Clinical trial NCT01581840
Conditions: Epidermoid Carcinoma Anus
Keywords: anus carcinoma panitumumab mitomycine 5Fu radiotherapy
Sponsor: Federation Francophone de Cancerologie Digestive
Start date: 2016-01-01; Completion date: 2021-02-01
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Treatment is based on radiochemotherapy for locally advanced tumours. The objective of treatment is to provide a cure without resorting to abdominoperineal amputation, while preserving sphincter function.

The prognosis is mainly related to tumour size and lymph node invasion. The large majority of patients do not show any spread remote from the tumour at the time of diagnosis (2).

Recurrences are mainly of a local/regional nature and require abdominoperineal amputation. This type of intervention is not always possible or complete, which then gives rise to the particularly distressing risk of local progression, with survival at 3 years of approximately 30% (3).

It is therefore very important to achieve a complete and permanent tumour response from initial treatment with radiochemotherapy.

Furthermore, the use of an anti-EGFR antibody in combination with exclusive radiotherapy in ENT cancer was able to increase recurrence-free survival and overall survival in these patients. These data are in favour of the use of a combination of chemotherapy and anti-EGFR antibodies in epidermoid cancer of the anus.

Detailed description:

Arms: arm 1: 5 FU = 400 or 600 or 80 or 1000 mg depending of phase I results, days 1 to 4 weeks 1, 5 and 8 mitomicyne = 10 mg/m² day 1 week 1 and days 1, weeks 5 and 8 Panitumumab = 3 or 6 mg/kg (depending of phase I results) days 1, weeks: 1, 3, 5, 8 and 10
Interventions: intervention 1: radiochemotherapy intervention 2: Panitumumab
Intervention descriptions: intervention 1: Radiotherapy : PTV1 45 Gy 5 weeks PTV2 20 Gy 2 weeks Chemotherapy : 5Fu (400 to 1000 mg/m²) mitomycin : 10 mg/m² intervention 2: 3 or 6 mg/kg (according to dose level)

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  1/34 
 
 
 
                                                                                 
FFCD 0904 
 
 
 
PHASE I-II TRIAL OF RADIOCHIMIOTHERAPY WITH PANITUMUMAB 
FOR THE TREATMENT OF LOCAL EPIDERMOID CARCINOMAS OF 
THE ANUS  
 
 
EudraCT N°: 2011-005436-26 
 
COORDINATOR  
Dr Véronique VENDRELY 
Radiotherapy Department 
Haut-Lévêque Hospital 
Avenue de Magellan  
33604 PESSAC Cedex  
Tel : 05 57 62 33 13 Fax : 05 57 68 33 05 
Email: veronique.vendrely@chu-bordeaux.fr  
 
CO-COORDINATOR 
Pr Thomas APARICIO 
Gastro-Enterology Department 
Avicenne Hospital 
125 rue de Stalingrad 93009 BOBIGNY CEDEX  
Tel : 01 48 95 54 31 Fax : 01 48 95 54 39  
Email: thomas.aparicio@avc.aphp.fr 
 
 
EDITORIAL COMMITTEE   
 
L Abramowitz (Paris), T Aparicio (Paris), L Bedenne (Dijon), F Bonnetain (Dijon), E Deutsch 
(Villejuif), E François (Nice), C Girault (Dijon), E Maillard (Dijon), F Mornex (Lyon), L Quero (Paris), 
Fabien Subtil (Dijon), V Vendrely (Bordeaux)  
 
TRANSLATIONAL RESEARCH COMMITTEE 
 
 
JF Emile (Boulogne), P Laurent-Puig (Paris), T Lecomte (Tours), I Sobhani (Créteil) 
 
SPONSOR AND RANDOMIZATION-MANAGEMENT-ANALYSIS CENTER (RMAC) :  
Fédération Francophone de Cancérologie Digestive (FFCD), Faculty of Medicine, 7 Boulevard Jeanne 
d'Arc, BP 87900, 21079 Dijon Cedex, France 
 
 
Administrative Director : 
 
Mrs Cécile GIRAULT 
 
Tel: 03 80 66 80 13 - Fax: 03 80 38 18 41 
 
Email: cgirault@u-bourgogne.fr 
 
Statistician :  
Mrs Emilie MAILLARD  
 
Tel: 03 80 39 34 81 - Fax: 03 80 38 18 41 
 
 
 
 
Email: emilie.maillard@u-bourgogne.fr  
 
Project manager:  
Ms. Marie MOREAU 
 
Tel: 03 80 39 34 04 - Fax: 03 80 38 18 41 
 
Email: marie.moreau@u-bourgogne.fr 
 
Subscribe to DeepL Pro to edit this document. 
Visit www.DeepL.com/profor more information. 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  2/34 
 
 
TABLE OF CONTENTS 
PROTOCOL AGREEMENT AND BPC .................................................................................................... 3 
SUMMARY............................................................................................................................................... 4 
STUDY SCHEDULE ................................................................................................................................ 6 
BIOLOGICAL STUDY SCHEDULE ......................................................................................................... 7 
LIST OF ABBREVIATIONS ..................................................................................................................... 8 
I. 
RESEARCH OBJECTIVES......................................................................................................... 9 
1. 
Main objective ................................................................................................................................. 9 
2. 
Secondary objectives ...................................................................................................................... 9 
II. 
SELECTION CRITERIA .............................................................................................................. 9 
1. 
Inclusion criteria .............................................................................................................................. 9 
2. 
Non-inclusion criteria ...................................................................................................................... 9 
III. 
INCLUSION .............................................................................................................................. 10 
IV. 
INCLUSION ASSESSMENT ..................................................................................................... 10 
V. 
TREATMENT ............................................................................................................................ 11 
a. 
PHASE I: Maximum tolerated dose estimation ............................................................................. 11 
b. 
PHASE II: estimation of efficacy and tolerance ............................................................................ 13 
a. 
Panitumumab ................................................................................................................................ 13 
b. 
Chemotherapy 5FU + mitomycin .................................................................................................. 14 
c. 
Radiotherapy ................................................................................................................................. 14 
VI. 
CRITERIA FOR DISCONTINUATION - DOSE ADJUSTMENT - TREATMENT OF TOXIC 
EFFECTS ............................................................................................................................................... 17 
VII. 
DURATION OF TREATMENT .................................................................................................. 21 
VIII. 
FOLLOW-UP OF PATIENTS DURING AND AFTER DISCONTINUATION OF TREATMENT 21 
IX. 
ANCILLARY RESEARCH ......................................................................................................... 22 
X. 
SAFETY ASSESSMENT .......................................................................................................... 23 
a. 
Adverse Event (AE) ...................................................................................................................... 24 
b. 
Serious Adverse Event (SAE) ....................................................................................................... 24 
c. 
Undesirable Effect ........................................................................................................................ 24 
d. 
Unexpected Serious Adverse Effect ............................................................................................. 24 
XI. 
JUDGING CRITERIA, DATA MANAGEMENT AND STATISTICS ........................................... 25 
XII. 
INTRODUCTION - RATIONALE FOR THE STUDY ................................................................ 29 
XIII. 
LEGAL AND ETHICAL ASPECTS ADMINISTRATIVE CONSIDERATIONS ........................... 32 
XIV. 
PUBLICATION .......................................................................................................................... 33 
XV. 
APPENDICES ........................................................................................................................... 34 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  3/34 
 
 
PROTOCOL AGREEMENT AND BPC 
 
Test FFCD 0904 
PHASE I-II TRIAL OF RADIOCHEMOTHERAPY COMBINED WITH PANITUMUMAB IN THE 
TREATMENT OF EPIDERMOID CARCINOMAS LOCATED TO THE ANUS  
 
EudraCT N°: 2011-005436-26 
Version 2.1 of 11.12.2017 
 
This version of the protocol is approved by : 
 
The Promoter :   
Ms. Cecile GIRAULT  Date:  14.08.2015  
Signature:  
 
The Coordinator :  
Dr Véronique VENDRELY   Date:  14.08.2015Signature : 
 
I, the undersigned, Doctor :  ..................................................................  
 
 
 
 
 
 
After having read the requirements of this research, the protocol and its appendices, I hereby certify that 
I will conduct this trial in compliance with Good Clinical Practice and in accordance with the applicable 
provisions of the Public Health Code. 
In particular, I agree to: 
- 
comply with the protocol and any modifications notified to it by the promoter 
- 
agree to supervise the research in the center and to train collaborators in the conduct of the research 
and provide a list of names  
- 
have each patient sign a written consent after having read the information note intended for him/her, 
before any research is carried out 
- 
Report serious adverse events or developments within 24 hours of learning of them, and as specified 
in the research protocol 
- 
respect the inclusion and non-inclusion criteria, as well as the start and end dates of the study 
- 
participate in the translational part of the study subject to the patient's signature of the specific consent 
and to send the samples according to the recommendations,  
- 
complete all the items in the observation book, ensure the quality of the data collection and the proper 
management of the products  
- 
retain research data and documents until notified by the sponsor that they are no longer required  
- 
inform the sponsor of any conflict of interest situation that may affect its scientific independence in the 
context of the research 
- 
inform the sponsor without delay of any action, whether amicable or contentious, brought by a person 
involved in the research or his or her beneficiaries, which may call into question the sponsor's liability 
- 
accept periodic visits from the sponsor's representatives, and make available to them all the source 
documents and materials relating to the research in order to ensure quality control of the data recorded 
in the case report book. The investigator accepts control in the form of an audit by the sponsor and/or 
inspection by the health authorities.  
- 
respond by phone or mail to requests for corrections or clarifications regarding the observation book, 
- 
Allow time for the ARC FFCD to sign the forms, answer any questions and take action 
 
Date:  
 
 
 
           Signature: 
 
 
 
 
 
 
STAMP of the CENTER : 
 
Send the original to the CRGA of the FFCD - 7 bd Jeanne d'Arc - BP 87900 - 21079 Dijon Cedex 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  4/34 
 
 
SUMMARY 
 
TITLE 
FFCD 0904 
 
Multicenter, prospective phase I-II trial of radiochemotherapy combined with 
panitumumab in the treatment of localized squamous cell carcinoma of the 
anus  
OBJECTIVES 
Phase I: 
Primary Objective: 
To determine the limiting dose (DLT) and maximum tolerated dose (MTD) of 5 FU-
Panitumumab combined with mitomycin and radiotherapy in patients with localized squamous 
cell carcinoma of the anus. 
Phase II 
Primary Objective:  
To assess the complete response rate 8 weeks after completion of 5 FU-panitumumab plus 
mitomycin and radiation therapy in patients with localized squamous cell carcinoma of the 
anus. 
Secondary objectives, assess:  
- 
Intermediate objective response rate (complete and partial) at week 6,  
- 
Partial response rate, stability and progression, 8 weeks after the end of treatment  
- 
Objective response rate 16 weeks after the end of treatment 
- 
Toxicity of 5FU + mitomycin C + panitumumab + radiotherapy 
- 
Colostomy-free survival at 3 years 
- 
3-year recurrence-free survival 
- 
Overall survival at 3 years 
- 
Quality of life (EORTC QLQ-C30 + Jorge and Wexner questionnaire) 
- 
Determination of predictive markers of response or survival 
TREATMENT 
Phase I: n=6 to 24 patients 
6 patients treated at the recommended dose 
Panitumumab: D1, D15, D29,  
5FU continuous infusion: D1 to D4 (S1) and D29 to D32 (S5) 
Mitomycin C at 10 mg/m2 : D1  
Radiotherapy: 45 Gy in 1.8 Gy fractions 5 days/week (IMRT mandatory) in 5 weeks 
 
LANDSCAPE 
5FU mg/m²/d 
Panitumumab mg/kg 
-1 
400 
3 
0 
600 
3 
1 
600 
6 
2 
800 
6 
3 
1000 
6 
 
Complementary radiochemotherapy: 
Radiotherapy: 20 Gy in 10 fractions of 2 Gy over 2 weeks (S6 and S7)  
+ panitumumab at D1 of S7) 
 
Phase II: n=45 patients 
The treatment will be identical to phase I but using the maximum tolerated dose determined in 
phase I. In view of the latest advances in treatment and in order to follow current standards, the 
elimination of the free interval between the two radiotherapy sequences, and consequently the 
elimination of a course of 5FU + Panitumumab, do not allow the integration of the 6 patients 
from Phase I at the selected level (level -1) in the analysis of Phase II.  
The dosage of 5 FU and panitumumab will be as determined by phase I (tier -1). 
ANCILLARY 
STUDY 
Three optional ancillary biological studies: 
1. Search for known mutations in receptor tyrosine kinase signaling pathways and viral 
oncogenic factors. Formalin fixed and kerosene embedded biopsies: KRAS, BRAF, PI3K, 
NRAS. Study of HPV subtypes by PCR. Study of EGFR signaling pathways  
2. Immuno-monitoring of myeloid and lymphocyte suppressive populations 
(circulating cells), blood samples at different stages of treatment 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  5/34 
 
 
3. Pharmacokinetic study of panitumumab. Blood samples at different time points during 
treatment 
POPULATION 
1- Inclusion criteria 
- 
Histologically proven squamous cell carcinoma of the anus   
- 
Locally advanced tumor without metastasis 
- 
Stage T2> 3 cm or T3 or T4 
- 
N1-N3 stage regardless of T stage (T1 to T4) 
- 
General status WHO 0-1 
- 
Life expectancy > 3 months 
- 
Signed informed consent 
- 
Age > 18 years 
- 
Effective contraception in women and/or men of childbearing potential during treatment and 
up to 6 months after the end of treatment 
- 
CD4 > 400 / mm3  (only for HIV+ patients) 
- 
Measurable tumor on at least one of the following tests: MRI, echo-endoscopy, clinical 
examination  
2- Non-inclusion criteria 
- 
Presence of metastases 
- 
Previous treatment with anti-EGFR 
- 
Stage T1N0 or T2< 3 cm N0 
- 
History of pelvic radiotherapy 
- 
At least one of the following laboratory findings: PNN < 1500/mm3 , platelets < 
100,000/mm3 , hb < 9 g/dl, WBC < 3000/mm3 , bilirubin > 1.5 times the upper limit of 
normal, transaminase (AST and ALT) > 2.5 times the upper limit of normal creatinine 
clearance < 50 mL/min (Cockcroft formula), Mg2+ < lower limit of normal, Ca2+ < lower limit 
of normal 
- 
Significant coronary artery disease or myocardial infarction within one year 
- 
History of interstitial lung disease or pulmonary fibrosis  
- 
History of malignancy within the last five years except for properly treated basal cell skin 
carcinoma or carcinoma in situ of the uterine cervix 
- 
Impossible to follow up for psychological or geographical reasons 
- 
Pregnant or breastfeeding women, women of childbearing age who have not taken a 
pregnancy test.  
Positive HIV status is not a criterion for non-inclusion 
STATISTICS 
Phase I 
A minimum of 6 patients and a maximum of 24 patients will be included, corresponding to a 
minimum of 3 patients per dose level (and 6 at the maximum tolerated dose). 
A minimum of 9 patients will be required to proceed to Phase II. 
 
