1. MITO (Multicentre Italian Trials in Ovarian cancer) - CERV2 trial: a randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer
Sandro Pignata1, Giovanni Scambia2, Domenica Lorusso3, Ugo De Giorgi4, Maria Ornella Nicoletto5, Rossella Lauria6, Annamaria Mosconi7, Cosimo Sacco8, Claudia Omarini9, Pierosandro Tagliaferri10, Gabriella Ferrandina2, Saverio Cinieri11, Carmela Pisano1, Sabrina Chiara Cecere1, Marilena Di Napoli1, Vanda Salutari2, Maria Carmela Piccirillo1, Gennaro Daniele1, Ciro Gallo12, Francesco Perrone1.
1 Istituto Nazionale Tumori di Napoli, Fondazione Pascale, IRCCS, Napoli; 2 Catholic University of The Sacred Heart of Rome, Roma; 3 Fondazione IRCSS National Cancer Institute, Milano ; 4 IRST-IRCSS National Cancer Institute, Meldola-Cesena; 5 Istituto Oncologico Veneto IRCCS, Padova; 6 Federico II University, Napoli; 7 Medical Oncology, University Hospital of Perugia, Perugia; 8 University Hospital "S. Maria della Misericordia", Udine; 9 Medical Oncology, University Hospital of Modena, Modena; 10 Medical Oncology - Magna Grecia University, Germaneto (CZ); 11Medical Oncology & Breast Unit, “Senatore Antonio Perrino” Hospital, Brindisi; 12 Medical Statistics, Department of Medicine and Public Health, Second University of Naples, Napoli; Italy.

2. Background
Carboplatin plus paclitaxel is a standard option for treatment of advanced or recurrent cervical cancer patients
Long-term results of systemic treatment are poor in this setting

3. Study rationale
Cervical cancer cells often express Epidermal Growth Factor receptor (EGFR)
Cetuximab, an anti-EGFR monoclonal antibody, can be safely combined with carboplatin and paclitaxel

4. Study aim
To assess the activity of a combination of cetuximab (weekly) with carboplatin + paclitaxel (every three weeks) compared to chemotherapy alone in terms of event-free survival (EFS)

5. Study endpoints Primary endpoint Secondary endpoints
Event-free survival
time from randomization to progression, death, definitive discontinuation of the whole treatment or loss to follow-up, whichever occurred first
Secondary endpoints
Overall survival
Progression-free survival
Response rate (RECIST 1.0)
Toxicity (CTCAE 3.0)

6. Study design RANDOM Carbo AUC 5 + Paclitaxel 175 mg/mq, d1 Q21
Carbo AUC 5 + Paclitaxel 175 mg/mq, d1 Q21 + Cetuximab 400 mg/m² one week before starting chemo, then 250 mg/m² day 1, weekly
Strata:
Previous Chemo
Distant mets
Centre
Chemotherapy was given for 3-6 cycles depending on clinical response
Cetuximab was continued until disease progression or unacceptable toxicity

7. Study population
Advanced and/or metastatic cervical cancer patients untreated or having failed only one previous chemotherapy (with at least 6 months of progression-free interval, with or without concomitant or sequential radiotherapy)
PS 0-1 according to ECOG
Age >18
Written informed consent

8. Sample size
This is a randomized phase II trial, with relaxed statistical criteria* :
one-tailed test, significance level 20%
power 80%
Assuming an expected median EFS 4.5 months and an auspicated median EFS 6.4 months (corresponding to a Hazard Ratio of 0.70) 89 events are required and 108 patients (54 per arm) were planned
*Rubinstein, J Clin Oncol 2005

9. Study conduction
The study was sponsored and supported by NCI Naples that has the property of data
Merck Serono provided cetuximab and partial funding
14 Italian centers actively recruited the patients
First patient enrolled: Feb 3, 2010
Last patient enrolled: May 8, 2013
Final analysis: May 5, 2015
Median Follow-up: 23 months

10. Carboplatin/Paclitaxel Carboplatin/Paclitaxel plus Cetuximab
Patients’ flow
Randomized
108 pts
Carboplatin/Paclitaxel
53 pts
Carboplatin/Paclitaxel plus Cetuximab
55 pts
1 patient: consent withdrawn immediately after random
EFS analysis
52 pts
EFS analysis
55 pts

