Randomized Phase 3 Study on the Optimization of Bevacizumab With mFOLFOX/mOXXEL in the Treatment of Patients With Metastatic Colorectal Cancer
Phase: PHASE3
Conditions: Colorectal Cancer
Sponsor: National Cancer Institute, Naples

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
1
EUDRACT NUMBER: 2011-004997-27; ClinicalTrials.gov number: NCT01718873 
1 
 
2 
 
3 
Randomized phase 3 study on the optimization of the combination of 
4 
bevacizumab with FOLFOX/OXXEL in the treatment of patients with 
5 
metastatic colorectal cancer. 
6 
 
7 
Nickname: OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy 
8 
Scheme)  
9 
 
10 
No-profit Sponsor: 
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National Cancer Institute of Naples (NCI) 
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13 
SYNOPSIS 
14 
 
15 
 
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Study coordinator (Principal Investigator and Chief Scientist of Study) : 
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Dr. A. Avallone  
Medical Abdominal Oncology, NCI of Naples 
 
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Principal Investigators (Co-Investigators):    
19 
Prof. R.V. Iaffaioli  
Medical Abdominal Oncology, NCI of Naples 
Dr. A. Budillon 
Experimental Pharmacology, NCI of Naples 
Dr. F. Perrone 
Clinical Trial Unit, NCI of Naples 
Dr. S. Lastoria 
Nuclear Medicine and Metabolic Therapy, NCI of Naples 
Prof. C.Gallo 
Medical Statistics, Second University of Naples  
To determinate 
Other Institutions 
 
 
Scientific Board: 
20 
R.Casaretti, G.Nasti  
Medical Abdominal Oncology, NCI of Naples 
G.Romano, P.Delrio, F.Izzo 
Abdominal Cancer Surgery, NCI of Naples 
E. Di Gennaro, A.Leone 
Experimental Pharmacology, NCI of Naples 
A.Petrillo, O.Catalano 
Radiology,  NCI of Naples 
L.Aloj, C.Caracò 
Nuclear Medicine and Metabolic Therapy, NCI of Naples 
F.Tatangelo, G.Botti, 
Pathological Anatomy, NCI of Naples 
S.Cavalcanti, L.Nitch, D.Grilli 
Clinical Pathology, NCI of Naples 
M.C.Piccirillo, F.Perrone 
Clinical Trial Unit, NCI of Naples 
 
 
Secretary and Coordinating Center of Clinical Study: 
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M.C.Piccirillo, P.Giordano,M.Florio Clinical Trial Unit, NCI of Naples 
 
 
Secretary and Coordinating of Biological Studies: 
22 
A.Budillon, E. Di Gennaro, 
A.Leone, A. De Caro  
Experimental Pharmacology, NCI of Naples 
 
 
Coordinating Ethics Committee: 
 
National Cancer Institute of Napoli 
 
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Version n.1 0   of  October 06, 2011 
24 
 
25 
 
26 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
2
 
27 
STUDY SYNOPSIS 
28 
 
29 
Rationale 
30 
Although the approval of bevacizumab has changed clinical practice in the treatment of 
31 
colorectal cancer (CRC), the efficacy demonstrated by this anti-vascular endothelial 
32 
growth factor (VEGF) in combination with chemotherapy, has thus far been rather modest.  
33 
Therefore, it is crucial  to develop  more effective ways to combine  anti-angiogenic drugs 
34 
with  chemotherapeutic treatments, and to identify valid predictive biomarkers of benefit 
35 
anti-angiogenic  approach, in order to avoid ineffective and expensive therapies in non-
36 
responder patients.  
37 
Increasing  evidences  show that, in combination with chemo e/o radiotherapy, anti-
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angiogenic schedule could  be relevant to optimize the  feasibility and efficacy of radio- 
39 
and chemotherapy.   
40 
 