Phase II 
Primary endpoint: Complete response rate 8 weeks after the end of treatment, as determined 
by morphological and clinical examinations. 
 
The Phase II study will be conducted at the maximum tolerated dose level determined in Phase 
I (Level -1). The 6 patients from Phase I treated at the recommended tier (tier -1) will not be 
eligible for inclusion in Phase II. 
The number of subjects required for the recommended tier is 45.   
A 2-step minimax Simon plan will be used. The assumptions are: 
H0: A complete response rate 8 weeks after the end of treatment of 60% is considered 
unattractive;  
H1: A complete response rate of 80% at 8 weeks after the end of treatment is expected. 
With an alpha risk of 5%, a power of 90%, the number of subjects needed for phase II is 45. 
 
An independent committee is formed. 
 
The theoretical duration of inclusion for phase II is 24 months The total duration of the phase II 
study is 72 months (3 years of minimum follow-up for the last patient included + 1 year of 
analysis) 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  6/34 
 
 
SCHEDULE OF THE STUDY 
 
Before the start of 
treatment 
During 
treatment 
 
 
Evaluations 
Follow-up of patients after 
discontinuation of the protocol 
treatment 
Within 21 
days prior 
to 
treatment 
Within 14 
days prior 
to 
inclusion 
Before each 
course of 
chemotherapy 
Before 
each 
administrati
on of 
panitumum
ab 
Every week 
during radiation 
therapy 
At 6 weeks 
8 weeks after the 
end of the 
treatment 
Every 4 months 
after the end of 
treatment for 2 
years 
Every 6 
months for 
the next 3 
years 
CLINICAL STUDY 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
Clinical examination 
 
X 
X 
 
 
X 
X 
X 
X 
Proctological examination 
X 
X 
X 
 
 
X 
X 
 
 
Weight 
 
X 
X 
 
X 
X 
X 
X 
X 
General status WHO 
 
X 
X 
 
X 
X 
X 
X 
X 
Smoking/non-smoking 
character 
 
X 
 
 
 
 
 
 
 
QoL Questionnaire (QLQ-
C30 + Jorge and Wexner) 
 
X 
 
 
 
X 
X 
X 
X 
HIV and HBV serology 1 
 
X 
 
 
 
 
 
 
 
Biological check-up  
 
X2 
X4 
X3 
 
X2 
X2 
X 
X 
CD4 count (if HIV+) 
 
X 
 
 
 
 
 
 
 
Blood ionogram + electrolyte 
(K+ , Na2+ , Ca2+ , Mg2+ ) 
 
X 
X5 
X 
 
X 
X 
 
 
SCC marker 
 
X 
 
 
 
X 
X 
X 
X 
Pregnancy test within 72 
hours before C1 
 
 
X 
 
 
 
 
 
 
ECG  
 
X 
 
 
 
 
 
 
 
Thoracic and abdominal-
pelvic CT   
X6 
 
 
 
 
 
X6 
X 
X 
Pelvic MRI  
X6 
 
 
 
 
X6 
X6 
X 
X 
Rectal echo-endoscopy  
X6 
 
 
 
 
 
X6 
X 
X 
PET-Scan 
X6 
 
 
 
 
 
 
X (6 months after 
the end of 
treatment) 
 
Assessment of treatment 
toxicity 
 
 
X 
X 
X 
X 
X 
X 
X 
 
1. Less than 1 year old 
2. CBC/platelets, creatinine, albumin, AST, ALT, alkaline phosphatase, total and conjugated 
bilirubin, GGT 
3. NFS-platelets 
4. CBC/platelets, creatinemia, AST, ALT, alkaline phosphatases 
5. To be performed if panitumumab is discontinued 
6. Make a copy on CD-ROM to be retrieved by the FFCD CRAs for the independent 
committee if necessary 
 
 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  7/34 
 
 
BIOLOGICAL STUDY SCHEDULE 
WEEKS 
DAYS 
Admi 
Panitumuma
b 
PHARMACOKINETI
C STUDY 
CIRCULATING 
CELLS 
SIGNALING 
PATHWAYS 
Phase II (1 dry tube) 
Phase II 
(5 ADC tubes) 
Inclusion 
report 
 
 
 
T0 
 4 biopsies  
S1 
J1 
X (1ière ) 
 
 
 
 
J2 
 
 
 
 
 
J3 
 
 
 
 
 
J4 
 
 
 
 
 
J5 
 
 
 
 
 
J6 
 
 
 
 
 
J7 
 
 
 
 
S2 
J8 
 
 
 
 
 
J9 
 
 
 
 
 
J10 
 
 
 
 
 
J11 
 
 
 
 
 
J12 
 
 
 
 
 
J13 
 
 
 
 
 
J14 
 
 
 
 
S3 
J15 
X (2ième ) 
 
 
 
 
J16 
 
 
 
 
 
J17 
 
 
 
 
 
J18 
 
 
 
 
 
J19 
 
 
 
 
 
J20 
 
 
 
 
 
J21 
 
 
 
 
S4 
J22 
 
 
 
 
 
J23 
 
 
 
 
 
J24 
 
 
 
 
 
J25 
 
 
 
 
 
J26 
 
 
 
 
 
J27 
 
 
 
 
 
J28 
 
 
 
 
S5 
J29 
X (3ième ) 
Before the 3ième 
infusion 
 
 
 
J30 
 
 
 
 
 
J31 
 
 
 
 
 
J32 
 
 
 
 
 
J33 
 
 
 
 
 
J34 
 
 
 
 
 
J35 
 
 
 
 
S6 
J36 
 
 
 
 
 
J37 
 
 
 
 
 
J38 
 
 
 
 
 
J39 
 
 
 
 
 
J40 
 
 
 
 
 
J41 
 
 
 
 
 
J42 
 
 
 
 
S7 
J43 
X (4ième ) 
 
 
 
 
J44 
 
 
 
 
 
J45 
 
 
 
 
 
J46 
 
 
 
 
 
J47 
 
 
 
 
 
J48 
 
 
 
 
 
J49 
 
 
 
 
S8 to S14 
D50 to 
D98 
 
 
 
 
S15 
J99 
 
 
T end of treatment 
 
 


 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  8/34 
LIST OF ABBREVIATIONS 
 
LDT :   
Toxic limiting dose 
MTD :   
Maximum tolerated dose 
QLQ-C30:  
Quality of Life Questionnary Cancer 
IMRT:   
Intensity-Modulated Radiation Therapy 
5FU :   
5 Fluorouracil 
ASAT :  
Aspartate amino transferase 
ALAT :  
Alanine amino transferase 
PAL :   
Alkaline phosphatase 
SCC :   
Squamous cell carcinoma 
MRI :   
Magnetic Resonance Imaging 
CT :   
Computed tomography 
TAP:  
Thoracoabdomino-pelvic 
WHO:   
World Health Organization 
CBC:   
Blood count 
CRGA:  
Center for Randomized Management and Analysis 
SP :   
Safety Population 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  9/34 
 
I. 
RESEARCH OBJECTIVES 
 
1. Main objective 
 
The primary objective of the phase I trial is to determine the limiting dose (LDT) of 5FU and 
panitumumab in combination with radiation therapy and mitomycin, and to derive the maximum 
tolerated dose (MTD) in patients with localized squamous cell carcinoma of the anus.  
 
The main objective of the phase II study is to determine the complete response rate 8 weeks 
after the end of the protocol treatment with radiochemotherapy (theoretically in week 15) in 
patients with localized squamous cell carcinoma of the anus, defined on MRI, endorectal echo-
endoscopy if necessary and proctological examination. 
 
2. Secondary objectives  
 
The secondary objectives of Phase II will be to evaluate: 
- 
Intermediate objective response rate (complete and partial) at week 6  
- 
Partial response rate, stability and progression 8 weeks after the end of treatment  
- 
Objective response rate 16 weeks after the end of treatment  
- 
Toxicity of 5FU + mitomycin C + panitumumab + radiotherapy 
- 
Colostomy-free survival at 3 years 
- 
3-year recurrence-free survival 
- 
Overall survival at 3 years 
- 
Quality of life (EORTC QLQ-C30 and Jorge and Wexner questionnaire) 
- 
Determination of predictive markers of response and/or survival 
 
II. 
SELECTION CRITERIA 
1. Inclusion criteria 
 
- 
Histologically proven squamous cell carcinoma of the anus  
- 
Locally advanced tumor without metastasis 
- 
Stage T2> 3 cm or T3 or T4, regardless of N 
- 
N1-N3 stage regardless of T stage (T1 to T4) 
- 
General status WHO 0-1 
- 
Life expectancy > 3 months 
- 
Signed informed consent 
- 
Age > 18 years 
- 
Effective contraception in women and/or men of childbearing potential during treatment and 
up to 6 months after the end of treatment 
- 
CD4 > 400 / mm3  (only for HIV+ patients) 
- 
Measurable tumor on at least one of the following tests: MRI, echo-endoscopy, clinical 
examination 
2. Criteria for non-inclusion 
 
- Presence of metastases 
- Previous treatment with anti-EGFR 
- Stage T1N0 or T2 < 3 cm N0 
- History of pelvic radiotherapy 
- At least one of the following laboratory findings: PNN < 1500/mm3 , platelets < 100,000/mm3 
, Hb < 9 g/dl, WBC < 3000/mm3 , bilirubinemia > 1.5 times the upper limit of normal, 
transaminase (AST and ALT) > 2.5 times the upper limit of normal creatinine clearance < 50 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  10/34 
 
mL/min (Cockcroft formula appendix 5), Mg2+ < lower limit of normal, Ca2+ < lower limit of 
normal 
- Significant coronary artery disease or myocardial infarction within one year 
- History of interstitial lung disease or pulmonary fibrosis  
- History of malignant pathologies in the last 5 years except for basal cell skin carcinoma or 
carcinoma in situ of the uterine cervix properly treated  
- Impossible to follow up for psychological or geographical reasons 
- Pregnant or breastfeeding women, women of childbearing age who have not taken a 
pregnancy test. 
 
Positive HIV status is not a criterion for non-inclusion 
 
III. 
INCLUSION  
 
Inclusion will be carried out, after the eligibility check-up and the signature of the informed 
consent, from MONDAY to FRIDAY from 9 am to 6 pm at the Randomization-Management-
Analysis Center of the French-speaking Federation of Digestive Oncology (CRGA of the FFCD) 
by faxing the inclusion form to : 03 80 38 18 41 
For further information, please call 03 80 66 80 13. 
 
A registration number will be provided by the CRGA. 
Treatment will be started within 2 weeks. 
 
IV. 
INCLUSION ASSESSMENT 
 
The inclusion assessment is identical for phase I and phase II. 
 
In order to evaluate the efficacy of the treatment, it is essential that the same technique, MRI +/- 
rectal echo-endoscopy +/- clinical examination (if performed at the time of the inclusion 
assessment), be used for the three assessments of the same patient (inclusion, assessment at 
6 weeks and assessment at 8 weeks after the end of the treatment)  
 
• 
Within 14 days prior to inclusion: 
- Clinical examination, weight, height    
- ECG  
- WHO General Status Estimate (Appendix 5)  
- Completion of the QLQ-C30 + Jorge and Wexner questionnaire (Appendix 6) 
- Biological workup including:  
• CBC-platelets 
• Blood ionogram and electrolyte (Mg2+ , Ca2+ , Na2+, K+ ), albumin, 
creatinemia 
• AST, ALT, PAL, GGT, total and conjugated bilirubin, CD4 for HIV+ patients 
- HIV and HBV serology less than one year old 
- Marker: squamous cell carcinoma (SCC) 
- Non-smoker/smoker status of the patient 
 
 
• 
Within 21 days before the first treatment  
- Thoraco-abdominal CT scan to ensure the absence of distant lesions 
- Pelvic MRI and/or rectal echo-endoscopy with measurement of tumor and 
adenopathy  
- Optional PET-scan 
 
Make a CD-ROM copy of the images that will be retrieved by the FFCD in order to transmit 
them to the independent committee if needed.  
 
• 
Within 72 hours before the first treatment: 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  11/34 
 
- For women of childbearing age, a blood pregnancy test and effective contraception 
throughout the study 
 
 
V. 
TREATMENT 
 
 
1. Scheme of the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
First part of treatment (S1 to S5) 
Chemotherapy: 
- Panitumumab (3 or 6 mg/kg depending on the dose level). As the dose level chosen by 
Phase I is -1, the dose of panitumumab will be 3 mg/kg at D1 and D15, D29 (S1, S3, 
S5) 
- 5FU as a continuous infusion (400-600-800 or 1000 mg/m²/d depending on the dose 
level). The dose level chosen by phase I being -1, 5FU will be at 400 mg/m² from D1 to 
D4 of week 1 and D1 to D4 of week 5.  
- Mitomycin C (10 mg/m2 regardless of dose level not to exceed 20 mg/cure): D1 week 1 
and D1 week 5 
Radiotherapy:  
- 45 Gy in 1.8 Gy fraction 5 days/week in IMRT. Considering the suppression of the free 
interval week 6 and 7, it is requested that the radiotherapy technique be IMRT. 
 
Additional radiochemotherapy at S6 and S7  
Chemotherapy: 
-  
Panitumumab (3 or 6 mg/kg depending on dose tier) Since the dose tier selected by Phase I is -
1, the panitumumab dose will be 3 mg/kg at: D1 week 7 Radiotherapy :  
- 20 Gy in 10 fractions over 2 weeks (S6 and S7), 2 Gy per session 
 
a. PHASE I: estimation of the maximum tolerated dose 
Dose levels 
Five dose levels, corresponding to different 5FU and panitumumab dose combinations, will 
potentially be analyzed. 
LANDSCAPE 
5FU mg/m²/d 
Panitumumab mg/kg 
-1 
400 
3 
5 FUc 
Mitomycin 
Panitumumab 
S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S15 
5 FUc 
45 Gy/25F/5 weeks. 
20Gy/10F 
MORPHOLOGICAL 
ASSESSMENT (MRI +/- 
EER) + CLINICAL 
EXAMINATION  
MORPHOLOGICAL 
REVIEW 8 weeks after the 
end of treatment (MRI +/- 
EER) + CLINICAL 
EXAMINATION  
 
MAIN CRITERION


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  12/34 
 
0 
600 
3 
1 
600 
6 
2 
800 
6 
3 
1000 
6 
 
Definition of the maximum tolerated dose (MTD) 
The maximum tolerated dose (MTD) is defined as the dose level before the dose level defining 
the limiting dose (LDT). It is also the recommended dose.  
 
