Conditions: Colorectal Cancer
Keywords: colorectal cancer advanced metastatic KRAS biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN) cetuximab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 221
Healthy volunteers: no

Brief summary:
Advanced colorectal cancer (ACRC) is a heterogeneous disease and classification of patients is nowadays inefficient. Roughly twenty per cent of patients present with favorable figures (less than 4 liver nodules and less than 5 cm) and are suitable for local treatments (surgery or local-ablative therapies). Additionally, 10-15% of patients have poor performance status (PS \>2) or are severe disabled due to geriatric syndromes or/and co-morbid diseases that preclude any treatment strategies than best supportive care alone. The rest of patients (fit patients not suitable for radical treatments) constitute the population of patients treated with palliative therapies. Despite of it not all these patients have the same prognosis. Patients with PS 0,1 and levels of LDH \<ULN (Intermediate-risk patients) have better PFS and OS irrespective of therapy in all randomized clinical trials (de Gramont et al, JCO 2000; Douillard et al, Lancet 2000; Koopman et al, 2007).

CRYSTAL trial shows a benefit in PFS (1.5 months) in RASWT of FOLFIRI plus cetuximab compared with FOLFIRI alone. Nowadays the selection of patients for cetuximab treatment is based on mutational status of KRAS, which allow to select those patients who will not respond to therapy. Other surrogate markers of activity should be also evaluated. Our hypothesis is that the suggested biomarkers will allow the selection of the patients who will benefit the most from the biweekly cetuximab treatment.

Detailed description:

Arms:
arm 1: FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.

Interventions: intervention 1: FOLFIRI (m) intervention 2: FOLFOX-6 (m) intervention 3: Cetuximab
Intervention descriptions: intervention 1: FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:

* Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
* l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.
* One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
* 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. intervention 2: FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:

* Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
* l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1.
* One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
* 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours. intervention 3: \- 500 mg/m2 i.v. Every 2 weeks.

Protocol document:
Prot_000.pdf: 
‌ 
‌ 
‌ 
Trial‌‌title:‌‌Prospective,‌‌multicenter,‌‌single-arm‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌validation‌‌in‌‌
 
 
 
 
 
   
 
 
 
 
 
 
patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌KRAS‌‌gene‌‌not‌‌mutated‌‌treated‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
with‌ ‌chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy.‌ ‌ 
‌ 
Protocol‌ ‌Code:‌ ‌GEMCAD-1002‌ ‌ 
‌ 
EudaCT‌ ‌Number:‌ ‌2010-019236-12‌ ‌ 
‌ 
Acronym:‌ ‌POSIBA‌ ‌ 
‌ 
Sponsor:‌ ‌ 
Grupo‌ ‌Español‌ ‌Multidisciplinar‌ ‌en‌ ‌Cáncer‌ ‌Digestivo‌ ‌(GEMCAD)‌ ‌ 
Ronda‌ ‌General‌ ‌Mitre‌ ‌200,‌ ‌entresuelo‌ ‌3ª‌ ‌ 
08006‌ ‌–‌ ‌Barcelona‌ ‌
 
Correo‌ ‌electrónico:‌ ‌secretaria@gemcad.org‌ ‌ 
Teléfono:‌ ‌+‌ ‌34‌ ‌93‌ ‌434‌ ‌44‌ ‌12‌ ‌ 
Fax:‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
Dr.‌ ‌Jesús‌ ‌García‌ ‌Foncillas‌
Dr.‌ ‌Joan‌ ‌Maurel‌ ‌Santasusana‌ ‌ 
Coordinador‌ ‌del‌ ‌Ensayo‌
Presidente‌ ‌GEMCAD‌ ‌ 
‌ 
‌ 
Confidentiality‌ ‌statement‌ ‌ 
This‌ ‌document‌ ‌contains‌ ‌confidential‌ ‌information‌ ‌of‌ ‌the‌ ‌GEMCAD‌ ‌group‌ ‌that‌ ‌should‌ ‌not‌ ‌be‌ ‌disclosed‌ ‌to‌ ‌anyone‌ ‌other‌ ‌than‌ ‌the‌ ‌study‌‌ 
staff‌ ‌and‌ ‌members‌ ‌of‌ ‌the‌ ‌Clinical‌ ‌Research‌ ‌Ethics‌ ‌Committee‌ ‌/‌ ‌Institutional‌ ‌Review‌ ‌Committee‌ ‌(IEC‌ ‌/‌ ‌IRB).‌ ‌This‌ ‌information‌ ‌may‌‌ 
not‌ ‌be‌ ‌used‌ ‌for‌ ‌any‌ ‌purpose‌ ‌other‌ ‌than‌ ‌the‌ ‌evaluation‌ ‌or‌ ‌conduct‌ ‌of‌ ‌clinical‌ ‌research‌ ‌without‌ ‌the‌ ‌prior‌ ‌written‌ ‌consent‌ ‌of‌ ‌GEMCAD.‌ ‌ 
‌ ‌
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Coordinating‌ ‌Investigator:‌ ‌
 