Preliminary results of BRANCH study, a  phase II study conducted at the National 
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Cancer  Institute of Naples, in patients with locally advanced rectal cancer, have shown a 
42 
reduced toxicity and an increased efficacy of experimental “timing” of bevacizumab 
43 
administration, 4 days before chemo-radiotherapy, compared with the standard 
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administration of bevacizumab and chemo-radiotherapy in combination, on the first day. 
45 
This experimental schedule of bevacizumab  induced a  lower  incidence of grade 3-
46 
4 neutropenia, and higher rate of  complete tumor regression rate (TRG1)  than reported 
47 
with the traditional concurrence administration of bevacizumab. 
48 
There is an unmet need for pharmacodynamic and predictive biomarkers of benefit 
49 
for anti-angiogenic drugs. 
50 
In cancer patients treated with anti-angiogenic therapy, the ability to noninvasively 
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measure single nucleotide polymorphisms (SNPs) of VEGF gene, the levels (baseline and 
52 
during treatment) of circulating endothelial precursors cells  (CECs) and their progenitors 
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(CEPs) count together with a broad profile of  cytokines and angiogenic  factors  could 
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help to select the patients most likely to benefit from these high-cost therapies, and to 
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identify possible mechanisms of resistance and consequently new targets for improving 
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anti-angiogenic therapy. 
57 
 
Multiplex technologies offer a noninvasive, easy and convenient method of 
58 
simultaneously assessing a much larger number of biologically relevant citochine and 
59 
angiogenic factor from small plasma volumes. Moreover, the high stability of  miRNA in the 
60 
plasma of patients with cancer and their correlation with the expression in the tumor, 
61 
suggest  the possibility to identify innovative predictive biomarkers of benefit for anti-
62 
angiogenic  therapy.   
63 
 
Pursuing imaging and circulating biomarkers shortly after treatment initiation might 
64 
be a fruitful approach, as many of the biomarker changes occur rapidily after the onset of 
65 
therapy. The ability to identify tumor-specific changes rapidily after treatment may allow 
66 
tailoring of therapy to those patients most likely to benefit, and early discontinuation of an 
67 
ineffective therapy in other.  
68 
 
In this study we  will compare the traditional concurrent administration of 
69 
bevacizumab in combination with chemotherapy,  with an experimental schedule, defined 
70 
on the basis of "normalization hypothesis", in which  bevacizumab will be  given 4 days 
71 
before chemotherapy. 
72 
 
73 
 
74 
 
75 
 
76 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
3
 
77 
Study Objectives 
78 
 
79 
    Primary Objective 
80 
  
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 To assess whether an experimental schedule of bevacizumab, given in sequence 
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instead of in combination with oxaliplatin regimen (mFOLFOX/mOXXEL), can 
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improve treatment activity (in terms of objective response rate) in patients with 
84 
metastatic colorectal cancer 
85 
 
86 
     Secondary Objectives 
87 
 
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 To evaluate the impact of the experimental schedule on:  
89 
 
90 
- 
 Progression free survival (PFS)  
91 
- 
 Overall survival (OS). 
92 
- 
 Toxicity. 
93 
- 
 Quality of life. 
94 
 
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 To evaluate prognostic and predictive value of : 
96 
- 
Circulating endothelial cells (CEC) and Circulating endothelial precursor cells (CEP) 
97 
count on patient blood samples. 
98 
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Cytokine and circulating angiogenic factors plasma levels on patient blood samples. 
99 
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Single nucleotide polymorphisms (SNPs) of VEGF on patient blood samples. 
100 
- 
WBC counts  at 24 hours after the 1st administration of bevacizumab on patient 
101 
blood samples. 
102 
- 
microRNAs (miRNAs) on patient blood samples. 
103 
- 
Change of tumor metabolic volume,  at 11 days after the start of the first cycle of 
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chemotherapy in both arms (15 days after the first administration of bevacizumab in 
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the experimental arm) evaluated by [18F]Fluorodeoxyglucose  positron emission 
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tomography (FDG-PET).       
107 
 
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Study Design 
109 
 
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This is a prospective, multicentre, open label, randomised phase 3 trial comparing 
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two treatment strategies. Eligible patients will be randomly assigned with 1:1 ratio to the 
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following arms :  
113 
 
114 
- 
Standard arm: bevacizumab in combination with modified FOLFOX-6 regimen 
115 
(mFOLFOX-6) or  modified OXXEL regimen (mOXXEL), in which bevacizumab  will 
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be administered before oxaliplatin, on day 1 of each cycle.  
117 
 
118 
- 
Experimental arm: bevacizumab in sequence with  mFOLFOX-6 or mOXXEL 
119 
regimen, in which bevacizumab  will be administered 4 days before oxaliplatin of 
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each cycle. 
121 
 