Definition of the limiting toxic dose (LDT) 
The limiting toxic dose is defined by the occurrence of specific toxicity during treatment at this 
dose up to 30 days after the end of S9 or after treatment discontinuation (Pre-Amendment 5 
scheme). 
 
Specific toxicities are:  
 
Hematological Toxicities (according to NCI-CT v4.0)  
• 
Febrile neutropenia (A disorder characterized by a decrease in neutrophils associated 
with fever)  
• 
Neutropenic infection  
• 
Neutropenia grade 4 for more than 7 days  
• 
Thrombocytopenia ≥ grade 3 for more than 7 days  
• 
Thrombocytopenia grade 4  
Non-hematological toxicities   
• 
Nausea grade ≥ 3, vomiting or diarrhea despite optimal medical treatment  
• 
Grade 3 fatigue for more than 7 days or grade 4 fatigue  
• 
Dermal toxicity > 3 
• 
Any other toxicity grade ≥ 3 (except alopecia)  
• 
First part of treatment incomplete (75% of planned doses)  
• 
Any toxicity that delays the next course of treatment or radiation therapy by more than 7 
days should be reviewed by the independent committee. Based on the opinion of the 
independent committee, this toxicity may be considered dose-limiting; if this toxicity is not 
related to the study treatments, the patient will be removed from the study and an 
additional patient will be included at the same dose level. 
 
In the case of patients who did not receive the full course of treatment for reasons other than 
specific toxicity, the independent committee may discuss the possibility of including additional 
patients as a replacement.  
 
Determination of the MTD 
 
MTD determination will be performed using the dose escalation method in groups of 3 patients, 
starting at step 0.  
The rules of evolution from one level to another are described in the following table: 
 
If toxicity in 
So 
If toxicity in 
So 
0/3 patients 
move to the next 
dose level 
 
 
1/3 patients 
add 3 patients at this 
dose level 
1 or 2/6 patients 
move to the next 
dose level 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  13/34 
 
2/3 patients 
add 3 patients at this 
dose level 
2/6 patients 
move to the next 
dose level 
 
 
more than 2/6 
patients 
STOP 
Previous level = 
LMD1 
3/3 patients 
STOP 
Previous level = 
LMD1 
 
 
 
 Except for the case where the previousstep is the -1 step. 
 
At a given level : 
• 
if none of the 3 patients show toxicity, go to the next level; 
• 
if 1 out of 3 patients has toxicity, include 3 additional patients at that same tier: 
o if 1 or 2 of the 6 patients in this tier show toxicity, move to the next tier; 
o if 3 or more of the 6 patients in that tier have toxicity, the dose associated with the 
lower tier is the MTD1 ; 
• 
if 2 out of 3 patients show toxicity, include 3 additional patients at that same tier: 
o if 2 out of 6 patients in this tier show toxicity, move to the next tier; 
o if 3 or more of the 6 patients in that tier have toxicity, the dose associated with the 
lower tier is the MTD1 ; 
• 
if 3 out of 3 patients show toxicity, the dose associated with the lower tier is the MTD1 ;  
 
If 3 or more out of 6 patients have toxicity in Tier 0, include 3 patients in Tier - 1 : 
• 
if fewer than 3 patients have toxicity, include 3 additional patients at that tier; if fewer than 
3 of the 6 patients have toxicity, then the dose associated with the -1 tier is the MTD; 
• 
if 3 out of 3 patients, or at least 3 out of 6 patients show toxicity, then there is no MTD. 
 
A total of six patients should be included at the LMD level, even in the absence of a DLT. In the 
absence of a DLT, Tier 3 will be used for Phase II.   
 
If no DMT is identified, then the protocol is not continued in Phase II. 
 
Following Phase I, the dose level selected is level -1. 
b. PHASE II: estimation of efficacy and tolerance 
It will be performed at the maximum tolerated dose of 5FU and panitumumab determined in 
Phase I. Patients who were treated at this dose in Phase I will not be retained for Phase II due 
to the deletion of the free interval at S6 and S7. 
An interim safety analysis will be performed after the inclusion of the first 12 new patients in 
Phase II to ensure the validity of the MTD estimated in Phase I. 
2. Experimental treatment  
 
a.  Panitumumab 
 
Panitumumab will be supplied in a vial containing a 20 mg/ml solution of panitumumab. One vial 
is used for a single course of panitumumab. Vials should be stored at 2-8°C and protected from 
light until use.  
 
For administration, panitumumab should be diluted in 100 ml of saline (concentration should not 
exceed 10mg/ml). The diluted solution should be infused within 6 hours if stored at room 
temperature or within 24 hours if stored at 2-8°C. 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  14/34 
 
The dose of Panitumumab is 3 mg/kg (according to the -1 tier retained by Phase I) and to be 
administered every 2 weeks (14 days) starting at D1 of S1, i.e. at D1, D15, D29, and then at D1 
week 7.  
 
Administration is done before chemotherapy, intravenously in an infusion equipped with a filter 
(filter pore size = 0.2 or 0.22 µm) and connected to a pump.  
 
The recommended infusion time is 60 minutes. If the first infusion is well tolerated, subsequent 
infusions can be given over 30 to 60 minutes. Doses above 1000 mg should be administered 
over 90 minutes. 
 
If the total infusion volume exceeds 150 ml, the treatment can be administered over 90 +/-15 
minutes.  
Caution: Panitumumab should not be administered as a bolus, mixed or infused simultaneously 
with any other product. The infusion should be flushed with saline before and after administration 
of panitumumab.  
 
Reduce the infusion rate in patients with mild to moderate infusion-related reactions (CTCAE 
v4.0 grades 1 and 2) for the duration of this infusion. Maintain this reduced infusion rate for all 
subsequent infusions. 
If a severe or life-threatening reaction occurs during an infusion or at any time after an infusion, 
panitumumab should be permanently stopped. 
. 
 
Anti-allergic premedication is not necessary for the administration of panitumumab. In case of a 
reaction, pre-medication with an anti-histamine may be introduced for subsequent infusions. 
Prophylactic treatment of acne may be proposed (see treatments associated with panitumumab, 
paragraph VI).  
 
Empty and expired vials will be kept by the center's pharmacy. The green light for the destruction 
of empty and/or expired vials will be given by the Sponsor. 
 
For further information on panitumumab, please refer to the product's SPC (Appendix 7).  
 
b. Chemotherapy 5FU + mitomycin 
Two concomitant treatments with radiotherapy (treatment 1 from D1 to D4 of week 1 and 
treatment 2 from D1 to D4 of week 5 according to the following modalities: 
− 
Mitomycin C (on Day 1 of the 2 courses): 10 mg/m² in bolus, not exceeding 20 mg per 
course   
− 
5FU: 400 mg/m²/d (dose retained at stage -1 of phase I) whatever the body surface and 
according to the dose stage determined in phase I, in continuous infusion over 4 days in 
G5% (QSP portable diffuser or syringe pump) 
Systemic prophylaxis with growth factors (G-CSF or others) is strongly recommended to reduce 
the risk of neutropenia. 
 
c. Radiotherapy 
 
Radiation therapy should be performed with intensity modulation (either conformal radiation 
therapy with intensity modulation or tomotherapy), using photons of energy greater than or equal 
to 6 MV. 
 
Radiation therapy will consist of two parts: 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  15/34 
 
• 
A 1ère part will deliver a dose of 45 Gy in 25 fractions of 1.8 Gy, (at a rate of one session per 
day, 5 days/7, over 5 weeks) in a volume including the tumor and the lymph node drainage 
areas 
 
• 
A 2ème part, will deliver a complement of 20 Gy in 10 fractions of 2 Gy in a volume including 
the tumor and the initially invaded lymph nodes. 
  
Treatment position:  
The patient will be treated in the supine position. A restraint system is desirable to ensure 
better reproducibility of patient positioning. 
 
Centering Scanner:  
The CT scan will be performed without and with injection of contrast medium at the arterial 
time, and in the treatment position, in contiguous sections of 3 to 5 mm maximum. 
The acquisition volume of the scanner will start above L3 and end below the lesser 
trochanters. 
Margin marking with a wire or a lead ball may be useful, as well as in case of skin 
extension of the tumor beyond the anal margin. 
The centering scan as well as the treatment sessions will be performed with a full bladder, 
asking the patient to drink 500 ml of water, 30 minutes before the scan or the irradiation session. 
 
Contouring of target volumes and critical organs:  
The contouring will be performed taking into account the data of the clinical examination 
and the paraclinical examinations (echo-endoscopy, pelvic MRI, PET scan if performed outside 
the trial). A fusion of the PET scan or even the pelvic MRI with the centring scan is recommended 
to help delineate the tumour and lymph node volume. 
The GTV (Gross Tumor Volume) includes the primary tumor and the lymph nodes 
considered pathological at the initial workup.  
The CTV (Clinical Target Volume) includes the GTV as well as areas at risk of 
microscopic invasion: 
- 
bilateral inguinal chains-external iliac ganglion chains 
- 
obturator and internal iliac chains (these chains will be outlined with a 7 mm 
margin around the arteriovenous axes of the same name, excluding muscular 
and bony structures) 
- 
ischio-rectal fossae 
- 
mesorectum and presacral space 
- 
anal canal and anal margin 
 
The PTV1 (Planning Target Volume) includes the CTV + a margin of 8 mm 
The PTV2 (corresponding to the volume irradiated during the second part of the 
irradiation) includes the GTV + a margin of 8 mm. 
 
Critical organs: 
- Bladder 
- Right and left femoral heads: from the upper end to the upper part of the lesser 
trochanter 
- External genitalia: penis and scrotum in men, vulva in women 
- Iliac crests: from the upper end to the acetabulum 
- Small intestine and colon will be outlined in the same block called digestive volume 
 
Dose prescription and constraints: 
 
They will be validated by the realization of dose-volume histograms. 
 
Intensity modulation : 
 
The prescription of the dose will be done according to the ICRU 62 criteria:  
- The dose is prescribed at the median of the PTV 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  16/34 
 
- 95% of the volume must receive 95% of the dose 
- 98% of the volume must receive at least 90% of the dose 
- 3% of the volume should not receive more than 107% of the dose. 
 
Dose constraints: 
 
The proposed dose constraints serve as a basis for optimization in IMRT. The priority remains 
the coverage of the PTV : 
 
From this point of view, the creation of "OAR - PTV" type structures helps in the optimization, as 
well as phantom structures (or dummies) can be designed with the objective of conforming the 
dose to the volume of the PTV. 
 
 
 
 
 
Treatment quality control:  
A verification of the treatment isocenter and the shape of the beams by portal imaging or 
gammagraphy will be performed during the first two sessions and then once a week. 
Volume 
Prescription 
Isodose  
of prescription 
PTV 45 
 
- The dose is prescribed at the median of the PTV 
- 95% of the volume must receive 95% of the dose, i.e. 42.75 
Gy 
- 98% of the volume must receive at least 90% of the dose, 
i.e. 40.5 Gy 
- 3% of the volume must not receive more than 107% of the 
dose, i.e. 48.15 Gy 
PTV 65 
 
45 Gy/1.8 
+ 
20 Gy/2 
- The dose is prescribed at the median of the PTV 
- 95% of the volume must receive 95% of the dose, i.e. 61.75 
Gy 
- 98% of the volume must receive at least 90% of the dose, 
i.e. 58.5 Gy 
- 3% of the volume should not receive more than 107% of the 
dose, i.e. 69.55 Gy 
 
SRO 
TOLERANCES 
Constraints 
Digestive - 
PTV 
V30Gy < 400 cc/ 40 
V35Gy < 300 cc/30 
V45Gy < 200 cc/20%. 
Vessie-PTV 
V50 Gy< 5% (1) 
V40 Gy < 35 
V35 Gy < 50 
EMB 
V50 Gy < 5 
V40 Gy < 60 
Iliac crests  
V10 Gy < 45 
V20 Gy < 30 
Femoral 
heads  
V44 Gy < 5 
V40 Gy < 35 
V30 Gy < 30 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  17/34 
 
In addition, the patient will be seen weekly by the radiotherapist to evaluate the tolerance of the 
treatment (NCI-CTC-AE toxicity scale version 4.0 (Appendix 8)). 
 
 
VI. 
DISCONTINUATION CRITERIA - DOSE ADJUSTMENT - TREATMENT OF 
TOXIC EFFECTS 
 
Toxicities will be evaluated before each treatment by questioning, clinical examination and 
biology, and graded according to the NCI version 4.0 criteria (Appendix 8). Toxicities observed 
during the treatment will be reported in the observation book. 
Dose adjustments are planned in case of toxicity observed 48 hours before the treatment or on 
the day of the treatment.  
 
 Doses that have been reduced for toxicity should not be increased again. 
1. Deferral and dose adjustment for 5FU 
 
Type of toxicity 
Toxicity grade (NCI-
CTC v4.0) on day of 
treatment 
Adjustment of 5FU dosage 
Non-hematological toxicity 
 
0-1 
No change 
2 
Decrease daily dose by 25 
3-4 
Delay treatment until toxicity is reduced to a grade 
< 1. Resume with a 25% decrease in daily dose. 
The reduction in dosage is maintained for the 
current course and the remainder of the treatment. 
Hematological toxicity  
 
0-1 
No change. 
2-4 
Postponement of treatment until grade < 1 then  
Resumption with a 25% reduction of 5 FU for the 
current treatment and the rest of the treatment. 
Toxicity after initial dose 
adjustment 
0-2 
No change 
3-4 
Stopping chemotherapy 
 
2. Deferral and dose adjustment for mitomycin C 
 
Type of toxicity 
Toxicity grade (NCI-
CTC v4.0) on day of 
treatment 
Adjustment of mitomycin dosage 
Non-hematological toxicity 
(except Panitumumab-related 
skin toxicity) 
 
0-2 
No change 
3-4 
Postponement of treatment until grade < 1. 
Resume at 8 mg/m2 
Hematological toxicity  
 
0-1 
No change. 
2 
Postponement of treatment until grade < 1 then  
100% recovery 
 
3-4 
Postponement of treatment until grade < 1.   
Resume at 8 mg/m2 
Toxicity after initial dose 
adjustment 
0-2 
No change. 
3-4 
Stopping chemotherapy 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  18/34 
 
 
Chemotherapy is permanently discontinued when there is a recurrence of grade 3-4 toxicity after 
an initial dose adjustment. Systemic prophylaxis with growth factors (G-CSF or others) is 
recommended to reduce the risk of neutropenia. 
 
