1. Niall C. Tebbutt
International randomised phase III study of capecitabine, bevacizumab, and mitomycin C in first-line treatment of metastatic colorectal cancer: Final results of AGITG MAX study

2. The MAX study: final results
Authors: Niall C. Tebbutt, Val Gebski, Kate Wilson, Michelle Cummins, YuJo Chua, Bridget Robinson, Adam Broad, David Cunningham, John Simes, Timothy Price; on behalf of the Australasian Gastro-Intestinal Trials Group (AGITG)
Funding: MAX was an investigator-initiated study sponsored by AGITG, supported by Roche Products Pty Ltd, and coordinated independently at the NHMRC Clinical Trials Centre, University of Sydney.

3. Background
Adding bevacizumab to oxaliplatin- or irinotecan-based doublet chemotherapy has shown benefit for patients with advanced colorectal cancer (CRC).
Some patients may not be suitable for oxaliplatin or irinotecan based regimens because of comorbidities. Other patients may not require initial treatment with combination chemotherapy.
Capecitabine ± mitomycin C (MMC) is an alternative, convenient chemotherapy regimen with a generally favourable toxicity profile in the Australasian population.
This study evaluated the impact of the addition of bevacizumab ± MMC to capecitabine in patients with advanced CRC.

4. MAX study objective
To identify a low-toxicity regimen suitable for a broad population of patients with previously untreated metastatic colorectal cancer.

5. Study schema C CB CBM capecitabine* Age, ≥65 vs <65 PS, 0,1 vs 2
Metastatic CRC (suitable for capecitabine monotherapy) stratified by:
d1 d8 d15 d22 R A N D O M I S E C
capecitabine*
Age, ≥65 vs <65
PS, 0,1 vs 2
Capecitabine dose
Institution CB
capecitabine*
Disease progression
bevacizumab†
bevacizumab†
CBM
capecitabine*
bevacizumab† + mitomycin C‡
bevacizumab†
* 1.25 or 1 g/m2 bd q3w; † 7.5 mg/kg q3w; ‡7 mg/m2 q 6w max 4 doses
Interim safety analysis by IDSM after 60 and 150 patients completed 2 cycles.

6. Eligibility
Histologically confirmed, unresectable metastatic colorectal cancer
no prior chemotherapy, other than adjuvant therapy with no relapse for 6 months
suitable for capecitabine monotherapy
adequate organ function
life expectancy at least 12 weeks
ECOG PS 0-2
informed consent

7. Primary endpoint Progression-free survival
The study was designed to detect a difference in median progression-free survival from 5.5 months in arm C to 8 months arm CB or CBM at P< with 80% power (450 patients required).
Analysis was by intention-to-treat.

8. Secondary endpoints response rate overall survival toxicity
quality of life
Response RECIST assessed every 6 weeks.
Toxicity (NCIC CTCAE v 3.0) analyses by treatment received.
Quality of life assessed at 3, 6, 9, 12 weeks, then 6 weekly, with UBQ-C, CAQ, EQ-5D.

9. Patient enrolment and progress
471 randomised C CB
CBM
156
157
158
No protocol treatment
Ineligible
Lost to follow-up
Did not complete QOL 2 7 1 12 1 5 16 3 1 15
Treatment not received: Chicken pox and died; declined; unable to tolerate oral medication
[1 patient in Arm A with pending eligibility status not mentioned here. ]
Included in analysis
156
157
158

10. Baseline characteristics
C CB CBM
Median age (range, years) 69 (37–86) 67 (32–85) 67 (33–84)
Male (%)
Performance status 0–1 (%)
Capecitabine 1000 mg/m2 bd (%)
Prior adjuvant treatment (%)
Liver metastases (%)
Lymph node metastases (%)
Lung metastases (%)
Peritoneal metastases (%)