‌ 
‌
 
‌ 
Nombre:‌ ‌Dr.‌ ‌Jesús‌ ‌García‌ ‌Foncillas‌ ‌ 
Servicio‌ ‌de‌ ‌Oncología‌‌ ‌
  
Clínica‌ ‌Universitaria‌ ‌de‌ ‌Navarra‌ ‌ 
Dirección:‌ ‌Avda.‌ ‌Pio‌ ‌XII‌ ‌36‌ ‌ 
31008‌ ‌–‌ ‌Pamplona‌‌ ‌
  
Teléfono:+‌ ‌34‌ ‌94‌ ‌825‌ ‌54‌ ‌00‌ ‌ 
Fax:‌ ‌+‌ ‌34‌  ‌94‌ ‌825‌ ‌55‌ ‌00‌ ‌ 
Correo‌ ‌electrónico:‌ ‌jgfoncillas@unav.es‌ ‌ 
Co-coordinating‌ ‌Investigator:‌ ‌
 
‌ 
‌
 
‌ 
Nombre:‌ ‌Dr.‌ ‌Xabier‌ ‌García-Albeniz‌ ‌ 
Servicio‌ ‌de‌ ‌Oncología‌‌ ‌
  
Hospital‌ ‌Clínic‌ ‌de‌ ‌Barcelona‌‌ ‌
  
Dirección:‌ ‌Villarroel‌ ‌170‌‌ ‌
  
08036‌ ‌-‌ ‌Barcelona‌‌ ‌
  
Teléfono:+‌ ‌34‌ ‌93‌ ‌227‌ ‌54‌ ‌02‌ ‌ 
Fax:‌ ‌+‌ ‌34‌  ‌93‌ ‌227‌ ‌65‌ ‌20‌ ‌ 
Correo‌ ‌electrónico:‌ ‌xagarcia@clinic.ub.es‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
1‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Investigator‌ ‌acceptance‌ ‌ 
‌ 
I‌‌have‌‌read‌‌the‌‌attached‌‌protocol‌‌entitled‌‌“Prospective,‌‌multicenter,‌‌single-arm‌‌phase‌‌II‌‌clinical‌‌trial‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
for‌‌validation‌‌of‌‌biomarkers‌‌in‌‌patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌ ‌with‌ ‌chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy”.‌ ‌ 
‌ 
I‌‌agree‌‌to‌‌abide‌‌by‌‌the‌‌Guidelines‌‌for‌‌Good‌‌Clinical‌‌Practice‌‌of‌‌the‌‌International‌‌Conference‌‌on‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tripartite‌ ‌Harmonization‌ ‌and‌ ‌all‌ ‌applicable‌ ‌regulations‌ ‌/‌ ‌guidelines.‌ ‌ 
‌ 
I‌‌agree‌‌to‌‌guarantee‌‌that‌‌the‌‌confidential‌‌information‌‌contained‌‌in‌‌this‌‌document‌‌will‌‌not‌‌be‌‌used‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
for‌‌any‌‌purpose‌‌other‌‌than‌‌the‌‌evaluation‌‌and‌‌conduct‌‌of‌‌clinical‌‌research‌‌without‌‌the‌‌prior‌‌written‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consent‌ ‌of‌ ‌the‌ ‌trial‌ ‌sponsor.‌ ‌ 
‌ 
‌ 
‌ 
Signature‌ ‌ 
‌ 
‌ 
Name‌ ‌of‌ ‌Principal‌ ‌Investigator‌ ‌ 
Principal‌ ‌Investigator‌ ‌site‌ ‌ 
Date‌‌ ‌
  
‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
2‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
1.‌ ‌Summary‌ 
‌ 
Title:‌‌Prospective,‌‌multicenter,‌‌single-arm‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌validation‌‌in‌‌patients‌‌
 
 
 
 
   
 
 
 
 
   
 
with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌with‌ ‌KRAS‌ ‌gene‌ ‌not‌ ‌mutated‌ ‌treated‌‌with‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy.‌ ‌ 
‌ 
Study‌ ‌Phase:‌ ‌Phase‌ ‌II‌ ‌ 
‌ 
Indication:‌‌ ‌
  