3. Deferral and dose adjustment for Panitumumab 
 
Panitumumab treatment may be delayed for up to 2 weeks. Panitumumab may be restarted at 
100% or reduced dose based on observed toxicities. 
Panitumumab treatment should be permanently discontinued in cases where more than 2 
consecutive infusions have not been administered at any dose. 
 
 
 
Skin and Nail Toxicity (NCI CTC version 3.0 with modifications) 
 
Relative skin and nail toxicities will be graded according to the modified NCI-CTC Version 3 
scale: 
 
Adverse event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nail modification 
Discoloration, wrink
(koilonychia) 
paronychia: 
unnecessary 
treatment 
Complete or partial 
loss of nails, nail 
pain, 
paronychia: 
necessary 
treatment 
 
Difficulty in the 
gestures of daily living 
(ADL) 
___ 
Erythema 
 
Erythema without 
pain 
Painful erythema 
Erythema with 
desquamation*. 
Vital prognosis engaged 
Pruritus/itching  
Moderate or 
localized 
Intense or 
generalized 
Intense or generalized 
disturbance of the 
gestures of daily life 
___ 
Acneiform rash 
Unnecessary 
treatment 
Treatment required 
Associated with pain 
requiring morphine 
analgesics, ulceration, 
or desquamation*. 
___ 
Skin 
rash/desquamatio
n 
 
Asymptomatic 
maculopapular or 
erythematous 
rash 
Asymptomatic 
maculopapular or 
erythematous rash 
with pruritus or 
other associated 
symptoms; 
localized scaling or 
other lesions 
covering less than 
50% of the body 
surface (BSA) 
Severe, generalized 
erythroderma or rash, 
vesicular scaling * 
covering more than 
50% of the body 
surface (BSA) 
Generalized ulceration 
or bullous dermatosis 
Ulceration  
___ 
superficial 
ulceration < 2 cm, 
local treatments, 
requiring 
Ulceration 2 cm, 
surgical debridement, 
primary closure or 
other invasive 
procedure required 
(e.g. hyperbaric 
chamber) 
Vital prognosis; major 
intervention required 
(e.g. complete tissue 
resection, 
reconstruction, grafting) 
*Desquamation is defined as skin peeling and not skin detachment. 
 
 
 
 
Type of toxicity (NCI-CTC v4.0) 
skin and nail (V3.0) 
non-cutaneous and non-nail (V4.0) 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  19/34 
 
Grade 1 or 2  
- 
initiation of anti-acne treatment 
 no panitumumab dose offset or reduction 
Grade 1 or 2  
- 
treatment of symptoms 
 no panitumumab dose offset or reduction 
Grade 3 or 4 
- symptoms 
requiring 
corticosteroids 
or 
intolerable for the patient,  
- infection requiring antibiotics or antifungals,  
- need for surgical debridement 
 cancel the treatment and start the next 
treatment  
 
Secondary effect returned to a grade 2 
- patients who have regained tolerable skin or nail 
symptoms and no longer require systemic 
treatment with corticosteroids, antibiotics or 
antifungals. 
A dermatological opinion is required 
 resumption of 100% panitumumab after 1 or 2 
weeks of deferral 
Any grade 3 or 4 toxicity including 
- symptomatic hypomagnesemia and/or hypocalcemia 
persisting despite supplementation 
- nausea, diarrhea or grade 3 or 4 vomiting despite 
maximum symptomatic treatment, 
- anemia and/or thrombocytopenia grade 3 or 4 despite 
transfusions 
 delay panitumumab administration until grade < 1 
 
Secondary effect returned to a grade 1 
  resumption of treatment at : 
 
100% at 1er episode.  
 
80% at 2ème episode  
 
60% at 3ème episode 
 
Final stop at 4ème 
 episode 
Once the panitumumab dosage is reduced, it will be saved 
for subsequent infusions.  
 
 
No discontinuation of CT (5 FU + mito) and RT in case of Panitumumab-related skin toxicities. 
Panitumumab should be withheld or discontinued if dermatologic or soft tissue toxicity occurs 
with severe or life-threatening inflammatory or infectious complications. 
 
4. Deferral and dose adjustment of radiation therapy 
 
Type of toxicity 
Toxicity grade (NCI-
CTC v4.0)  
Adaptation of radiotherapy 
Digestive toxicity: diarrhea 
 
0 
No change 
1-2 
Prescription of transit slowers, continuation of 
radiotherapy 
3-4 
Stopping radiation therapy sessions, resuming 
from a grade < 2 
Hematological toxicity  
 
0-2 
No change. 
3-4 
Stopping the sessions until grade < 2 
 
 
5. Associated treatments  
 
With chemotherapy 
 
− 
Anti-emetic treatment with metoclopropamide or setron if necessary  
− 
If chest pain: stop 5 FU; do ECG and cardiac enzymes 
− 
If hand-foot syndrome: moisturizing lotion, greasy creams 
− 
If severe mucositis: mouthwash with bicarbonate at 140 /00 , fungizone oral 
suspension, Xylocaine® viscous if pain and acyclovir if history of herpes. 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  20/34 
 
− 
If diarrhea: loperamide at first loose stool take loperamide 2 capsules after each loose 
stool. If diarrhea persists after 48 hours despite treatment or in case of concomitant 
vomiting, fever or neutropenia, rapid hospitalization is necessary. 
− 
Corticosteroids are authorized on an occasional basis, for anti-emetic purposes, but 
are not recommended for long-term use. 
− 
The use of a cooling helmet is allowed 
− 
All other anti-cancer treatments are prohibited 
− 
Contraindicated with 5FU and Mitomycin C: Phenytoin, yellow fever vaccine, live 
attenuated vaccines 
− 
Systemic prophylaxis with growth factors (G-CSF or others) is recommended to reduce 
the risk of neutropenia. 
 
With panitumumab 
 
Preventive and active treatment for skin toxicities such as acneiform rash: 
To be started 24 hours before the start of panitumumab treatment and continued for at least 6 
weeks depending on the patient and the type of skin toxicity: 
- In case of skin dryness, the use of emollient creams is beneficial. To be applied to the face, 
hands, feet, neck, back and chest  
 
CAUTION: CREAM APPLICATIONS in the irradiated area (pelvis) MUST NOT BE 
DONE BEFORE RADIOTHERAPY SESSIONS  
 
- Skin cracks may occur in case of dryness; they can be treated with dressings 
- A local anti-acne treatment (e.g. benzoyl peroxide, erythromycin) or systemic antibiotic 
therapy (e.g. tetracycline such as doxycycline 200 mg/day) may be considered. The patient 
should then avoid sun exposure. 
- Anti-UV creams are recommended. 
- In case of pruritus, oral treatment with antihistamines is recommended.  
 
Preventive treatment of nail lesions: 
- A consultation with a pedicurist is recommended. 
 
In case of skin lesions, refer to the recommendations of the national digestive cancer thesaurus 
(www.tncd.org) in the chapter on metastatic colon cancer. 
 
With radiotherapy  
 
- A residue-free diet will be recommended from the beginning of the radiotherapy treatment 
and throughout its duration. 
- The main digestive toxicity expected is the occurrence of diarrhea, justifying, as of grade 
1, the prescription of transit slowing agents to which intestinal dressings may be associated. 
Compliance with the residue-free diet should also be checked. If diarrhea persists after 48 
hours despite treatment or in the event of concomitant vomiting, fever or neutropenia, rapid 
hospitalization is necessary 
- Radioepithelitis (inguinal folds in particular) may appear from the third week of radiotherapy 
treatment: applications of biafine-type cream may be suggested after the radiotherapy 
session.  
- If there is a reaction at the anal margin, sitz baths can be offered. 
- Any application of alcoholic lotions, irritating products, at the level of the irradiated zone is 
disadvised 
- Sitz baths may be suggested, as well as applications of biafine after the radiotherapy 
session (any application of cream to the treated area before the radiotherapy session 
is to be avoided). 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  21/34 
 
 
VII. 
DURATION OF TREATMENT 
 
The treatment consists of two sequences. The initial treatment lasts 5 weeks, followed by an 
additional 2 weeks of radiochemotherapy.  
An evaluation is performed at week 6. If there is no response or progression, surgical resection 
may be decided. Treatment may be stopped prematurely for the following reasons 
- 
Toxicity 
- 
Progression of the disease 
- 
Refusal to continue the trial 
- 
Lost to view 
 
Whenever possible, patients who have stopped their treatment prematurely will be followed up 
in the same way as other patients. 
 
 
VIII. 
FOLLOW-UP OF PATIENTS DURING AND AFTER TREATMENT 
DISCONTINUATION 
1. Before each course of chemotherapy  
Within 48 hours before the treatment:  
- Assessment of tolerance to chemotherapy and radiotherapy (NCI-CTC criteria version 4.0 
- appendix 8) 
- Proctological examination, weight, general condition WHO 
- CBC/platelets, creatinine, transaminases (AST and ALT), alkaline phosphatases  
- If Panitumumab is discontinued, electrolyte levels (K+ , Na2+ , Ca2+ , Mg2+ ) 
2. Once a week during radiation therapy 
- Weight, 
- General status WHO 
- Toxicity assessment: NCI-CTC-AE version 4.0 toxicity scale (Appendix 8) 
3.  Before each administration of Panitumumab 
- CBC-platelets  
- Blood ionogram and electrolytes (K+ , Na2+ , Ca2+ , Mg2+ ) 
4. Assessment at 6 weeks  
- 
Proctological examination, weight, general condition WHO 
- 
CBC/platelets, blood ionogram + electrolyte (K+ , Na2+ , Ca2+ , Mg2+ ), creatinine, 
albumin, AST, ALT, alkaline phosphatases, GGT, total and conjugated bilirubin, SCC 
marker. 
- 
Pelvic MRI and/or rectal echo-endoscopy. Use the same technique as for the initial 
evaluation.  
- 
Quality of life assessment (QLQC30 + JORGE and WEXNER questionnaire) 
 
Make a CD-ROM copy of the images that will be retrieved by the FFCD in order to transmit them 
to the independent committee if needed. 
5. Assessment 8 weeks after the end of the treatment if no deferral 
- Proctological examination, weight, general condition WHO 
- CBC-platelets, blood ionogram + electrolyte (K+ , Na2+ , Ca2+ , Mg2+ ), creatinine, 
albumin, AST, ALT, alkaline phosphatases, GGT, total and conjugated bilirubin, CSC 
- Abdominal-pelvic MRI and/or rectal echo-endoscopy. Use the same technique as for 
the initial evaluation  
- Thoracic-abdominal-pelvic CT 
- Quality of life assessment (QLQ-C30 + JORGE and WEXNER questionnaire) 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  22/34 
 
- Effective contraception in women and/or men of childbearing age for up to 6 months after 
the end of treatment 
Make a CD-ROM copy of the images that will be retrieved by the FFCD in order to transmit them 
to the independent committee if needed. 
6. Check-ups every 4 months for 2 years after the end of treatment 
- NFS-Plates 
- Proctological examination, weight, general condition WHO  
- SCC 
- Pelvic MRI and/or rectal echo-endoscopy. Use the same technique as for the initial 
evaluation  
- Thoracic-abdominal-pelvic CT 
- Optional PET scan 6 months after the end of treatment 
- Quality of life assessment (QLQC30 + JORGE and WEXNER questionnaire) 
- Effective contraception in women and/or men of childbearing age for up to 6 months after 
the end of treatment 
7. Check-ups every 6 months for 3 years  
- NFS-Plates 
- Proctological examination, weight, general condition WHO 
- SCC 
- Pelvic MRI and/or rectal echo-endoscopy. Use the same technique as for the initial 
evaluation  
- Thoracic-abdominal-pelvic CT 
- Quality of life assessment (QLQC30 + JORGE and WEXNER questionnaire) 
 
Protocol monitoring will be discontinued in case of tumor recurrence  
 
IX. 
ANCILLARY RESEARCH  
 
There are 3 translational biology studies performed on 3 different biological collections 
(Appendix 1). 
Participation in ancillary research is optional. 
For details of these 3 studies, please refer to Appendix 1 of the protocol. 
1. Analysis of signaling pathways (Phase I and II) 
 
Samples: 4 biopsy specimens obtained at diagnosis, from tumor tissue fixed in formalin and 
embedded in kerosene. 
 
Sending: The blocks will be sent to the PRODIGE Biological Resource Center (45 rue des saints 
pères 75006 Paris) (Pr Pierre Laurent-Puig).  
 
2. Study of local and peripheral anti-tumor immune response as a predictor 
of overall response (circulating immunocompetent cells) (Phase II only) 
 
This study will be implemented for Phase II.  
Samples: Collection of 5 ACD tubes (7 ml)  
 
Sampling schedule : 
- 
before the start of treatment (D0 or T0), before the panitumumab infusion 
- 
8 weeks after the end of the treatment (S15 if no postponement of treatment)  
 
That is a total of 2 samples (10 tubes) for each patient. 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  23/34 
 
Shipment of samples: Blood samples will be sent at room temperature by DHL to the Biological 
Resource Center (BRC) of PRODIGE (45 rue des Saints Pères 75006 Paris) (Pr Pierre 
Laurent-Puig).  
PBMCs will be isolated, frozen and stored on site; RNAs will be extracted extemporaneously 
and stored on site.  
3. Sampling for pharmacokinetic study  (mandatory for Phase I and optional 
for Phase II) 
 
The pharmacokinetic study is mandatory for Phase I and optional for Phase II. 
 
Samples: Collect one dry tube (5 ml) for measurement of serum panitumumab concentrations. 
Complete the sample identification form 
 
Tube preparation and shipping: 
At each sampling :  
- 
Identify the tube (patient initials + inclusion number + sampling time). 
- 
Put the blood tube + the pharmacokinetic sheet* corresponding to the sample(s) in the 
DHL box.  
- 
Call DHL within 24 hours for collection (delivery within 48 hours after collection). If there 
is a delay between collection and pick-up, keep the tube at 4°C. 
- 
At the same time, notify the CRB of Tours of the shipment:  
Contact : Mrs Ludivine Diot or Mrs Coraline Gadras 
Phone : 02.47.36.01.73 
Opening hours: Monday to Friday from 9:30 am to 5 pm 
Address : CRB de Tours, EFS - Hôpital Bretonneau, 2 boulevard Tonnellé, 37044 
Tours cedex 9 
 
*Note on the PK sheet the exact dates and times of the start and duration of the panitumumab 
infusion corresponding to the sample(s) as well as the dates and times of the PK sample(s). 
 