11. Baseline characteristics
Carboplatin/Paclitaxel
(n =52)
Carboplatin/Paclitaxel + Cetuximab
(n=55)
Median age (interquartile range - IQR) 52
(44-62) 47
(41-60)
Previous chemotherapy No 22
(42%) 24
(44%)
Yes 30
(58%) 31
(56%)
Distant metastasis 9
(17%) 10
(18%) 43
(83%) 45
(81%)
ECOG performance status 33
(64%) 40
(73%) 1 19
(36%) 15
(27%)
Histotype
Adenocarcinoma 11
(21%) 12
(22%)
Squamous 41
(79%)
(78%)

12. Compliance to chemotherapy
Carboplatin/Paclitaxel
Carboplatin/Paclitaxel + Cetuximab
(n =52)
(n=55)
Number of cycles
median (IQR)
6 (4-6)
At least one delay
17 (33%)
21 (38%)
At least one dose reduction
12 (23%)
8 (14%)
Cause of treatment interruption
Completion
35 (67%)
34 (62%)
Progression or death
14 (27%)
14 (25%)
Toxicity or refusal
2 (4%)
7 (13%)
Other
1 (2%)
0 (0%)
A median number of 6 (IQR 4-6) CP cycles was given in both arms.

13. Compliance to cetuximab
Carboplatin/Paclitaxel
Carboplatin/Paclitaxel + Cetuximab
(n =52)
(n=55)
Weeks on treatment
median (IQR) -
26 (14-35)
At least one delay
27 (49%)
At least one dose reduction
4 (7%)
Cause of treatment interruption
Progression or death
41 (74%)
Toxicity or refusal
13 (24%)
On treatment
1 (2%)
Reason for discontinuation of cetuximab was progression/death in 41 (74%) cases and toxicity/refusal in 13 (24%) . A patient was on treatment at the time of the analysis.

14. Events After a median follow-up of 23 months (95% CI:20-26)
102 patients had an event
97 progressed
61 died

15. Carboplatin/Paclitaxel Carboplatin/Paclitaxel + Cetuximab
Event-free survival
Patients
Events
Median EFS
months (95% CI)
Carboplatin/Paclitaxel 52 48
4.7 (4.1 – 6.5)
Carboplatin/Paclitaxel + Cetuximab 55 54
6.0 (4.4 – 7.6)
Unadjusted HR=0.97 (95% CI )
Log-rank p=0.43
Patients at risk
Carboplatin/Paclitaxel 52 21 7 5 3 2
Carboplatin/Paclitaxel + Cetuximab 55 28 8 -

16. Progression-free survival
Patients
Events
Median PFS
months (95% CI) CP 52 45
5.2 (4.5 – 7.8)
CP + CET 55
7.6 (5.6 – 9.0)
Unadjusted HR=0.84 (95% CI )
Log-rank p=0.20
Patients at risk CP 52 22 8 6 3 2
CP + CET 55 34 14 -

17. Overall survival Patients Events Median OS months (95% CI) CP 52 30
17.7 (11.0 – 31.6)
CP + CET 55 31
17.0 (12.5 – NA)
Unadjusted HR=0.85 (95% CI )
Log-rank p=0.27
Patients at risk CP 52 39 29 16 10 4 2
CP + CET 55 48 30 19 11 -

18. Response Rate (RECIST 1.0)
Carboplatin/Paclitaxel
(n=44)
Carboplatin/Paclitaxel + Cetuximab
(n=42) P*
Responders (CR+PR)
19 (43%)
95%CI: 30%-58%
16 (38%)
95%CI: 25%-53%
0.79 CR
4 (9%)
2 (5%) PR
15 (34%)
14 (33%)
*Chi-square test
Out of 86 patients eligible for RECIST

19. Safety One patient died for a stroke during standard treatment
There was no difference in the occurrence of severe side-effects, except for diarrhoea and skin toxicity

20. Adverse events CP (n=52) CP + CET (n=55) Dry skin 2% 0% 9% 4% 0.03
Grade 1 2 3 4 5 p*
Dry skin 2% 0% 9% 4%
0.03
Flushing
11% 5%
0.003
Nail changes 7%
0.006
Rash/ desquamation
18%
0.05
Rash/acneiform
24%
25%
<0.001
Diarrhoea 6%
16%
0.02

21. Conclusions
The addition of cetuximab to carboplatin/paclitaxel is feasible but not worthy of further investigation in unselected advanced cervical cancer patients
Efforts are ongoing to retrospectively collect tumor samples for an exploratory biomarker analysis