‌ 
Advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌(CCRA)‌ ‌ 
‌ 
Principal‌ ‌Objective:‌ ‌ 
‌ 
Validation‌ ‌of‌ ‌the‌ ‌biomarkers‌ ‌BRAF,‌ ‌IGF1P‌ ‌/‌ ‌MMp7‌ ‌(DP)‌ ‌and‌ ‌PI3K-PTEN‌ ‌to‌ ‌predict‌ ‌PFS‌ ‌in‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌non-mutated‌‌KRAS‌‌treated‌‌with‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
standard‌ ‌chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy.‌ ‌ 
‌ 
Secondary‌ ‌Objectives:‌ ‌ 
‌ 
Secondary‌‌biological‌‌markers‌‌(MMP-7,‌‌IGF-1‌‌and‌‌IGFBP3)‌‌will‌‌be‌‌analyzed‌‌in‌‌serum‌‌and‌‌tumor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tissue‌ ‌to‌ ‌predict‌ ‌acquired‌ ‌resistance.‌ ‌ 
OS‌ ‌based‌ ‌on‌ ‌proposed‌ ‌classification‌ ‌ 
Objective‌ ‌response‌ ‌according‌ ‌to‌ ‌RECIST‌ ‌1.1‌ ‌(‌E.J.‌ ‌Cáncer‌ ‌2009;‌ ‌228-47‌)‌ ‌ 
Safety‌ ‌of‌ ‌administration‌ ‌of‌ ‌cetuximab‌ ‌500‌ ‌mg‌ ‌/‌ ‌m2‌ ‌every‌ ‌2‌ ‌weeks.‌ ‌ 
‌ 
Clinical‌ ‌Hypothesis:‌ ‌ 
‌ 
Our‌‌hypothesis‌‌is‌‌that‌‌the‌‌proposed‌‌markers‌‌will‌‌make‌‌it‌‌possible‌‌to‌‌select‌‌those‌‌patients‌‌who‌‌will‌‌
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
benefit‌ ‌the‌ ‌most‌ ‌from‌ ‌biweekly‌ ‌cetuximab‌ ‌treatment.‌ ‌ 
‌ 
Study‌ ‌design:‌ ‌ 
‌ 
Single-arm‌ ‌prospective‌ ‌phase‌ ‌II‌ ‌clinical‌ ‌trial.‌ ‌ 
‌ 
Prior‌‌to‌‌inclusion‌‌in‌‌the‌‌trial‌‌and‌‌to‌‌confirm‌‌eligibility,‌‌the‌‌investigator‌‌or‌‌designee‌‌will‌‌review‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
status‌ ‌of‌ ‌KRAS,‌ ‌BRAF,‌ ‌IGF1P‌ ‌/‌ ‌MMP7‌ ‌(DP)‌ ‌and‌‌PI3K-PTEN,‌‌existing‌‌radiological‌‌images‌‌in‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
addition‌‌to‌‌any‌‌other‌‌relevant‌‌clinical‌‌documents‌‌(‌‌reports,‌‌notes,‌‌etc.)‌‌to‌‌confirm‌‌that‌‌the‌‌subject‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
has‌ ‌previously‌ ‌untreated‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌ 
‌ 
FOLFIRI‌ ‌(m)‌ ‌/‌ ‌FOLFOX6‌ ‌(m)‌ ‌will‌ ‌be‌ ‌administered‌ ‌once‌ ‌every‌ ‌2‌ ‌weeks‌ ‌until‌ ‌6‌ ‌months‌ ‌of‌‌
 
   
 
 
 
 
 
 
   
 
   
 
 
treatment,‌‌disease‌‌progression‌‌(PE),‌‌or‌‌unacceptable‌‌toxicity.‌‌Cetuximab‌‌will‌‌be‌‌administered‌‌every‌‌
 
 
 
 
 
 
 
 
 
 
 
 
2‌‌weeks‌‌until‌‌disease‌‌progression.‌‌If‌‌patients‌‌do‌‌not‌‌show‌‌progression‌‌after‌‌6‌‌months‌‌of‌‌treatment‌‌
 
 
 
 
   
 
 
 
 
 
   
 
 