At the end of the study, the tubes will be sent in a group to the pharmacology-toxicology laboratory 
of the CHRU of Tours (Pr Gilles PAINTAUD) where the panitumumab assays will be performed 
by ELISA technique.  
 
Sampling schedule PHASE I:  
- 
before each panitumumab infusion at weeks 3, 5, 8 and 10 [PaniT0]. 
- 
2 hours after completion of panitumumab infusion at weeks 1, 3 and 8 [PaniT2h]. 
- 
24 hours after the end of the panitumumab infusion at week 3 (in practice when the patient 
comes to the radiotherapy session the day after the panitumumab infusion) [PaniT1j] 
- 
7 days after the 2ème  panitumumab infusion, i.e. beginning of week 4 [PaniT7j]. 
- 
After 5FU in weeks 1 and 8 (weekend)  
That is a total of 11 samples for each patient in Phase I. 
 
Sampling schedule PHASE II :  
- 
before the 3ième panitumumab infusion  
That is a total of 1 sample for each patient in Phase II. 
 
X. 
SAFETY ASSESSMENT 
 
1. Security assessment parameters 
Safety will be assessed by evaluating the general, clinical and biological status of patients at 
the time of scheduled visits and by collecting events occurring between visits. Toxicities will be 
assessed using the NCI-CTC-AE version 4.0 toxicity scale (Appendix 8). 
In case of an emergency, the patient, his family or his physician should call the investigator to 
inform him of an event.  


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  24/34 
 
 
2. Definitions 
a. Adverse Event (AE) 
An adverse event is a harmful occurrence in a person who is a subject of biomedical research, 
whether or not the occurrence is related to the research or the product being investigated. 
 
All adverse events will be recorded in the observation book on the pages provided. 
b. Serious Adverse Event (SAE) 
A serious adverse event is any event that meets at least one of the following criteria: 
 
• 
Resulting in death, 
• 
Life-threatening, 
• 
Leading to hospitalization or prolonged hospitalization, 
• 
Causing permanent disability or severe temporary incapacity, 
• 
Causing a birth defect, fetal malformation or abortion, 
• 
Medically significant (examples: overdoses, second cancers, pregnancies and new 
developments may be considered medically significant) 
The terms disability and incapacity correspond to any temporary or permanent physical or 
psychological handicap, clinically significant and affecting the physical activity and/or quality of 
life of the patient.  
Any clinical event or laboratory result considered serious by the investigator and not 
corresponding to the severity criteria defined above is considered medically significant. They may 
put the patient at risk and require medical intervention to prevent an outcome corresponding to 
one of the above mentioned severity criteria (e.g. overdose, second cancers, pregnancies and 
new events may be considered as medically significant). 
Pregnancy is an exclusion criterion in this trial. However, if a pregnancy is discovered after 
inclusion, the patient must be excluded from the trial. The sponsor should be informed without 
delay via the serious adverse event reporting form (no severity criteria should be checked). The 
patient should be followed until the outcome of the pregnancy and this outcome, whatever it may 
be, should be reported to the sponsor. 
 
Disease progression should not be considered as an SAE.  Events that are potentially related to 
progression but may also be secondary to treatment will continue to be reported (e.g. 
thromboembolic events, perforations, etc.) 
Due to the severity of the disease in this study, certain conditions defined as SAEs will be 
excluded from the SAE reporting procedure, namely:  
- Hospitalization as per protocol  
- Hospitalization or surgery specifically related to the treatment of the disease  
- Hospitalization performed to simplify study treatments or procedures 
c. Undesirable Effect  
Any noxious and unintended response to an investigational drug at any dose or to any 
investigational component. An adverse reaction is serious if it meets the severity criteria (see 
above). 
d. Unexpected Serious Adverse Effect 
A serious unexpected adverse reaction is an event that is not mentioned, or is different in nature, 
intensity, or evolution compared to the product reference document  
 
In this essay the reference documents will be: 
• 
For panitumumab, the Investigator's Brochure version 14.0 or its latest update  


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  25/34 
 
• 
For 5-fluorouracil, the Summary of Product Characteristics for FLUOROURACILE EBEWE 
(Appendix 7) 
• 
For mitomycin C, the Summary of Product Characteristics for Ametycin® (Appendix 7) 
 
The versions of the PCRs used for the definition of expected or unexpected will be the latest 
available on the anniversary date of the start of the trial. 
3. Course of action  
The investigator informs the sponsor of all Serious Adverse Events (Expected and Unexpected), 
whether or not attributable to the research, that occur during treatment and within 30 days of the 
last treatment administration.  
 
All Delayed Serious Adverse Events (occurring after this 30-day period) considered reasonably 
related to the protocol treatment(s) or research should be reported without time limitation. 
 
The report is made by faxing the "notification of a serious adverse event" form (Appendix 9), 
documented as precisely as possible, dated and signed, within 24 working hours of their 
discovery to the FFCD's Randomization Management Analysis Center (CRGA): by fax to 03 
80 38 18 41 
 
Modalities and duration of follow-up of individuals following the occurrence of adverse 
events 
The investigator is responsible for appropriate medical follow-up of patients until resolution or 
stabilization of the effect or until the patient's death. This may sometimes mean that this follow-
up extends beyond the patient's discharge from the trial.  
 
He/she transmits the additional information to the sponsor using an SAE reporting form (checking 
the Follow-up No. X box to specify that it is a follow-up report and not an initial report) within 24 
hours of obtaining it. It also forwards the last follow-up to the resolution or stabilization of the 
SAE. Responds to requests for additional information to document the initial observation. 
He keeps the documents concerning the suspected adverse reaction in order to allow, if 
necessary, to complete the information previously transmitted. 
 
The sponsor is responsible, upon receipt of the investigator's report of the serious adverse 
event, for issuing an opinion on the causal relationship between the serious adverse event and 
the study product(s).  
If the serious adverse event is linked by the investigator and/or sponsor to one of the study 
products (i.e., it is a serious adverse event), the investigator and/or sponsor must establish the 
expected or unexpected nature of the event.  
If it is a serious unexpected adverse reaction, or if it is a new fact, the sponsor writes an initial 
report which will be transmitted to the ANSM, the CPP and the EMA (via EudraVigilance) within 
7 days in case of death or life-threatening situation, otherwise within 15 days.  
If it is an expected serious adverse event, it will be collected for the semi-annual and annual 
safety reports. 
 
XI. 
JUDGING CRITERIA, DATA MANAGEMENT AND STATISTICS 
1.  Response criteria 
 
Response criteria will be defined based on clinical and morphological examinations performed at 
patient inclusion, at 6 weeks, 8 weeks after the end of treatment (week 15) and 24 weeks (6 
months) after the end of treatment.  
These criteria are detailed in the table below: 
 
 
Response to treatment  
Criterion 
Full answer  
Disappearance of all lesions on all examinations  


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  26/34 
 
Partial response  
Tumor shrinkage of at least 30% on imaging or 
significant shrinkage on clinical examination*.  
Progressive disease  
Increase of at least 20% on imaging or significant on 
clinical examination*. 
Stable disease  
No progression, no complete response, no partial 
response 
 
* Tumor size will be measured in the largest dimension on any imaging 
2. Primary endpoint: complete response rate 8 weeks after the end of 
treatment  
 
It is defined by the complete disappearance of the tumor on proctological examination 
and morphological examinations (MRI and/or echo-endoscopy) and the absence of the 
appearance of a secondary lesion, a response validated by an independent committee (see 
paragraph XI.8)  
 
3. Secondary criteria  
 
- Intermediate objective response rate (complete and partial) at 6 weeks. The rate of 80% 
decrease in the largest tumor diameter will also be recorded. 
 
- Objective response rate 16 weeks after the end of treatment 
 
- Partial response rate, stability and progression 8 weeks after the end of treatment  
 
- Survival without colostomy: analysis of time interval from date of inclusion to date of colostomy 
or death if no colostomy. Patients alive without a colostomy will be censored at the last count. 
Colostomy-free survival will be estimated at 3 years. If a patient has a bypass colostomy and 
continuity is restored at 3 years, the patient will be counted as a colostomy-free patient. 
 
- Recurrence-free survival: analysis of the time interval from the date of inclusion to the date of 
first recurrence (local, regional, metastatic and second anal cancer) or death in the absence of 
recurrence. Living patients without recurrence will be censored at last count. Second cancers 
other than anal will be censored. Recurrence-free survival will be estimated at 3 years. 
 
- Overall survival: analysis of the time interval between the date of inclusion and the date of death 
(regardless of cause). Living patients will be censored at last count. Overall survival will be 
estimated at 3 years. 
 
- Quality of life (EORTC QLQ-C30 + Jorge and Wexner questionnaire): the global quality of life 
will be assessed using the EORTC QLQ-C30 questionnaire (version 3). In particular, the 
evolution of the global health score and the fatigue score will be described. A difference of 5 
points in these scores will be considered as the minimum to define a clinical difference. A 
sensitivity analysis will be performed using a difference of 10 points as the minimum difference. 
Quality of life, for global health and fatigue, will be characterized by the rates of patients with an 
improved, deteriorated or stabilized score, as well as by the time to definitive deterioration of the 
score. 
Time to definitive deterioration of a score will be defined as the time interval between the date of 
inclusion and the first date of a score decrease of more than 5 points with no subsequent 
improvement of more than 5 points or with no subsequent available score. Patients alive or 
deceased without a score decrease of more than 5 points or with a score decrease of more than 
5 points with a subsequent improvement of more than 5 points will be censored at the latest. A 
sensitivity analysis will be performed using a minimum difference of 10 points. 
The impact of incontinence on quality of life will be measured by the Jorge and Wexner score. A 
difference of 2 points in this score will be considered the minimum to define a clinical difference. 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  27/34 
 
The rates of patients with an improved, deteriorated or stabilized score will be calculated, as well 
as the time to final deterioration of this score. 
 
4.  
Management 
 
The CRGA in Dijon (Tel: 03 80 66 80 13; Fax: 03 80 38 18 41) will be responsible for data 
management and analysis. 
A clinical research associate (CRA), designated by the FFCD, may complete the case report 
forms under the supervision of the center's investigator. A copy of the case report forms will be 
sent to the CRGA in Dijon by the investigator. The CRGA will validate the data and send 
correction requests to the investigator in case of errors or incomplete data. 
 
 
5. Statistical methodology  
The study is a Phase I-II trial evaluating the safety and efficacy of the Panitumumab -
RTCT combination.  
Three populations are defined according to the criterion studied: 
• 
the strict intention-to-treat (ITT) population, corresponding to all patients included 
regardless of their eligibility criteria and the treatment received; 
• 
the per-protocol (PP) population, corresponding to the ITT population without major 
protocol deviations; 
• 
the population for the phase II safety analysis (SP), corresponding to all ITT patients 
who received at least one dose of 5FU + mitomycin + panitumumab and one radiation 
session. 
 
The primary analysis of the Phase II trial will be done on a strict intention-to-treat (ITT) 
basis. A secondary analysis will be performed on the per-protocol population. 
 
 
 
 
6.  
Number of subjects needed 
 
Phase I 
A minimum of 6 and a maximum of 24 patients will be included, corresponding to a minimum of 
3 patients per dose level (and 6 at the maximum tolerated dose). 
The 6 patients treated at the maximum tolerated dose will be included in the Phase II trial. 
A minimum of 9 patients will be required to proceed to Phase II. 
Based on the Phase I results, the -1 dose level was selected for the transition to Phase II. In 
order to follow as closely as possible the treatment practices that have evolved since the launch 
of Phase I, an amendment to the treatment schedule was made. As a result, patients in the -1 
dose level of Phase I will not be analyzed in Phase II.  
 
A suspension of inclusions will be made between each tier and between Phase I and Phase II. 
 
Phase II 
The Phase II study will be conducted with the maximum tolerated dose determined in Phase I 
(=Tier -1).  
A 2-step minimax Simon design will be used, with a one-sided α risk of 5% and a power (1-β) of 
90%. 
The assumptions are: 
• 
H0: A complete response rate 8 weeks after the end of treatment of 60% is considered 
unattractive; 
• 
H1: A complete response rate of 80% is expected 8 weeks after the end of treatment. 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  28/34 
 
 
Total number of patients required for Phase II: 45. 
 
Step 1 
Include 26 patients (the 6 patients from Phase I - 1 cannot be included in Phase II due to 
amendment #5). The analysis of step 1 will be performed once complete responses have been 
determined for each of these 26 patients 8 weeks after the end of their treatment. 
During analysis: 
• 
if 15 or fewer patients have a complete response at 8 weeks (58%), then the trial is 
stopped, as the response rate is not significantly higher than 60%; 
• 
if 16 or more patients have a complete response at 8 weeks (61%), the trial is continued 
with step 2. 
 
Step 2 
Include 19 additional patients. Stage 2 analysis includes the 26 patients from stage 1 and the 19 
patients from stage 2. 
During analysis: 
• 
if 32 or fewer patients have a complete response at 8 weeks (71%), the complete 
response rate cannot be considered significantly higher than 60%, no Phase III study is 
considered. 
• 
if 33 or more patients have a complete response at 8 weeks (73%), the complete 
response rate is significantly higher than 60%. 
 
The probability of stopping the study at the end of step 1 if H0 cannot be rejected is 48%; the 
average number of patients included to show that H0 cannot be rejected is 35.9. 
 
Statistical analysis 
Continuous variables will be described using means, standard deviations, medians, minimum, 
and maximum. Categorical variables will be described using frequencies and percentages. 
Percentages will be calculated with or without the missing modality. 
A detailed analysis plan will be defined before the base is frozen. 
 
Analysis of the judging criteria 
 
Response rates will be reported using percentages and numbers with their 95% confidence 
intervals. 
Survival and time estimates will be made by the Kaplan Meier (KM) method. They will be 
described by median survival times and survival rates at different time points, and their 95% 
confidence intervals.  
Analysis of prognostic factors for complete response will be performed using univariate and 
multivariate Cox models. 
Quality of life scores will be generated according to the algorithms in the EORTC QLQ-C30 
manual. These scores will be described at each measurement time. 
For overall health, fatigue, and incontinence scores, the rates of patients whose scores improved, 
deteriorated, or stabilized will be reported by frequencies and percentages. 
The times to final deterioration of global health, fatigue, and incontinence scores will also be 
estimated by the Kaplan Meier method; the median time and rates at different time points, along 
with their 95% confidence intervals, will be reported. 
 
