 3 0

Haemolytic uraemic syndrome (n=)

0 0 2

% 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 PriceSenior Consulting Medical OncologistOncology Dept

Queen Elizabeth HospitalWoodville Rd

Woodville South SA 5011 Tel: +61 8 8222 6000

Fax: +61 8222 7054