 
with‌ ‌FOLFIRI‌ ‌(m)‌ ‌and‌ ‌FOLFOX6‌ ‌(m),‌ ‌they‌ ‌will‌ ‌continue‌ ‌to‌ ‌receive‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
monotherapy‌ ‌until‌ ‌progression.‌ ‌ 
‌ 
Subjects‌ ‌who‌ ‌stop‌ ‌receiving‌ ‌FOLFOX6‌ ‌(m)‌ ‌/‌ ‌FOLFIRI‌ ‌(m),‌ ‌for‌ ‌example‌ ‌due‌ ‌to‌ ‌toxicity,‌ ‌may‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
receive‌‌biweekly‌‌cetuximab‌‌as‌‌monotherapy‌‌until‌‌disease‌‌progression.‌‌Following‌‌discontinuation‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
biweekly‌‌cetuximab,‌‌the‌‌treatment‌‌period‌‌will‌‌end‌‌and‌‌subjects‌‌will‌‌attend‌‌a‌‌follow-up‌‌safety‌‌visit‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
3‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
30‌ ‌±‌ ‌3‌ ‌days‌ ‌later.‌ ‌ 
‌ 
Throughout‌‌the‌‌trial,‌‌subjects‌‌will‌‌undergo‌‌tumor‌‌response‌‌assessment‌‌(using‌‌the‌‌revised‌‌[RECIST‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
1.1]‌ ‌Solid‌ ‌Tumor‌ ‌Response‌ ‌Assessment‌ ‌Criteria)‌ ‌every‌ ‌12‌ ‌weeks‌ ‌(three‌ ‌months)‌ ‌until‌ ‌disease‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
progression.‌‌In‌‌subjects‌‌with‌‌symptoms‌‌that‌‌indicate‌‌disease‌‌progression,‌‌tumor‌‌response‌‌should‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
assessed‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌ ‌symptoms.‌ ‌ 
‌ 
Biologic‌ ‌study‌ ‌ 
‌ 
K-RAS,‌ ‌in‌ ‌patients‌‌who‌‌do‌‌not‌‌have‌‌a‌‌determination,‌‌and‌‌other‌‌markers‌‌of‌‌tumor‌‌tissue‌‌will‌‌be‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
measured‌ ‌at‌ ‌the‌‌Navarra‌‌University‌‌Clinic‌‌(CUN)‌‌and‌‌the‌‌markers‌‌of‌‌the‌‌blood‌‌samples‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
measured‌ ‌at‌ ‌the‌ ‌Hospital‌ ‌Clínic‌ ‌de‌ ‌Barcelona‌ ‌(HCB).‌ ‌ 
Biomarkers‌ ‌will‌ ‌be‌ ‌measured‌ ‌prior‌ ‌to‌ ‌patient‌ ‌enrollment.‌ ‌In‌ ‌addition,‌ ‌blood‌ ‌samples‌ ‌will‌ ‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
collected‌ ‌every‌ ‌3‌ ‌months‌ ‌until‌ ‌disease‌ ‌progression.‌ ‌ 
‌ 
Endpoints:‌ ‌ 
‌ 
Principal‌ ‌endpoint:‌ ‌ 
‌ 
The‌ ‌main‌ ‌endpoint‌ ‌is‌ ‌progression-free‌ ‌survival‌ ‌comparing‌ ‌two‌ ‌cohorts,‌ ‌which‌ ‌will‌ ‌be‌ ‌defined‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
according‌ ‌to‌ ‌the‌ ‌classification‌ ‌based‌ ‌on‌ ‌the‌ ‌predictive‌ ‌capacity‌ ‌of‌ ‌the‌ ‌response‌ ‌of‌ ‌the‌ ‌biomarkers.‌ ‌ 
‌ 
Secondary‌ ‌endpoint:‌ ‌ 
‌ 
Secondary‌ ‌biological‌ ‌markers‌ ‌in‌ ‌serum‌ ‌and‌ ‌tumor‌ ‌tissue‌ ‌will‌ ‌be‌ ‌analyzed‌ ‌to‌ ‌predict‌ ‌acquired‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
resistance.‌ ‌ 
OS‌ ‌based‌ ‌on‌ ‌proposed‌ ‌classification‌ ‌ 
Objective‌ ‌response‌ ‌according‌ ‌to‌ ‌RECIST‌ ‌1.1‌ ‌(‌E.J.‌ ‌Cancer‌ ‌2009;‌ ‌228-47‌)‌ ‌(objective‌ ‌response‌ ‌rate)‌ ‌ 
Response‌ ‌duration‌ ‌ 
Safety‌ ‌(Type,‌ ‌frequency‌ ‌and‌ ‌intensity‌ ‌of‌ ‌appearance‌ ‌of‌ ‌Adverse‌ ‌Events)‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
4‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Sample‌ ‌size:‌ ‌ 
‌ 
A‌ ‌sample‌ ‌size‌ ‌of‌ ‌170‌ ‌patients‌ ‌will‌ ‌be‌ ‌needed.‌ ‌ 
‌ 
Principal‌ ‌Inclusion‌ ‌Criteria:‌ ‌ 
‌ 
Patients,‌‌men‌‌or‌‌women‌‌aged‌‌18‌‌years‌‌or‌‌older,‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
with‌ ‌non-mutated‌ ‌KRAS,‌ ‌histologically‌ ‌or‌ ‌cytologically‌‌confirmed‌‌and‌‌radiologically‌‌evaluable,‌‌
 
 
 
 
 
 
 
 
 
 
ECOG‌‌performance‌‌status‌‌of‌‌0‌‌to‌‌2‌‌with‌‌adequate‌‌hematological,‌‌renal‌‌and‌‌hepatic‌‌function‌‌and‌‌
 
 
 
   
   
 
 
 
 
 
 
 
 