7. Tolerance analysis 
Tolerance analyses will be performed on the SP population. 
Adverse events will be reported using frequencies and percentages for all grades, grades 3-4, 
and by relationship to treatment. 
The incidence of SAEs will be described.  
Changes in biological values and vital signs will be described using mean (standard deviation), 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  29/34 
 
median, minimum, and maximum. 
The dose intensity will be calculated and the changes in the general WHO status will be 
described. 
Deaths related to toxicities and unexpected serious side effects after discontinuation of treatment 
will be described. 
 
A safety analysis, based on toxicities and SAEs collected during treatment and the first 30 days 
following its administration, will be performed after the inclusion of the first 12 patients in phase 
II to ensure the validity of the MTD estimated in phase I and the change in the radiation therapy 
administration scheme. 
 
8. Independent Committee 
An independent committee is set up and includes two physicians (a radiotherapist and an 
oncologist), and a pharmacovigilance expert.  
 
For Phase I, the independent committee met, among others: 
• 
to review the AEs reported during Phase I; 
• 
after each level to validate the DLTs and determine the passage to the next or next lower 
level; 
• 
to determine, in view of the toxicities observed during phase I, the passage to phase II, 
and to confirm the choice of doses according to the definition of the DLT and DMT noted 
in the protocol. 
 
For Phase II, the independent committee will meet, among others: 
• 
to validate the complete responses to the treatment, based on the reports of the various 
examinations (clinical and morphological);  
o In the event of a discrepancy between the investigator and the independent committee, 
the independent committee's response will be used; 
o in case of uncertainty of the investigator on the response, the committee will decide on 
the response in view of the clinical and morphological data; 
o the Promoter undertakes to provide, at the request of the committee, all additional 
information necessary for the validation of these answers 
• 
to review the SAEs and serious toxicities reported in Phase II  
 
In Phase II, the committee will meet at the end of Stage 1 and 2. 
Advancement to Step 2 will require approval by the Efficacy and Tolerability Data Committee.  
 
The independent committee may also meet at any time during the course of the protocol when 
deemed necessary by the Sponsor. 
 
XII. 
INTRODUCTION - RATIONALE OF THE STUDY 
 
1. Treatment of squamous cell carcinoma of the anus 
Squamous cell carcinoma of the anus (SCC) accounts for 4% of cancers of the lower 
digestive tract. Squamous cell carcinoma of the anal canal accounts for 95% of anal canal 
cancers. Only 5% are metastatic at diagnosis. In addition to female gender and age, 
homosexuality, HPV infection and smoking are risk factors. Its incidence is increasing and varies 
by country (2/105 inhabitants in the United States vs. 0.5 to 1.2/105 inhabitants in Switzerland). 
The incidence has particularly increased in male homosexuals in the last 30 years, with an even 
more marked increase in HIV-positive male homosexuals in whom anal cancer is twice as 
frequent as in HIV-negative male homosexuals. In a recent French study, cancer of the duct 
ranks 4th among cancers in HIV-infected patients (ONCOVIH cohort, provisional results). With 
the progress of antiretroviral treatments, the prognosis of AECs has improved in HIV-infected 
patients to reach the prognosis of non-infected patients (1).  


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  30/34 
 
 Treatment is based on radiochemotherapy for locally advanced tumors. The objective of 
the treatment is to allow a cure without recourse to abdomino-perineal amputation and with 
preservation of sphincter function. 
The prognosis is essentially related to tumor size and lymph node involvement. The vast 
majority of patients do not have distant spread of their tumor at the time of diagnosis (2). 
Recurrences are essentially loco-regional and require abdominoperineal amputation. This 
operation is not always possible or not always complete, which then exposes the patient to a 
particularly painful local evolution with a 3-year survival rate of about 30%. (3). 
It is therefore very important to obtain a complete and definitive tumor response from the 
initial treatment with radiochemotherapy  
Radiation therapy techniques have evolved with the development of Intensity Modulated 
Conformal Radiation Therapy (IMCR), which allows the dose to be tailored to the complex shaped 
volume to be treated with better homogeneity and coverage while decreasing the dose received 
by healthy organs (9-10). 
2. Treatment by radiotherapy 
These dosimetric advantages translate into a reduction in acute toxicities during 
treatment, which allowed a reduction in the total treatment spread by eliminating or reducing the 
planned therapeutic pause at the end of the first treatment phase (11-12). The RTOG 0529 trial 
showed a significant reduction in acute gastrointestinal and hematological toxicities, while 
reducing the total treatment duration to 43 days (median) compared with 49 days for RTOG 98-
11 (11;14). This break (or free interval) was necessary with non-intensity-modulated conformal 
radiotherapy techniques because of the acute toxicity of the treatment, and was routinely planned 
in phase 1 of the study. Nevertheless, recent studies with intensity modulation have shown that 
a short spread (total treatment time) was significantly associated with tumor response and 
survival: current recommendations are to eliminate the break between the first and second phase 
of treatment (15-16). Rationale for radiochemotherapy with 5FU + mitomycin 
 
Non-surgical treatment of localized AECs initially relied on radiotherapy alone (4). 
However, the local control rate of large tumors was insufficient. It was then demonstrated that 
the combination of radiotherapy + chemotherapy with 5FU-mitomycin improved local control and 
survival (5; 6). The combination of 5FU + mitomycin + radiotherapy provides better local control 
than the combination of 5FU + radiotherapy (7).  Finally, a recent randomized trial showed that 
the combination of chemotherapy with radiotherapy 5FU + cisplatin was not superior to the 
combination of 5FU + mitomycin and that there was no benefit to perform induction chemotherapy 
before radiotherapy. (8). The data from the ACCORD 03 trial coordinated by D. Peiffert confirm 
the absence of benefit of induction treatment (17). Finally, the long-term results of the RTOG 
9811 trial confirm the superiority of the combination of mitomycin and 5FU over the combination 
of platinum and 5FU, both in terms of overall survival and recurrence-free survival (14) 
With the combination of radiotherapy + 5FU + mitomycin, the complete response rate is 
about 80% and the 3-year recurrence-free survival is 67%. (6) and the recurrence-free survival 
at 3 years is 67% and the colostomy rate at 3 years is 10%. (8).   
 
3. Rationale for combining radiochemotherapy with anti-EGFR therapy 
 
  
EGFR receptor expression increases progressively in preneoplastic lesions of the anus, 
depending on their grade, up to cancer (18-20) which makes it possible to consider the EGFR 
receptor as a therapeutic target. There are currently no results from studies that have combined 
radiotherapy, chemotherapy and anti-EGFR targeted therapy in anal cancers. 
The use of a monoclonal antibody directed against the EGF receptor results in an 
increased response to radiotherapy of tumour lines both in vitro and in vivo (21). In ENT 
squamous cell carcinoma, the addition of an anti-EGFR antibody to cisplatin has been shown to 
significantly increase the response rate to local and/or metastatic recurrence compared to 
cisplatin alone (22). In addition, the use of an anti-EGFR antibody in combination with exclusive 
radiotherapy in ENT cancers increased the recurrence-free survival and overall survival of these 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  31/34 
 
patients (23). These data support the use of a combination of chemotherapy and anti-EGFR 
antibody in anal squamous cell carcinoma. 
The combination of panitumumab with radio-chemotherapy has never been tested. In the 
study by Ajani et al, the grade 4 toxicity rate of the combination of 5FU + mitomycin + radiotherapy 
reached 34%. (8).  
 
4. References 
  
 1. Abramowitz L, Mathieu N, Roudot-Thoraval F, Lemarchand N, Bauer P, Hennequin C, Mitry E, 
Romelaer C, Aparicio T, Sobhani I. Epidermoid anal cancer prognosis comparison among HIV-
infected and non-infected patients: a multicentric cohort study in 151 patients. Aliment Pharmacol 
Ther 2009. 
 2. Bedenne L, Janoray I, Arveux P, Janoray P, Ledorze C, Horiot JC.  Squamous cell cancer of the 
anal canal in the Côte d'Or department. Gastroenterol.Clin Biol. 15, 130-6. 1991.  
Ref Type: Abstract 
 3. Pocard M, Tiret E, Nugent K, Dehni N, Parc R. Results of salvage abdominoperineal resection for 
anal cancer after radiotherapy. Dis Colon Rectum 1998;41:1488-1493. 
 4. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal. A series of 276 cases. Dis 
Colon Rectum 1987;30:324-333. 
 5. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus 
radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-
ordinating Committee on Cancer Research. Lancet 1996;348:1049-1054. 
 6. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Peiffert D, van 
Glabbeke M, Pierart M. Concomitant radiotherapy and chemotherapy is superior to radiotherapy 
alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of 
the European Organization for Research and Treatment of Cancer Radiotherapy and 
Gastrointestinal Cooperative Groups. J Clin Oncol 1997;15:2040-2049. 
 7. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, Quivey J, Rotman M, Kerman H, Coia 
L, Murray K. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage 
chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: 
results of a phase III randomized intergroup study. J Clin Oncol 1996;14:2527-2539. 
 8. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB, III, Thomas CR, Jr, Mayer RJ, 
Haddock MG, Rich TA, Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, 
cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 
2008;299:1914-1921. 
9. Bazan JG, Hara W, Hsu A, Kunz PA, Ford J, Fisher GA, Welton ML, Shelton A, Kapp DS, Koong AC, 
Goodman KA, Chang DT: Intensity-modulated radiation therapy versus conventional radiation 
therapy for squamous cell carcinoma of the anal canal. Cancer 2011, 117:3342-3351 
10. Servagi-Vernat S, Giraud P, Fenoglietto P, Azria D, Lisbona A, la Rochefordiere De A, Zefkili S, Fau 
P, Resbeut M, Huger S, Peiffert D, Meyer P, Noël G, Mazurier J, Latorzeff I, Biston MC, Pommier 
P, Ledu D, Garcia R, Chauvet B, Dudouet P, Belhomme S, Kantor G, Mahé MA: Contribution of 
rotational IMRT and helical tomotherapy in pelvic cancers: a prospective dosimetric study of 51 
patients. Cancer Radiother 2014:1-8. 
11. Kachnic LA, Winter K, Myerson RJ, Goodyear MD, Willins J, Esthappan J, Haddock MG, Rotman M, 
Parikh PJ, Safran H, Willet C: RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity 
Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the 
Reduction of Acute Morbidity in Carcinoma of the Anal Canal. Radiation Oncology Biology 2013, 
86:27-33. 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  32/34 
 
12. Vieillot S, Fenoglietto P, Lemanski C, Moscardo CL, Gourgou S, Dubois J-B, Aillères N, Azria D: 
IMRT for locally advanced anal cancer: clinical experience of the Montpellier Cancer Center. 
Radiat Oncol 2012, 7:45. 
13.Franco P, Mistrangelo M, Arcadipane F, Munoz F, Sciacero P, Spadi R, Migliaccio F, Angelini V, 
Bombaci S, Rondi N, Numico G, Ragona R, Cassoni P, Morino M, Racca P, Ricardi U: Intensity-
Modulated Radiation Therapy with Simultaneous Integrated Boost Combined with Concurrent 
Chemotherapy for the Treatment of Anal Cancer Patients: 4-Year Results of a Consecutive Case 
Series. Cancer Invest 2015. 
14. Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB, Thomas CR, Mayer RJ, 
Haddock MG, Rich TA, Willett CG: Long-term update of US GI intergroup RTOG 98-11 phase III 
trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation 
involving fluorouracil/mitomycin versus fluorouracil/cisplatin. Journal of Clinical Oncology 2012, 
30:4344-4351. 
15.Glynne-Jones R, Sebag-Montefiore D, Adams R, McDonald A, Gollins S, James R, Northover JMA, 
Meadows HM, Jitlal M, UKCCCR Anal Cancer Trial Working Party: "Mind the gap--"the impact of 
variations in the duration of the treatment gap and overall treatment time in the first UK Anal 
Cancer Trial (ACT I). Int J Radiat Oncol Biol Phys 2011, 81:1488-1494. 
16. Ben-Josef E, Moughan J, Ajani JA, Flam M, Gunderson L, Pollock J, Myerson R, Anne R, Rosenthal 
SA, Willett C: Impact of Overall Treatment Time on Survival and Local Control in Patients With 
Anal Cancer: A Pooled Data Analysis of Radiation Therapy Oncology Group Trials 87-04 and 98-
11. Journal of Clinical Oncology 2010, 28:5061-5066. 
17. Peiffert D, Tournier-Rangeard L, Gérard J-P, Lemanski C, François E, Giovannini M, Cvitkovic F, 
Mirabel X, Bouché O, Luporsi E, Conroy T, Montoto-Grillot C, Mornex F, Lusinchi A, Hannoun-
Lévi J-M, Seitz J-F, Adenis A, Hennequin C, Denis B, Ducreux M: Induction Chemotherapy and 
Dose Intensification of the Radiation Boost in Locally Advanced Anal Canal Carcinoma: Final 
Analysis of the Randomized UNICANCER ACCORD 03 Trial. Journal of Clinical Oncology 2012, 
30:1941-1948. 
 18. Alvarez G, Perry A, Tan BR, Wang HL. Expression of epidermal growth factor receptor in squamous 
cell carcinomas of the anal canal is independent of gene amplification. Mod Pathol 2006;19:942-
949. 
 19. Aparicio T, Abramowitz L, enabderrahmane D, uval X, enin D, lbano V, ehy T, alker F. Expression of 
growth factor receptors (EGFR, HER2, c-Met, VEGFR1) and p16 and Ki67 proteins in anal 
intraepithelial neoplasia (AIN) and invasive cancers of HIV-infected and HIV-uninfected patients. 
Gastroenterol.Clin.Biol. 32. 2008.  
Ref Type: Abstract 
 20. LH, Chetty R, Moore MJ. Epidermal growth factor receptor expression in anal canal carcinoma. Am 
J Clin Pathol 2005;124:20-23. 
 21. Milas L, Mason KA, Ang KK. Epidermal growth factor receptor and its inhibition in radiotherapy: in 
vivo findings. Int J Radiat Biol 2003;79:539-545. 
 22. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of 
cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and 
neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646-8654. 
 23. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, 
Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. 
Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 
2006;354:567-578. 
 
