Download ATTAX: Randomised phase II study evaluating weekly docetaxel in

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.
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 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
TREATMENT
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
PRIMARY ENDPOINT
ARM A:
CAPECITABINE
ARM B:
CAPECITABINE
+ BEVACIZUMAB
ARM C:
CAPECITABINE
+ BEVACIZUMAB
+ MITOMYCIN C
PROGRESSION
FREE
SURVIVAL
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
Baseline Demographics
Cap (n=156)
Cap/Bev (n=157)
69 (37-86)
67 (32-85)
Cap/Bev/
MMC
(n=158)
67 (33-84)
63/37
96
66
65/35
92
67
60/40
93
67
Liver metastases (%)
72
75
77
Nodal metastases (%)
44
50
44
Pulmonary metastases (%)
39
40
39
Peritoneal metastases (%)
21
13
19
Prior adjuvant treatment (%)
22
27
16
Median age (years, range)
Male/Female %
PS 0-1 (%)
Cap dose 2000mg/m2/day (%)
General toxicities
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)
(2)
(2)
(3)
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)
(2)
(1)
(1)
Febrile neutropenia
Infection with neutropenia
Bilirubin
% all grades (grade 3/4/5)
Events of special interest
Cap (n=156)
Cap/Bev (n=157)
Cap/Bev/MMC
(n=158)
13 (<1)
31 (3)
43 (7)
13 (<1%)
25 (3)
23 (5)
(8)
(8)
(10)
1 (0)
4 (3)
3 (1)
(0)
(0)
(3)
4 (0)
29 (0)
26 (0)
(3)
(1)
(4)
GI perforation (n=)
1
3
0
Haemolytic uraemic
syndrome (n=)
0
0
2
Proteinuria
Hypertension
VTE
Cardiac ischemia
CNS ischemia
Epistaxis
Haemorrhage
% 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: +61 8 8222 6000
Fax: +61 8222 7054