informed‌ ‌consent‌ ‌signed.‌ ‌ 
‌ 
Ver‌ ‌listado‌ ‌completo‌ ‌de‌ ‌Criterios‌ ‌de‌ ‌Inclusión‌ ‌en‌ ‌el‌ ‌apartado‌ ‌6.1‌ ‌del‌ ‌protocolo‌ ‌ 
‌ 
Principal‌ ‌Exclusion‌ ‌Criteria:‌ ‌ 
‌ 
Patients‌ ‌who‌ ‌have‌ ‌received‌ ‌prior‌ ‌systemic‌ ‌treatment‌ ‌for‌‌metastatic‌‌colorectal‌‌carcinoma‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
excluded‌ ‌from‌ ‌the‌ ‌trial.‌ ‌Patients‌ ‌with‌ ‌previous‌ ‌surgery‌ ‌for‌ ‌metastases‌ ‌(liver,‌ ‌lung‌ ‌or‌ ‌other),‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases‌ ‌in‌ ‌the‌ ‌central‌ ‌nervous‌ ‌system‌ ‌or‌ ‌with‌ ‌significant‌ ‌cardiovascular‌ ‌disease‌‌will‌‌also‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
excluded.‌ ‌ 
‌ 
Ver‌ ‌listado‌ ‌completo‌ ‌de‌ ‌Criterios‌ ‌de‌ ‌Exclusión‌ ‌en‌ ‌el‌ ‌apartado‌ ‌6.2‌ ‌del‌ ‌protocolo‌ ‌ 
‌ 
Dosage‌ ‌and‌ ‌administration‌ ‌of‌ ‌the‌ ‌investigational‌ ‌product:‌ ‌ 
‌ 
FOLFOX6‌ ‌(m)‌ ‌chemotherapy‌ ‌regimen:‌ ‌ 
‌ 
FOLFOX6‌‌(m)‌‌chemotherapy‌‌will‌‌be‌‌given‌‌on‌‌day‌‌1‌‌of‌‌each‌‌14-day‌‌treatment‌‌cycle.‌‌FOLFOX6‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
(m)‌ ‌will‌ ‌be‌ ‌administered‌ ‌at‌ ‌the‌ ‌following‌ ‌doses:‌ ‌ 
‌ 
85‌ ‌mg‌ ‌/‌ ‌m2‌ ‌of‌ ‌oxaliplatin‌ ‌infusion‌ ‌i.v.‌ ‌120‌ ‌minutes‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle.‌ ‌ 
400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌leucovorin‌ ‌infusion‌ ‌i.v.‌ ‌120‌ ‌minutes‌ ‌on‌ ‌day‌ ‌1.‌ ‌ 
One‌ ‌i.v.‌ ‌bolus‌ ‌(2‌ ‌to‌ ‌4‌ ‌minutes)‌ ‌of‌ ‌400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌5-FU‌ ‌on‌ ‌day‌ ‌1.‌ ‌ 
5-FU‌ ‌in‌ ‌continuous‌ ‌infusion‌ ‌2400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌administered‌‌by‌‌ambulatory‌‌pump‌‌over‌‌a‌‌period‌‌of‌‌
 
 
 
 
 
   
 
 
 
 
 
   
 
 
46-48‌ ‌hours‌ ‌ 
‌ 
FOLFIRI‌ ‌(m):‌ ‌ 
‌ 
FOLFIRI‌ ‌(m)‌ ‌chemotherapy‌ ‌will‌ ‌be‌ ‌administered‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each‌ ‌14-day‌ ‌treatment‌ ‌cycle.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFIRI‌ ‌(m)‌ ‌will‌ ‌be‌ ‌administered‌ ‌at‌ ‌the‌ ‌following‌ ‌doses:‌ ‌ 
‌ 
Irinotecan‌ ‌180‌ ‌mg‌ ‌/‌ ‌m2‌ ‌in‌ ‌infusion‌ ‌i.v.‌ ‌120‌ ‌minutes‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle.‌ ‌ 
Leucovorin‌ ‌200‌ ‌mg‌ ‌/‌ ‌m2,‌ ‌in‌ ‌infusion‌ ‌i.v.‌ ‌120‌ ‌minutes‌ ‌on‌ ‌day‌ ‌1.‌ ‌ 
One‌ ‌i.v.‌ ‌bolus‌ ‌(2‌ ‌to‌ ‌4‌ ‌minutes)‌ ‌of‌ ‌400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌5-FU‌ ‌on‌ ‌day‌ ‌1.‌ ‌ 
5-FU‌ ‌in‌ ‌continuous‌ ‌infusion‌ ‌2400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌administered‌‌by‌‌ambulatory‌‌pump‌‌over‌‌a‌‌period‌‌of‌‌
 
 
 
 
 
   
 
 
 
 
 
   
 
 
46-48‌ ‌hours.‌ ‌ 
‌ 
CETUXIMAB:‌ ‌ 
‌ 
Administer‌ ‌500‌ ‌mg‌ ‌/‌ ‌m2‌ ‌i.v.‌ ‌every‌ ‌2‌ ‌weeks.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
5‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
It‌‌is‌‌recommended‌‌to‌‌administer‌‌cetuximab‌‌first‌‌and‌‌start‌‌with‌‌the‌‌administration‌‌of‌‌FOLFOX6‌‌(m)‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
/‌ ‌FOLFIRI‌ ‌(m),‌ ‌at‌ ‌least‌ ‌one‌ ‌hour‌ ‌after‌ ‌cetuximab‌ ‌administration‌ ‌has‌ ‌ended.‌ ‌ 
‌ 
Statistical‌ ‌considerations:‌ ‌ 
‌ 
Prospective,‌ ‌multicenter,‌ ‌phase‌ ‌II‌ ‌clinical‌ ‌trial‌ ‌designed‌ ‌for‌ ‌the‌ ‌validation‌ ‌of‌ ‌predictive‌ ‌tumor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarkers‌‌in‌‌patients‌‌with‌‌metastatic‌‌colorectal‌‌cancer‌‌and‌‌tumor‌‌with‌‌non-mutated‌‌KRAS,‌‌treated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
with‌ ‌chemotherapy‌ ‌and‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌treatment.‌ ‌ 
The‌ ‌main‌ ‌objective‌ ‌of‌ ‌this‌ ‌trial‌ ‌is‌ ‌to‌ ‌validate‌ ‌the‌ ‌biomarkers‌ ‌BRAF,‌ ‌IGF1P‌ ‌/‌‌MMp7‌‌(DP)‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
PI3K-PTEN‌ ‌to‌ ‌predict‌ ‌PFS‌ ‌in‌ ‌patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
non-mutated‌‌KRAS‌‌treated‌‌with‌‌standard‌‌chemotherapy‌‌plus‌‌biweekly‌‌cetuximab‌‌as‌‌therapy.‌‌From‌‌
 