XIII. 
LEGAL AND ETHICAL ASPECTS ADMINISTRATIVE CONSIDERATIONS 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  33/34 
 
1. Study sponsor 
The sponsor of the study is the Fédération Francophone de Cancérologie Digestive (FFCD). The 
study was registered under the number EudraCT 2011-005436-26.  
2. Reminder of the texts in force 
This test will be carried out according to the new European Directive 2001/20/EC.  
3. Public liability insurance 
Insurance was purchased by the sponsor on 10/26/2011 from SHAM insurance under number 
137681, in accordance with Article L 1121-10 of the Public Health Code (Appendix 11).  
4. Application for authorization to the CPP and AFSSAPS 
This protocol was authorized by the CPP (Committee for the Protection of Individuals) ILE DE 
FRANCE X on 09/02/2012 (appendix 12). 
This protocol received a favorable opinion from the AFSSAPS (French Agency for the Safety of 
Health Products) on 12/03/2012 (appendix 13). 
5. Collection of the patient's consent 
The investigator undertakes to collect, after information, the clinical and biological consents of 
the patient in writing (information sheets and consent forms in appendices 2 and 3). A copy of 
these consents must be kept by the investigator for 15 years, to be presented to the supervisory 
authorities in case of inspection. The original must be given to the patient. 
6. Hospital management information and research agreement 
Prior to the implementation of the study, the hospital management will be informed by the sponsor 
of the investigator's interest in participating in this trial. 
A no-cost research agreement will be established between the investigating center administrator 
and the sponsor.  
Data archiving 
The files will remain confidential and can only be consulted under the responsibility of the doctors 
in charge of the patients. The sponsor and the health authorities in case of inspection will have 
direct access to these documents. 
At the end of the trial, the observation book will be kept for 15 years by the investigator. 
7. Computer support 
In accordance with the text of the law n° 78-17 of January 6, 1978 modified by the law of August 
9, 2004, relating to data processing, files and freedoms, the data of the trial will be recorded in a 
data bank of the Center of Randomization and Management Analysis of the FFCD, with the 
exception of the elements relating to the identity of the patients. 
8. Data processing 
The FFCD's Center for Randomization Management and Analysis (CRGA) will be responsible 
for data management and analysis.  
9. Monitoring, quality assurance and inspections by authorities 
The investigator agrees in advance that the records of the patients included in the trial may be 
consulted by a person mandated by the FFCD and/or by the health authorities to conduct an 
audit. On-site visits to the files, scheduled after agreement by the investigator, may take place 
during or after the period of inclusion in the trial 
This protocol will be monitored by the FFCD's mobile ARCs.  
 
 
XIV. 
PUBLICATION 
 
The current FFCD publication rules will be applied (Appendix 10) 
 


 
 
 
Protocol 0904 V 2.1 of 11.12.2017 containing amdt 10  34/34 
 
XV. 
APPENDICES 
 
 
  

SAP_001.pdf: 
 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 1 on 15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase I-II trial of radiochemotherapy combined with Panitumumab in the treatment 
of localized squamous cell carcinoma of the anus 
FFCD 0904 
 
 
Statistical Analysis Plan 
Final analysis 
Phase II 
 
 
 
 
 
 
 
 
Version: v 2.0 
Date: 11/30/18 
 
Editor: Emilie Barbier/ Karine Le Malicot 
Review Committee: Véronique Vendrely; Thomas Aparicio; Daniel Gonzalez; Karine Le Malicot. 
Subscribe 
to 
DeepL 
Pro 
to 
edit 
this 
Visit www.DeepL.com/profor more information. 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 2 on 15 
 
Sponsor  
FFCD 
French-speaking Federation of Digestive Oncology 
Faculty of Medicine 
7, Boulevard Jeanne d'Arc BP 87 900 
21 079 DIJON 
 
Coordinator 
Dr Véronique VENDRELY 
Radiation therapy department 
Haut-Lévêque Hospital 
Avenue de Magellan 
33604 PESSAC Cedex 
Tel : 05.57.62.33.13 - Fax : 05.57.68.33.05 
Email : veronique.vendrely@chu-bordeaux.fr 
 
Co-coordinator 
Pr Thomas APARICIO 
Gastro-Enterology Department 
Avicenne Hospital 
125 rue de Stalingrad 
93009 BOBIGNY Cedex 
Tel : 01.48.95.54.31 - Fax : 01.48.95.54.39 
Email : thomas.aparicio@avc.aphp.fr 
 
Project Manager 
Daniel Gonzalez 
French-speaking Federation of Digestive Oncology (FFCD) 
Faculty of Medicine 
7, Boulevard Jeanne d'Arc BP 87 900 
21 079 DIJON 
Tel : 03.80.39.34.04 - Fax : 03.80.38.18.41  
Email: Daniel.gonzalez@u-bourgogne.fr 
 
Biostatistics Manager Mrs Karine Le Malicot 
French-speaking Federation of Digestive Oncology (FFCD) 
Faculty of Medicine 
7, Boulevard Jeanne d'Arc BP 87 900 
21 079 DIJON 
Tel : 03.80.39.34.71 - Fax : 03.80.38.18.41  
Email: karine.lemalicot@u-bourgogne.fr 
  
 
 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 3 on 15 
1 Table of contents 
1 
Table of contents ........................................................................................................................................................................................................... 3 
2 
Abbreviations and definitions ................................................................................................................................................................................. 5 
3 
Introduction .................................................................................................................................................................................................................... 6 
3.1 
Objectives of the trial....................................................................................................................................................................................... 6 
3.1.1 
Main objective ............................................................................................................................................................................................... 6 
3.1.2 
Secondary objectives .................................................................................................................................................................................. 6 
4 
Experimental design .................................................................................................................................................................................................... 6 
4.1 
Scheme of the study ......................................................................................................................................................................................... 6 
4.2 
Treatment arms ................................................................................................................................................................................................. 6 
4.3 
Randomization and blinding ........................................................................................................................................................................ 7 
4.4 
Chronological sequence ................................................................................................................................................................................. 7 
4.5 
Justification of the number of subjects needed .................................................................................................................................... 7 
4.6 
Steps of the test .................................................................................................................................................................................................. 7 
4.6.1 
Step One: Interim Analysis ...................................................................................................................................................................... 7 
4.6.2 
Step Two: Final Analysis ........................................................................................................................................................................... 7 
4.6.3 
Transition between steps ......................................................................................................................................................................... 8 
4.6.1 
Adjustments ................................................................................................................................................................................................... 8 
5 
Study Populations for Analysis ............................................................................................................................................................................... 8 
5.1 
Definition of Analysis Populations ............................................................................................................................................................ 8 
5.1.1 
Intent-to-treat (ITT) population ........................................................................................................................................................... 8 
5.1.2 
Per-protocol population (PP) ................................................................................................................................................................. 8 
5.1.3 
Population for Tolerance Analysis (SP) ............................................................................................................................................. 8 
6 
General information about statistical methods ............................................................................................................................................... 8 
6.1 
Software ................................................................................................................................................................................................................ 8 
6.2 
Agreements concerning dates and durations ....................................................................................................................................... 8 
6.3 
Missing Data Conventions ............................................................................................................................................................................. 9 
6.4 
Definition of the baseline ............................................................................................................................................................................... 9 
6.5 
Statistics ................................................................................................................................................................................................................ 9 
7 
Statistical analysis ........................................................................................................................................................................................................ 9 
7.1 
Patient characteristics at inclusion ........................................................................................................................................................ 10 
7.1.1 
Patient eligibility ....................................................................................................................................................................................... 10 
7.1.2 
Demographic characteristics ............................................................................................................................................................... 10 
7.1.3 
Clinical characteristics ........................................................................................................................................................................... 10 
7.1.4 
Biological characteristics ...................................................................................................................................................................... 10 
7.1.5 
Disease-related characteristics .......................................................................................................................................................... 11 
7.2 
Monitoring characteristics ......................................................................................................................................................................... 11 
7.3 
Main criterion .................................................................................................................................................................................................. 11 
7.3.1 
Definition of the primary efficacy endpoint .................................................................................................................................. 11 
7.3.2 
Evaluation of the primary endpoint ................................................................................................................................................. 11 
7.4 
Secondary efficacy endpoints ................................................................................................................................................................... 11 
7.4.1 
Response rate ............................................................................................................................................................................................. 12 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 4 on 15 
7.4.2 
Overall survival .......................................................................................................................................................................................... 12 
7.4.3 
Survival without colostomy ................................................................................................................................................................. 12 
7.4.4 
Recurrence-free survival ....................................................................................................................................................................... 12 
7.5 
Tolerance criteria ........................................................................................................................................................................................... 13 
7.5.1 
Administration of chemotherapy ...................................................................................................................................................... 13 
7.5.2 
Administration of radiotherapy ......................................................................................................................................................... 13 
7.5.3 
Duration of the CT+RT sequence ....................................................................................................................................................... 14 
7.5.4 
Surgery .......................................................................................................................................................................................................... 14 
7.5.5 
Toxicities ...................................................................................................................................................................................................... 14 
7.5.6 
ISG .................................................................................................................................................................................................................... 14 
7.6 
Quality of life (Late analysis) .................................................................................................................................................................... 14 
7.6.1 
QLQ-C30 ........................................................................................................................................................................................................ 15 
7.6.2 
Wexner .......................................................................................................................................................................................................... 15 
 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 5 on 15 
2 Abbreviations and definitions 
 
CEACarcinoma  Epidermoid of the Anus 
CRGACentre  
of Randomization Management Analysis in Dijon 
 
SAESerious adverse event 
IMRT  Intensity Modulated Radiation Therapy 
ITTIntention to  treat 
PTVPlanning  
Target Volume 
PPPer-protocol 
ROR  
Objective response 
SPPopulation  
of Safety (tolerance) 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 6 on 15 
3 Introduction 
 
3.1 Objectives of the trial 
3.1.1 
Main objective 
The primary endpoint of Phase II is the complete response rate 8 weeks after completion of 5FU-panitumumab plus mitomycin 
and radiotherapy. 
 
3.1.2 
Secondary objectives 
The secondary objectives of this study are:  
- 
Partial response rate, stabilized and progression 8 weeks after the end of treatment 
- 
Intermediate objective response rate at 6 weeks (prior to adjunctive RTCC) 
- 
Objective response rate 16 weeks after the end of treatment 
- 
Toxicity of 5FU + mitomycin C + panitumumab + radiotherapy 
- 
Colostomy-free survival at 3 years 
- 
3-year recurrence-free survival 
- 
Overall survival at 3 years 
- 
Quality of Life 
- 
Determination of predictive markers of response or survival 
 
4 Experimental design 
 
4.1 Scheme of the study 
This is a multicenter, prospective, single-arm Phase II study. 
 
4.2 Treatment arm 
There is a single treatment arm in the study: 5FU-Panitumumab plus mitomycin and radiation. The treatment doses are 
the tier -1 doses determined by Phase I: 
First part of treatment (S1 to S5) 
Chemotherapy: 
- 
Panitumumab (3 mg/kg): D1, D15, D29 (S1, S3, S5) 
- 
5FU continuous infusion (400 mg/m²/d): D1 to D4 of S1 and D1 to D4 of S5  
- 
Mitomycin C (10 mg/m2 not to exceed 20 mg/cure): D1 S1 and D1 S5 
Radiotherapy:  
- 
45 Gy in fractions of 1.8 Gy 5 days/week (IMRT) 
Additional radiochemotherapy at S6 and S7  
Chemotherapy: 
- 
Panitumumab (3 mg/kg): D1 S7 
Radiotherapy:  
- 
20 Gy in 10 fractions over 2 weeks (S6 and S7), 2 Gy per session 
 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 7 on 15 
4.3 Randomization and blinding 
There is no randomization in this trial, it is an open label trial. 
 
4.4 Chronological sequence 
 
Each patient will follow the following therapeutic sequence: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5 Justification of the number of subjects needed 
The assumptions for calculating the number of subjects needed are: 
• 
H0: A complete response rate 8 weeks after the end of treatment of 60% is considered unattractive; 
• 
H1: A complete response rate of 80% at 8 weeks after the end of treatment is expected. 
Using a 2-step minimax Simon design with a 5% one-sided α risk and a power (1-β) of 90%, a total of 45 patients are 
required to be included. 
 
4.6 Steps of the test 
 
4.6.1 
First step : intermediate analysis 
The interim analysis was performed in July 2017 on the first 26 patients included. The independent committee met on 
7/24/17 to rule on complete responses at 8 weeks after the end of treatment. 
The decision rule was: if 16 or more patients had a complete response 8 weeks after the end of their treatment (61%), the 
trial was continued with step 2. 
17 of 26 patients had a complete response at 8 weeks after the end of treatment, so the trial continued. 
 
4.6.2 
Second step: final analysis 
This second step will be performed after the inclusion of 19 additional patients (Total number of patients = 26+19 = 45): 
• 
if 32 or fewer patients have a complete response 8 weeks after the end of their treatment (71%), the complete 
response rate cannot be considered significantly higher than 60%, no phase III study is considered. 
5 FUc 
Mitomycin 
Panitumumab 
S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S15 
5 FUc 
45 Gy/25F/5 weeks. 
20Gy/10F 
MORPHOLOGICAL 
ASSESSMENT (MRI +/- 
EER) + CLINICAL 
EXAMINATION
MORPHOLOGICAL 
REVIEW 8 weeks after the 
end of treatment (MRI +/- 
EER) + CLINICAL 
EXAMINATION  
MAIN CRITERION


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 8 on 15 
• 
if 33 or more patients have a complete response 8 weeks after the end of their treatment (73%), the complete 
response rate is significantly higher than 60%. 
The probability of stopping the study at the end of step 1 if H0 cannot be rejected is 48%; the average number of patients 
included to show that H0 cannot be rejected is 35.9. 
 
4.6.3 
Transition between steps 
Inclusions were suspended at the end of Stage 1 on 09/02/17 pending the results of the interim analysis. Inclusions then 
resumed on 01/08/17. 
4.6.1 
Adjustments  
Adjustments may be made to this analysis plan in case of amendments to the protocol, or if phenomena not initially 
foreseen require statistical adaptations. In all cases, these modifications must be made before the database is frozen. 
 
5 Study populations for analysis 
The study focuses on patients with localized squamous cell carcinoma of the anus. 
 
5.1 Definition of Analysis Populations  
 
5.1.1 
Intent-to-treat (ITT) population 
The intention-to-treat (ITT) population is defined as all patients included in the study, regardless of eligibility criteria and 
treatment received.  
 
5.1.2 
Per-protocol (PP) population 
The per-protocol (PP) population is defined as the ITT population that received at least one dose of 5FU and one dose of 
mitomycin and one dose of panitumumab and one radiation session. 
 