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In both arms of treatment, the patients without progression after 12 cycles (24 
123 
weeks) of treatment will stop chemotherapy and will continue bevacizumab (7,5mg/kg 
124 
every 3 weeks)  until progression, unacceptable toxicity or patient’s choice to stop.  
125 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
4
Oxaliplatin regimen (mFOLFOX/mOXXEL) will be chosen according to centre policy 
126 
at the beginning of the study. 
127 
Primary end point is objective response rate (RR) according to RECIST criteria.  
128 
The sample size of study depends on the expected response rate for the control 
129 
arm; it varies as a function of the proportion of patients enrolled in first and in second line 
130 
of treatment. Assuming 40% as response rate for the first line of therapy and 20% for the 
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second line, the sample size is calculated within three different expected response rate: 
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35% (75% as first line and 25% as second line), 30% (50% and 50% respectively) and 
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25% (25% and 75% respectively). In the following table, the expected sample size is 
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reported, under the three hypothesized conditions, fixing an odds ratio of 2,25, 80% 
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statistical power and 2-sided alpha error of 0.05. We have also reported the auspicated 
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response rates, in the experimental arm, and the corresponding relative risks, ranging 1.6 
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to 1.7. As expected, odds ratio represents an overestimation of relative risk, and the extent 
138 
of overestimation increases with increasing the expected response rate.   
139 
 
140 
% expected 
response in 
standard arm  
# 
patients  
% expected response 
in experimental arm 
Relative risk 
(experimental vs 
standard) 
35 
201 
54,8% 
1,57 
30 
209 
49,1% 
1,63 
25 
225 
42,9% 
1,71 
 
141 
Therefore, a  sample size of 220-230 patients will allow reliable assessment in all 
142 
plausible case-mix conditions. 
 
143 
With a sample size of 225 patients and a speed of accrual of 15 patients/month, the 
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study will achieve 163 events, necessary for identifying a 5 months PFS prolongation, 
145 
corresponding to a 0.64 hazard ratio, with an expected PFS of 9 months in the standard 
146 
arm, and a 2-sided alpha error of 0.05.  
147 
 
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Inclusion criteria 
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 Histological diagnosis of adenocarcinoma of the colon or rectum  
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 Stage IV of disease 
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 Presence at least one measurable target lesion (according to the  RECIST criteria) not 
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previously treated with radiotherapy.  
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 Ages  > 18 and < 75 years 
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 ECOG performance status 0 or 1 at study entry 
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 Life expectancy > 3 months 
158 
 Adequate recovery from recent surgery (at least 28 days after a major surgery or a 
159 
biopsy). 
160 
 Effective contraception  both for male and female patients, if the risk of conception 
161 
exists. 
162 
 Signed informed consent.  
163 
 
164 
 
165 
Exclusion Criteria 
166 
 
167 
 More than one line of treatment for metastatic disease.  
168 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
5
 Previous treatment with bevacizumab or oxaliplatin (a previous treatment with 
169 
fluoropirymidines, folic acid, irinotecan or cetuximab is allowed). 
170 
 Presence of primary colorectal cancer that produces stenosis or full-thickness wall 
171 
infiltration. 
172 
 Regular use of NSAID or aspirin (more than 325 mg/die). 
173 
 Bleeding diathesis or pre-existing coagulopathy. 
174 
 Use of anticoagulants  at therapeutic dose. 
175 
 Known or suspected brain metastases ( determined exclusively in the presence of at 
176 
least one clinical symptom) 
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 Neutrophils < 2000/mm3 or platelets < 100.000/ mm3 or haemoglobin <9 gr/dl. 
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 Creatinine >1.5 time the upper normal limit (UNL). 
179 
 GOT and/or GPT > 2.5 time the UNL and/or bilirubin >1.5 time the UNL in absence of 
180 
liver metastasis.  
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 GOT and/or GPT >  5 time the UNL and/or bilirubin > 3 time the UNL in presence of 
182 
liver metastasis 
183 
 Any concurrent malignancy other than non-melanomatous skin cancer, or carcinoma in 
184 
situ of the cervix. Patients with a previous malignancy but without evidence of disease 
185 
for 5 years will be allowed to enter the trial.  
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 Congestive heart failure, recent ischemic coronary disease (in the last 12 months), 
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uncontrolled arrhythmia. 
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 Uncontrolled hypertension.  
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 Active or uncontrolled infection. 
190 
 A serious uncontrolled medical disorder that in the opinion of the investigator would 
191 
impair the ability of the subject to receive protocol therapy. 
192 
 Pregnancy (absence to be confirmed by B-HCG test) or lactation period. 
193 
 History or current evidence on physical examination of central nervous system disease 
194 
or Peripheral Neuropathy > Grade 1 (CTCAE v. 4.0)  
195 
 