 
 
 
 
 
 
 
 
 
 
 
first‌ ‌line.‌ ‌ 
Two‌‌groups‌‌will‌‌be‌‌defined‌‌based‌‌on‌‌the‌‌classification‌‌constructed‌‌from‌‌the‌‌clinical‌‌variables‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌proposed‌ ‌biomarkers.‌ ‌ 
A‌‌minimum‌‌difference‌‌of‌‌20%‌‌(60‌‌vs.‌‌40%)‌‌in‌‌PFS‌‌is‌‌expected‌‌at‌‌12‌‌months‌‌between‌‌groups‌‌and‌
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
with‌ ‌the‌ ‌following‌ ‌assumptions:‌ ‌ 
‌ 
Alpha‌ ‌error‌ ‌(bilateral):‌ ‌5%‌ ‌ 
Beta‌ ‌error:‌ ‌20%‌ ‌ 
‌ 
The‌‌number‌‌of‌‌patients‌‌required‌‌is‌‌155‌‌patients.‌‌Assuming‌‌10%‌‌non-evaluable‌‌patients,‌‌a‌‌total‌‌of‌‌
 
 
 
 
   
 
 
 
 
 
   
 
 
170‌ ‌patients‌ ‌will‌ ‌be‌ ‌included.‌ ‌ 
‌ 
The‌‌Cox‌‌regression‌‌analysis‌‌will‌‌be‌‌performed‌‌with‌‌the‌‌experimental‌‌biomarkers‌‌and‌‌the‌‌following‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prognostic‌ ‌variables‌ ‌(LDH,‌ ‌functional‌ ‌status,‌ ‌age,‌ ‌limited‌ ‌resectable‌ ‌disease‌ ‌(<3‌ ‌nodules‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
<5cm).‌ ‌A‌ ‌classification‌ ‌will‌ ‌be‌ ‌performed‌ ‌using‌ ‌the‌ ‌most‌ ‌discriminatory‌ ‌variables.‌ ‌The‌‌
 
 
 
 
 
 
 
 
 
 
 
 
classification‌‌It‌‌will‌‌be‌‌carried‌‌out‌‌with‌‌all‌‌the‌‌clinical‌‌variables‌‌of‌‌impact‌‌in‌‌the‌‌univariate‌‌analysis‌‌
   
 
 
 
 
 
 
 
 
 
 
   
 
 
 
including‌‌the‌‌4‌‌clinical‌‌variables‌‌(LDH,‌‌functional‌‌status,‌‌age,‌‌limited‌‌resectable‌‌disease‌‌<3‌‌nodules‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌<5‌ ‌cm)‌ ‌and‌ ‌the‌ ‌3‌ ‌pathways‌ ‌previously‌ ‌described‌ ‌(BRAF,‌ ‌DP‌ ‌and‌ ‌PTEN-‌ ‌PI3K)‌ ‌.The‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
classification‌ ‌will‌ ‌be‌ ‌carried‌ ‌out‌ ‌with‌ ‌the‌ ‌variables‌ ‌with‌ ‌the‌ ‌greatest‌ ‌impact‌ ‌in‌‌the‌‌multivariate‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
analysis.‌ ‌ 
The‌ ‌proposed‌ ‌sample‌ ‌size‌ ‌ensures‌ ‌the‌ ‌construction‌ ‌of‌ ‌a‌ ‌consistent‌ ‌multivariate‌ ‌analysis.‌ ‌ 
‌ 
The‌‌analysis‌‌of‌‌the‌‌main‌‌variable‌‌“progression-free‌‌survival‌‌comparing‌‌two‌‌cohorts,‌‌which‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
defined‌ ‌according‌ ‌to‌ ‌the‌ ‌classification‌ ‌based‌ ‌on‌ ‌the‌ ‌prediction‌ ‌capacity‌ ‌of‌ ‌the‌ ‌response‌ ‌of‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarkers”‌‌and‌‌the‌‌secondary‌‌variable‌‌“efficacy”,‌‌will‌‌be‌‌based‌‌on‌‌the‌‌revised‌‌version‌‌of‌‌RECIST‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.1‌ ‌criteria‌ ‌(Appendix‌ ‌E)‌ ‌for‌ ‌the‌ ‌intention-to-treat‌ ‌analysis‌ ‌group.‌ ‌ 
‌ 
Changes‌ ‌in‌ ‌laboratory‌ ‌values‌ ‌​and‌ ‌vital‌ ‌signs‌ ‌will‌ ‌be‌ ‌summarized‌ ‌with‌ ‌descriptive‌ ‌statistics.‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
6‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Sponsor:‌‌ ‌
  