5.1.3 
Population for Tolerance Analysis (SP) 
It is defined as the ITT population that received at least one dose of 5FU or mitomycin or panitumumab or one radiation 
session. 
 
6 General information about statistical methods 
Statistical analyses will be performed by the CRGA. 
 
6.1 Software 
Statistical analyses will be performed with SAS software version 9 or later. Some graphs can be made with R software 
version 2.11 or later. 
 
6.2 Agreements concerning dates and durations 
Time since inclusion will be defined as the time since the day of inclusion, with the day of inclusion considered day 1. 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 9 on 15 
The time since the start of treatment will be defined as the time since the day of the first course of treatment, with the day 
of the first course of treatment being considered as day 1.  
Therefore, the durations will be calculated according to the following rule, for example for the duration between death 
and inclusion: day of death - day of inclusion + 1. 
The day before the day of inclusion (resp. the day before the day of treatment) will be considered as day -1 (day 0 does 
not exist). 
The last date of news will be the later of the date of the last examination performed, the last treatment administered, or 
the last contact. 
The following conversion rules will be used to convert the number of days into months or years: 1 month = 30.4375 days; 
1 year = 365.25 days. 
 
6.3 Missing Data Conventions 
Except in the cases specified, missing data will not be replaced. 
 
6.4 Definition of the baseline 
Inclusion measurements will be the last measurements taken before inclusion. In case of missing data, the first 
measurement performed before the first administration of the treatment will be used. 
 
6.5 Statistics 
Quantitative data will be described using the following descriptive statistics: count, mean, standard deviation, median, 
first and third quartile, and minimum and maximum. These statistics will be considered the usual statistics for the analysis 
of quantitative variables. Quantitative variables can be categorized using their median or a cut-off known from the medical 
literature.  
 
Categorical variables will be summarized using the following descriptive statistics: frequencies and percentages for each 
level of the variable (missing values will not be included in the denominator of the frequency calculation). These statistics 
will be considered as the usual statistics for the analysis of categorical variables. 
 
When necessary, confidence intervals for the proportions will be calculated from the exact binomial distribution. 
The confidence intervals provided will be two-sided 95% confidence intervals, except for the primary criterion where a 
one-sided 95% confidence interval will be given. 
 
Survival data will be estimated and plotted using the Kaplan-Meier method (Kaplan and Meier, 1958).  
This will be described by the median and rates calculated at different times. Two-sided 95% confidence intervals will be 
provided. Confidence intervals for the rates will be constructed from the Greenwood variance calculated using the log-log 
transformation. 
The median follow-up time will be calculated using the reverse Kaplan-Meier method (Shemper, 1996). 
 
7 Statistical analysis 
 
ITT 
SP 
PP 
Analysis for 
ASCO 2019 
Late analysis at
3 years 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 10 on 15 
Eligibility 
X 
 
 
X 
 
Characteristics at inclusion 
X 
 
X 
X 
 
Main criterion 
CR rate at 8 weeks after the end of treatment 
X 
 
X 
X 
 
Secondary criteria 
OR rate at 6 weeks after the start of treatment 
X 
 
X 
X 
 
OR rate at 8 weeks after the end of treatment 
X 
 
X  
X 
 
OR rate at 16 weeks after the end of treatment 
X 
 
X 
X 
 
Overall survival 
X 
 
X 
X 
X 
Recurrence-free survival 
X 
 
X 
X 
X 
Survival without colostomy 
X 
 
X 
X 
X 
Treatment administration 
 
X 
 
X 
 
NCI-CTC Toxicities 
 
X 
 
X 
 
Quality of life 
X 
 
 
 
X 
 
7.1 Patient characteristics at inclusion 
 
7.1.1 
Patient Eligibility 
Patient eligibility at inclusion will be verified and described by: 
▪ Number and percentage of patients who met all inclusion criteria  
▪ Number and percentage of patients who met all non-inclusion criteria  
▪ Number and percentage of patients who met all criteria (inclusion and non-inclusion)  
▪ Description of the populations 
 
7.1.2 
Demographic characteristics 
The following characteristics at inclusion will be described: 
▪ 
Age (years) 
▪ 
Gender (Male vs Female) 
▪ 
Inclusion center (number of patients included per center) 
 
7.1.3 
Clinical characteristics 
The following characteristics at inclusion will be described: 
▪ 
General status WHO 
▪ 
TNM Stage T (according to UICC v6 2002) 
▪ 
TNM Stage N (according to UICC v6 2002) 
▪ 
Tumor size (mm) 
 
7.1.4 
Biological characteristics 
The following characteristics at inclusion will be described: 
▪ 
PNN (/mm3 ) 
▪ 
Wafers (x103 /mm3 ) 
▪ 
Hemoglobin (g/dL) 
▪ 
Leukocytes (/mm3 ) 
▪ 
Creatinine (µmol/L) 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 11 on 15 
▪ 
Total bilirubin (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N)  
▪ 
ASAT (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N)  
▪ 
ALAT (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N)  
▪ 
Magnesium (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N vs.)  
▪ 
Calcium (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N)  
▪ 
PAL (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N vs.)  
▪ 
Albumin level (µmoL/L) 
▪ 
Potassium (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N)  
▪ 
Sodium (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N vs.)  
▪ 
Conjugated bilirubin (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N)  
▪ 
CD4 (/mm3 ) 
▪ 
CSC (≤ N vs. ]N-2.5N] vs. ]2.5N-5N] vs. > 5N vs.)  
 
7.1.5 
Characteristics related to the disease 
The following characteristics at inclusion will be described: 
▪ 
HIV test (Done vs. Not Done) and if Done, the result (Positive vs. Negative)  
▪ 
HBsAg test (Done vs. Not Done) and if Done, the result (Positive vs. Negative) 
 
7.2 Monitoring characteristics 
The median follow-up time and its 95% confidence interval will be calculated in months.  
 
7.3 Main criterion 
 
7.3.1 
Definition of primary efficacy endpoint  
Complete response is defined by the complete disappearance of the tumor on proctological examination and 
morphological examinations (MRI and/or echo-endoscopy) and the absence of secondary lesion appearance. The 
responses will be validated by an independent committee:  
• 
In the event of a discrepancy between the investigator and the independent committee, the independent committee's 
response will be used; 
• 
in case of uncertainty of the investigator on the response, the committee will decide on the response in view of the 
clinical and morphological data; 
This endpoint will be assessed 8 weeks after the end of treatment (week 15). 
A patient who dies (regardless of cause) is evaluable and considered a failure for the primary endpoint. 
 
7.3.2 
Evaluation of the primary endpoint 
The rate of patients in complete response 8 weeks after the end of treatment will be calculated on the ITT population and 
presented using its one-sided 95% confidence interval (exact confidence interval, binomial distribution). 
 
7.4 Secondary efficacy criteria 
 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 12 on 15 
7.4.1 
Response rate 
7.4.1.1 
Definition  
Objective response rates (complete and partial) will be assessed by the investigator: 
- 
6 weeks after the start of treatment (before the additional radiochemotherapy) 
- 
8 weeks after the end of the treatment 
- 
16 weeks after the end of treatment 
At 8 weeks, the objective response rate will be evaluated by the investigator and the independent committee. 
 
7.4.1.2 
Evaluation  
Response rates (CR, PR, S, P, NE) and objective response rates will be described at different time points using frequency 
and percentage. 
 
7.4.2 
Overall survival 
7.4.2.1 
Definition  
It is defined as the time between the date of inclusion and the date of death (regardless of cause). Patients lost to follow-
up or alive at the time of analysis will be censored at the date of last news. 
 
7.4.2.2 
Evaluation  
The time scale considered will be the month. 
Overall survival will be plotted using the Kaplan Meier estimator. Median survival and survival rates at 4, 8, 12, 18, 24, 36 
months will be calculated along with their 95% confidence intervals. 
 
7.4.3 
Survival without colostomy 
7.4.3.1 
Definition  
It is defined as the time from the date of inclusion to the date of colostomy or death (from any cause) in the absence of 
colostomy. Living patients without a colostomy will be censored at last count. If a patient has a shunt colostomy and 
continuity is restored, the patient will be counted among the patients without a colostomy. 
 
7.4.3.2 
Evaluation  
The time scale considered will be the month. 
Colostomy-free survival will be plotted using the Kaplan Meier estimator. Median survival and survival rates at 4, 8, 12, 
18, 24, 36 months will be calculated along with their 95% confidence intervals. 
 
7.4.4 
Recurrence-free survival 
7.4.4.1 
Definition  
It is defined as the time from the date of inclusion to the date of first recurrence (local, regional, metastatic and second 
anal cancer) or death in the absence of recurrence. Living patients without recurrence will be censored at last count. 
Second cancers other than anal will be censored.  
 
7.4.4.2 
Evaluation  
The time scale considered will be the month. 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 13 on 15 
Colostomy-free survival will be plotted using the Kaplan Meier estimator. Median survival and survival rates at 4, 8, 12, 
18, 24, 36 months will be calculated along with their 95% confidence intervals. 
 
7.5 Tolerance criteria 
 
7.5.1 
Chemotherapy administration 
7.5.1.1 
Duration of chemotherapy treatment 
The duration of chemotherapy treatment (converted to months) will be calculated by the formula: 
Start date of last administration - start date of first administration + 1 day 
Temporary stoppages and any deferral days during this period will not be subtracted from this duration. It will be 
described according to the usual descriptive statistics. 
 
7.5.1.2 
Doses administered 
The number of courses will be reported by treatment type: Panitumumab/5FU/Mitomycin C. 
The body surface area used will be the one provided by the investigator on the treatment form, otherwise, if it is not 
provided, it will be calculated from the formula of Gehan and Georges: 
0.0235 × height(cm)0.42246 × weight(kg)0.51456 
The weight used will be the weight indicated at the time of the treatment in question. If the weight is missing, the non-
missing weight from the previous treatment will be used instead. If no weight information is available, the weight at 
inclusion will be used. 
The ratios of treatment doses received to theoretical doses will be described by type of treatment according to standard 
descriptive statistics. 
 
7.5.1.3 
Modification of doses and postponement of treatments 
The number of patients who had at least one dose modification and the number of patients who had at least one deferral 
of 
treatment 
will 
be 
described 
according 
to 
the 
usual 
descriptive 
statistics 
by 
type 
of 
molecule: 
Panitumumab/5FU/Mitomycin C and overall. 
 
7.5.1.4 
Stop treatment 
The number and percentage of patients permanently discontinuing protocol treatment and the reasons for discontinuing 
protocol treatment (% of the number of patients discontinuing treatment) will be described using standard descriptive 
statistics. 
 
7.5.2 
Administration of radiotherapy 
7.5.2.1 
Duration of radiotherapy treatment 
The duration of radiotherapy treatment (converted to days) will be calculated by the formula: 
Start date of last session - start date of first session + 1 day 
It will be described according to the usual descriptive statistics. 
 
7.5.2.2 
Doses administered 
The number of sessions/weeks and the total number of sessions will be reported. 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 14 on 15 
The average dose administered per week and the total dose (over all sessions) will be calculated in Gy. 
Treatment interruptions, their duration and reasons will be described 
 
7.5.2.3 
Quality criteria for radiotherapy 
The quality of radiation therapy will be described by: 
- 
The type of control imaging performed 
- 
The type of radiotherapy (respect of IMRT) and the type of energy used 
- 
The volumes PTV45 and PTV65 
- 
Compliance with dose constraints  
- 
 
7.5.3 
Duration of the CT+RT sequence 
The duration of the total treatment sequence (TC+RT) will also be calculated by the formula (converted to days): 
Start date of last CT or RT administration - start date of first CT or RT administration + 1 day 
Temporary stoppages and any deferral days during this period will not be subtracted from this duration. It will be 
described according to the usual descriptive statistics. 
 
7.5.4 
Surgery 
The number of surgeries, type of surgery and reason for surgery will be described according to standard descriptive 
statistics. 
 
7.5.5 
Toxicities 
Toxicities (graded according to NCI-CTC v 4.0) will be described in the same way: 
- 
during treatment (CT+RT),  
- 
8 weeks after the end of the treatment  
- 
during post-treatment follow-up 
By: 
▪ The total number of patients by maximum grade of toxicity by grouping grades (Grade 1-2, Grade 3-4 and Grade 5) 
▪ The number of patients and the maximum grade of toxicity achieved by grouping grades (Grade 1-2, Grade 3-4 and 
Grade 5) by causality, SOC and type of toxicity 
 
7.5.6 
ISG 
A summary of the SAEs will be provided by pharmacovigilance. 
 
7.6 Quality of life (Late analysis) 
 
The number of analyzable patients for QoL (having at least one questionnaire) and the percentage (out of the number of 
patients included) will be described. 
Questionnaires will be collected at different times: within 14 days before inclusion, every 6 weeks during treatment, at 8 
weeks after the end of treatment and during follow-up every 4 months for 2 years, then every 6 months for 3 years.  
The number of patients with a questionnaire available will be described at each measurement time.  
Inclusion scores will be calculated and described according to standard statistics. 
 


 
Statistical Analysis Plan - FFCD 0904 - Final Analysis - Phase II - Version 2.0 
 
Page 15 on 15 
7.6.1 
QLQ-C30 
Global quality of life will be assessed using the EORTC QLQ-C30 questionnaire (version 3).  
This 30-item scale has 15 dimensions to calculate 15 scores: 5 functional ability scores (physical ability, ability to work or 
perform any household task, cognitive ability, emotional state, social state), a global quality of life score, a financial 
problems score, and 8 symptom scores (fatigue, nausea/vomiting, pain, dyspnea, sleep disturbance, loss of appetite, 
constipation, diarrhea). 
In particular, the overall health and fatigue scores will be studied.  
A difference of 5 points in these scores will be considered the minimum to define a clinical difference. Quality of life, for 
overall health and fatigue, will be studied over time until definitive deterioration of the score.  
Time to definitive deterioration of a score will be defined as the time interval between the date of inclusion and the first 
date of score decrease of more than 5 points (compared to the score at inclusion) without subsequent improvement of 
more than 5 points or death. Living patients without a decrease in score of more than 5 points will be censored at the last 
news. It will be plotted using the Kaplan Meier estimator. 
 
7.6.2 
Wexner 
The impact of incontinence on quality of life will be measured by the Wexner score. A difference of 2 points in this score 
will be considered the minimum to define a clinical difference. The time to definitive deterioration of this score will be 
calculated. It will be represented graphically using the Kaplan Meier estimator.