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Treatment Plan 
198 
 
199 
Arms of study: 
200 
 
201 
- 
Standard Arm: Bevacizumab (5mg/kg) and mFOLFOX-6 regimen (oxaliplatin 
202 
85 mg/m2 i.v. infusion on day 1 followed by  levo-folinic acid 200 mg/m2 i.v. 
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infusion followed by i.v bolus.  5-fluorouracil 400 mg/m2, and a 46-hour  i.v. 
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infusion of   5-fluorouracil 2400 mg/m2) or mOXXEL regimen (oxaliplatin 85 
205 
mg/m2 i.v. infusion on day 1 plus oral capecitabine 1000 mg/m2 twice daily on 
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days 1 to 10) every 2 weeks for 12 cycles (24 weeks); Bevacizumab  will be 
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administered as 20- to-30 minute intravenous infusion before oxaliplatin on day 
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1 of each cycle of treatment. 
209 
 
210 
- 
Experimental Arm: Bevacizumab (5mg/kg) on day 1 and  mFOLFOX-6 or  
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mOXXEL regimen ( at same doses used in the standard arm) after 4 days  every 
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2 weeks for 12 cycles (24 weeks) 
213 
 
214 
 In both arms of treatment the patients who will be progression free after 12 cycles 
215 
(24 weeks) of treatment will stop chemotherapy and will continue bevacizumab (7,5mg/kg 
216 
every 3 weeks)  until progression, unacceptable toxicity or patients chose to stop. 
217 
 
218 
 Unable to comply with follow-up 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
6
 
219 
 
220 
Baseline  Procedures   
221 
 
222 
Before any study procedure: 
223 
 Signed informed consent 
224 
 
225 
Within 14  days prior to registration: 
226 
 Complete medical history, physical examination, evaluation of ECOG PS and vital 
227 
signs ( included blood pressure).  
228 
 Evaluation of quality of life (QoL) by EORTC QLQ-C30 questonnaire. 
229 
 Blood count  and biochemistry analyses ( included B-HCG test for the women of 
230 
childbearing age) 
231 
 CEA and CA19.9 
232 
 CEC and CEP counts, evaluation of cytochine and circulating angiogenic factors 
233 
plasma levels, evaluation of SNPs of VEGF and miRNAs.  
234 
 
235 
Within 21 days prior to registration: 
236 
 18FDG-PET for the tumor metabolic volume assessment. 
237 
 Other tests may be performed at the Researcher’s discretion. 
238 
 
239 
During the treatment with bevacizumab and chemotherapy 
240 
 Physical examination and  vital signs ( included blood pressure)  at 1st day of every 
241 
cycle of treatment. 
242 
 Blood pressure evaluation immediately after the administration of bevacizumab (in 
243 
the hospital) and 24 and 48 hours after the administration of bevacizumab of every 
244 
cycle of treatment,in both arms of treatment (even at home) 
245 
 WBC counts  24 hours   after the 1st administration of bevacizumab in both arms of 
246 
treatment 
247 
 Blood count  every week and at 1st day  of  every cycle of treatment 
248 
 Biochemistry and Urinalysis 1st day  of  every cycle of treatment. 
249 
 Bloods samples for CEC and CEP counts, evaluation of cytochine and circulating 
250 
angiogenic factors plasma levels and  evaluation of miRNAs will be collected at 
251 
15th day after starting treatment (the day  in which starting 2nd cycle of  treatment) 
252 
before the administration of bevacizumab. Further bloods samples must be 
253 
collected at 12th and 24th week (at 1st and 2nd response evaluation). 
254 
 CEA and CA19.9,  ECG,  QoL and thoracic and abdomen CT scan at 12th and 24th 
255 
week after starting treatment 
256 
 Tumor metabolic volume assessment by 18FDG-PET at 11th +/- 2 days after 
257 
starting chemotherapy treatment in both arms ( 15 days after the first administration 
258 
of bevacizumab in the experimental arm; in all cases the PET scan must be done 
259 
before the 2nd administration of bevacizumab). 
260 
 Anyone tests that the Researcher will believe clinically indicated 
261 
 
262 
During the follow up after the stop of chemotherapy and the treatment with 
263 
bevacizumab 
264 
 ECG 
 Thoracic and abdomen computer tomography (CT) scan. 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
7
 