‌ 
Grupo‌ ‌Español‌ ‌Multidisciplinar‌ ‌en‌ ‌Cáncer‌ ‌Digestivo‌ ‌(GEMCAD)‌ ‌ 
Ronda‌ ‌General‌ ‌Mitre‌ ‌200,‌ ‌entresuelo‌ ‌3ª‌ ‌ 
08006‌ ‌–‌ ‌Barcelona‌ ‌ 
Tel:‌ ‌+‌ ‌34‌ ‌93‌ ‌434‌ ‌44‌ ‌12‌ ‌ 
FAX:‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68‌ ‌ 
e-mail:‌ ‌secretaria@gemcad.org‌ ‌ 
‌ 
Name‌ ‌of‌ ‌the‌ ‌Organization‌ ‌responsible‌ ‌for‌ ‌Monitoring:‌‌ ‌
  
‌ 
Secretaría‌ ‌Técnica‌ ‌GEMCAD‌ ‌ 
Secretari‌ ‌Coloma,‌ ‌64-68,‌ ‌esc.‌ ‌B‌ ‌entlo.‌ ‌5ª‌ ‌ 
08024‌ ‌Barcelona‌ ‌ 
Tel:‌ ‌+‌ ‌34‌ ‌93‌ ‌434‌ ‌44‌ ‌12‌ ‌ 
FAX:‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68‌ ‌ 
e-mail:‌ ‌secretaria@gemcad.org‌ ‌ 
‌ 
Schedule‌ ‌and‌ ‌expected‌ ‌completion‌ ‌date:‌ ‌ 
‌ 
Start‌ ‌date:‌ ‌Second‌ ‌quarter‌ ‌2010‌ ‌ 
First‌ ‌Inclusion‌ ‌Date:‌ ‌Fourth‌ ‌quarter‌ ‌2010‌ ‌ 
Recruitment‌ ‌period:‌ ‌24‌ ‌months‌ ‌ 
End‌ ‌of‌ ‌Trial‌ ‌Period:‌ ‌Year‌ ‌2014‌ ‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
7‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Study‌ ‌scheme‌ ‌ 
‌ ‌
  
‌ 
‌ 
a‌ ‌Day‌ ‌1‌ ‌=‌ ‌day‌ ‌of‌ ‌the‌ ‌first‌ ‌treatment‌ ‌administration.‌ ‌ 
b‌‌Subjects'‌‌tumor‌‌response‌‌will‌‌be‌‌assessed‌‌every‌‌12‌‌weeks,‌‌throughout‌‌the‌‌trial‌‌until‌‌PE‌‌(per‌‌revised‌‌RECIST‌‌1.1‌‌criteria)‌‌or‌‌withdrawal‌‌from‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study.‌ ‌ 
c‌ ‌Subsequent‌ ‌cycles‌ ‌could‌ ‌be‌ ‌delayed‌ ‌due‌ ‌to‌ ‌toxicities‌ ‌associated‌ ‌with‌ ‌cetuximab‌ ‌or‌ ‌chemotherapy.‌ ‌ 
d‌ ‌All‌ ‌subjects‌ ‌who‌ ‌permanently‌ ‌discontinue‌ ‌treatment‌ ‌(discontinuation‌ ‌is‌ ‌considered‌ ‌completion‌ ‌of‌ ‌all‌‌treatment)‌‌for‌‌any‌‌reason‌‌will‌‌undergo‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
follow-up‌‌safety‌‌assessment‌‌30‌‌days‌‌±‌‌3‌‌days‌‌after‌‌the‌‌last‌‌dose‌‌of‌‌treatment.‌‌After‌‌the‌‌safety‌‌follow-up‌‌visit,‌‌subjects‌‌who‌‌have‌‌not‌‌progressed‌‌will‌‌
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be‌‌followed‌‌up‌‌every‌‌12‌‌weeks‌‌as‌‌defined‌‌in‌‌the‌‌study.‌‌Subjects‌‌who‌‌undergo‌‌surgery‌‌for‌‌metastases‌‌should‌‌follow‌‌the‌‌controls‌‌every‌‌12‌‌weeks‌‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
established‌ ‌in‌ ‌the‌ ‌protocol.‌ ‌In‌ ‌case‌ ‌of‌ ‌progression‌ ‌by‌ ‌RECIST‌ ‌1.1‌ ‌criteria‌ ‌,.‌ ‌Subjects‌ ‌will‌ ‌be‌ ‌monitored‌ ‌for‌ ‌disease‌ ‌status,‌ ‌subsequent‌ ‌cancer‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
treatment,‌ ‌and‌ ‌survival‌ ‌(long-term‌ ‌follow-up).‌ ‌ 
e‌ ‌All‌ ‌subjects‌ ‌who‌ ‌discontinue‌ ‌treatment‌ ‌prior‌ ‌to‌ ‌disease‌ ‌progression‌ ‌(eg,‌ ‌due‌ ‌to‌ ‌unacceptable‌ ‌toxicities)‌ ‌will‌ ‌be‌ ‌followed‌ ‌up‌ ‌for‌ ‌PFS‌ ‌(eg,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiographic‌‌tumor‌‌assessments)‌‌every‌‌12‌‌weeks‌‌until‌‌the‌‌progression‌‌of‌‌the‌‌disease‌‌or‌‌the‌‌end‌‌of‌‌the‌‌study‌‌(unless‌‌the‌‌reason‌‌for‌‌abandoning‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌ ‌was‌ ‌the‌ ‌total‌ ‌withdrawal‌ ‌of‌ ‌consent).‌ ‌ 
F.‌‌The‌‌end‌‌of‌‌treatment‌‌is‌‌understood‌‌to‌‌be‌‌the‌‌last‌‌day‌‌the‌‌patient‌‌has‌‌received‌‌the‌‌last‌‌drug‌‌of‌‌the‌‌combination‌‌under‌‌test‌‌(FOLFOX6‌‌(m)‌‌/‌‌FOLFIRI‌‌
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
(m)‌‌/‌‌Cetuximab).‌‌The‌‌safety‌‌visit‌‌should‌‌be‌‌carried‌‌out‌‌30‌‌±‌‌3‌‌days‌‌after‌‌the‌‌end‌‌of‌‌the‌‌treatment,‌‌regardless‌‌of‌‌the‌‌cause‌‌that‌‌caused‌‌it.‌‌If‌‌the‌‌patient‌‌
   