11. Chemotherapy toxicity (%)
C CB CBM
Grade* Grade Grade
Type of toxicity All (3–5) All (3–5) All (3–5)
Diarrhoea 62 ( (17) 71 (16)
Hand-foot syndrome † 65 (16) 77 (26) 78 (28)
Stomatitis 26 (3) 48 (1) 53 (4)
Vomiting 31 (5) 38 (5) 40 (4)
Nausea 54 (6) 67 (5) 70 (6)
Fatigue 74 (10) 78 (10) 85 (13)
Febrile neutropenia 2 (2) 3 (3) 2 (2)
Infection, no neutropenia 26 (6) 35 (10) 35 (11)
Neutropenia, no infection 10 (1) 12 (0) 21 (2)
Thrombocytopenia 10 (0) 15 (0) 44 (4)
High bilirubin 8 (3) 6 (1) 7 (1)
† The only toxicity occurring more often in CB and CBM than C was HFS. When the rate was adjusted for duration of treatment (average cycles: C, 8.4; CB, 10.9; CBM, 10.7), the rate of HFS was no higher in CB or CBM than C (unadjusted OR for HFS: CB vs C was 1.85, for CBM v C was 2.02 (P=0.03), and after adjustment, these were 1.30 and 1.39, respectively (P=0.40)).
* NCI CTCAE version 3.0
Grades -- NCI CTCAE version 3.0

12. Bevacizumab toxicity (%)
C CB CBM
Grade* Grade Grade
Type of toxicity All (3–5) All (3–5) All (3–5) Proteinuria 12 (1) 31 (3) 47 (6)
Hypertension 12 (1) 29 (4) 25 (6)
Thrombosis or embolism 10 (7) 10 (9) 11 (10)
Bowel perforation 1 (1) 3 (3) 1 (1)
Haemorrhage 13 (3) 15 (1) 27 (6)
Grades -- NCI CTCAE version 3.0
* NCI CTCAE version 3.0

13. Tumour response (%)* C CB CBM Complete response 1 2 2
Partial response
Overall response
Stable disease
Progressive disease
* C vs CB, P=0.2; C vs CBM, P=0.006

14. Progression-free survival
P values adjusted for level of significance 0.025

15. Multivariate analysis: progression-free survival
Variable % HR (95% CI) P
Treatment group C
CB (0.50–0.79) <0.001
CBM (0.44–0.71) <0.001
Performance status
≥ (1.25–1.85) <0.001
Primary tumour resected No
Yes (0.57–0.92) 0.007
Number of metastatic sites <
≥ (1.05–1.55) 0.01
Alkaline phosphatase U/L <
≥ (1.12–1.67) 0.002
Serum bilirubin µmol/L <
≥ (1.03–1.68) 0.03

16. Quality of life at 3 and 6 weeks
CB vs C CBM vs C
First 3 are UBQ summary scales.
favours C favours CB favours C favours CBM

17. Overall survival

18. Multivariate analysis: overall survival
Variable % HR (95% CI) P
Treatment group C
CB (0.68–1.13) 0.3
CBM (0.73–1.21) 0.6
Performance status 0 56
1 or (1.54–2.35) <0.001
Neutrophils  109/L <8 85
≥ (1.12–2.01) 0.007
Alkaline phosphatase U/L <140 64
≥ (1.35–2.10) <0.001
Prior radiotherapy No 87
Yes (1.05–1.95) 0.02
Primary tumour resected No 21
Yes (0.57–0.93) 0.01

19. Subsequent treatment after progression(%)
C CB CBM
Any systemic therapy
Oxaliplatin
Irinotecan
Anti-EGFR
Bevacizumab 4 1 1
Oxaliplatin + irinotecan
Oxaliplatin + irinotecan + EGFR
* Rates are not exclusive: that is, patients treated with multiple regimens are also listed under individual regimens. Each row refers to any regimen containing this drug with or without a fluoropyrimidine.

20. Conclusions All treatment regimens were well tolerated.
Adding bevacizumab, with or without mitomycin C, to capecitabine significantly improves progression-free survival without causing major additional toxicity or impairment of quality of life.
Overall survival results were not significantly different between arms, but are promising for a relatively older patient cohort.
Capecitabine and bevacizumab, with or without mitomycin C, is an active, low-toxicity regimen that may be considered as a treatment option for patients with metastatic colorectal cancer.

21. Contact Dr Niall Tebbutt Consultant Medical Oncologist Austin Hospital
Heidelberg VIC 3084
Australia
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