265 
 Physical examination,  vital signs (included blood pressure),  blood count  and 
266 
biochemistry every three weeks, before every administration of bevacizumab.  . 
267 
 CEA and Ca19.9,  ECG,  QoL and  thoracic and abdomen CT scan every three 
268 
months. 
269 
 Bloods samples for CEC and CEP counts, evaluation of cytochine and circulating 
270 
angiogenic factors plasma levels and miRNA, will be collected at progression of 
271 
disease  
272 
 Anyone tests that the Researcher will believe clinically indicated 
273 
 
274 
During the follow-up after the progression disease   
275 
 Physical examination, evaluation of  vital signs  and registration of any medical 
276 
treatment every three months. 
277 
 
278 
 
279 
Toxicity evaluation criteria 
280 
 
281 
Toxicity will be graded according to the Common Terminology Criteria for Adverse 
282 
Events (CTCAE) of the National Cancer Institute, version 4.0, June 14, 2010  (see 
283 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_ 2010-06-14_QuickReference_ 5x7.pdf). 
284 
 
285 
Response evaluation criteria 
286 
          Response evaluation will be performed at weeks 12 and 24, after the onset of the 
287 
trial, and every 3 months thereafter, until disease progression, with the following 
288 
examination : 
289 
 
290 
-CT scan of chest, abdomen and pelvis   
291 
-CEA, CA 19.9 
292 
-Any other tests positive results during staging 
293 
 
294 
Objective response will be categorized according to Response Evaluation Criteria in 
295 
Solid Tumors (RECIST) v. 1.1.  An independent blinded central review of radiologic 
296 
examinations will be performed.  
297 
 
298 
Registration and data collection procedures  
299 
 
300 
Web-based procedures for registration, randomization and data collection will be 
301 
centralized through the Clinical Trials Unit of the NCI of Naples (http://www.usc-
302 
intnapoli.net). Biological data collection will be done centrally at the Experimental 
303 
Pharmacology Unit  of the NCI of Naples. Randomization will be performed with a 
304 
minimization procedure that will account for the following parameters as strata: center, 
305 
performance status (0 vs 1), previous chemotherapy for advanced disease (yes vs no) and 
306 
number of metastatic sites (1 vs more). 
307 
Statistical analysis 
308 
All analyses will be performed according to an intention to treat strategy 
309 
 
310 

Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme - OBELICS trial  
Randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in 
the treatment of patients with metastatic colorectal cancer. 
 
OBELICS  
Version n.1.0  
October 2011 
 
National Cancer Institute of Naples  
www.usc-intnapoli.net  
Tel 0815903571 - fax  0817702938 
 
8
 
311 
Objective Response rate (RR) 
312 
RR is defined as the number of complete plus partial response divided by the total 
313 
of patients enrolled in each comparison arm. Objective RR will be described by 2x2 
314 
contingency tables and statistical significance of the possible difference will be estimated 
315 
by chi-square test. The difference between RR in the two arms will be estimated with 95% 
316 
confidence  interval. 
317 
 
318 
Progression Free Survival  (PFS) 
319 
           PFS is defined as the time from randomization to the date of progression, the date of 
320 
death without progression or  the date of the last follow-up information available (for patients 
321 
losT before the trial end date), whichever occurred first. Curves will be drawn with the 
322 
Kaplan-Meier product-limit method. Statistical significance will be calculated by  a model of 
323 
multivariable analysis considering stratification factors as covariates. 
324 
 
325 
Overall Survival  (OS) 
326 
OS is defined as the time from randomization to the date of death or the date of termination 
327 
of the trial (for patients alive at the time end of the study), or the date of the last follow-up 
328 
information available (for patients loss before the trial end date). Curves will be drawn with 
329 
the Kaplan-Meier product-limit method. Statistical significance will be calculated by  a model 
330 
of multivariable analysis considering stratification factors as covariates. 
331 
Toxicity 
332 
For each patient and type of toxicity, the worst degree suffered during the treatment 
333 
will be describe. Patients who will have not received assigned treatment will be excluded. 
334 
Statistical analysis will be performed by contingency tables and statistical significance of 
335 
the possible differences between the treatment groups will be calculated with a linear 
336 
permutation test accounting for ordinal nature of data (linear rank test). 
337 
 
338 
Administrative aspects 
339 
 
340 
The trial is a multicentre, independent investigator-initiated study; it is supported by 
341 
a grant of  the Ministry of Health (RF-2009-1539464). NCI of Naples will take out insurance 
342 
coverage for trial participants.   
343 
 
344 
Drugs on study 
345 
 
346 
All drugs are approved by the Italian National Health Service for the treatment of 
347 
metastatic colorectal cancer patients. 
348 
 
349