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
has‌ ‌not‌ ‌progressed,‌ ‌imaging‌ ‌and‌ ‌biomarker‌ ‌determinations‌ ‌should‌ ‌continue‌ ‌every‌ ‌12‌ ‌weeks‌ ‌until‌ ‌progression‌ ‌as‌ ‌specified‌ ‌in‌ ‌this‌ ‌protocol.‌ ‌ 
g.‌ ‌In‌ ‌order‌ ‌to‌ ‌mobilize‌ ‌any‌ ‌biological‌ ‌sample,‌ ‌the‌ ‌signing‌ ‌of‌ ‌the‌ ‌informed‌ ‌consent‌ ‌will‌ ‌be‌ ‌mandatory.‌ ‌If‌ ‌the‌ ‌patient‌ ‌already‌ ‌has‌ ‌a‌ ‌previous‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
determination‌ ‌of‌ ‌the‌ ‌status‌ ‌of‌ ‌the‌ ‌KRAS‌ ‌gene,‌ ‌he‌ ‌can‌‌be‌‌included‌‌in‌‌the‌‌test‌‌without‌‌it‌‌being‌‌necessary‌‌to‌‌re-determine‌‌the‌‌mutational‌‌status‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
K-RAS.‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
8‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
2.‌ ‌INDEX‌ ‌ 
‌
 
‌ 
 ‌1.‌ ‌SYNOPSIS‌
3‌ ‌ 
 ‌3.‌ ‌GENERAL‌ ‌INFORMATION‌‌ 
14‌ ‌ 
 ‌3.1‌ ‌Trial‌ ‌identification‌
14‌ ‌ 
 ‌3.2‌ ‌Clinical‌ ‌trial‌ ‌type‌
14‌ ‌ 
 ‌3.3‌ ‌Study‌ ‌product‌ ‌descriptions‌
14‌ ‌ 
 ‌3.4‌ ‌Sponsor‌ ‌data‌‌ 
14‌ ‌ 
 ‌3.5‌ ‌Coordinating‌ ‌investigator:‌
14‌ ‌ 
 ‌3.6‌ ‌Co-coordinating‌ ‌investigator:‌
15‌ ‌ 
 ‌3.7‌ ‌Monitor‌‌ 
15‌ ‌ 
 ‌3.8‌ ‌Sites‌
15‌ ‌ 
 ‌3.9‌ ‌Estimated‌ ‌duration‌ ‌of‌ ‌the‌ ‌trial‌
15‌ ‌ 
 ‌4.‌ ‌Rationale‌ ‌and‌ ‌objectives‌
16‌ ‌ 
 ‌4.1‌ ‌Colorrectal‌ ‌cancer‌
16‌ ‌ 
 ‌4.3.‌ ‌Previous‌ ‌experience‌ ‌and‌ ‌justification‌ ‌for‌ ‌the‌ ‌biweekly‌ ‌cetuximab‌ ‌regimen‌‌ 
21‌ ‌ 
 ‌4.4‌ ‌Justification‌ ‌of‌ ‌the‌ ‌biomarkers‌ ‌under‌ ‌study‌
24‌ ‌ 
 ‌4.5‌  ‌Trial‌ ‌rationale‌
26‌ ‌ 
 ‌4.6‌ ‌OBJECTIVES‌
27‌ ‌ 
 ‌4.6.1‌ ‌Principal‌ ‌objective‌
27‌ ‌ 
 ‌4.6.2‌ ‌Secondary‌ ‌objectives‌‌ 
27‌ ‌ 
 ‌5.‌ ‌EXPERIMENTAL‌ ‌PLAN‌‌ 
28‌ ‌ 
 ‌5.1‌ ‌Study‌ ‌design‌
28‌ ‌ 
 ‌5.2‌ ‌Number‌ ‌of‌ ‌sites‌
32‌ ‌ 
 ‌5.3‌ ‌Number‌ ‌of‌ ‌subjects‌
32‌ ‌ 
 ‌5.4‌ ‌Estimated‌ ‌duration‌ ‌of‌ ‌the‌ ‌trial‌
32‌ ‌ 
 ‌6.‌ ‌ELEGIBILITY‌ ‌OF‌ ‌SUBJECTS‌
33‌ ‌ 
 ‌6.1‌ ‌Inclusion‌ ‌criteria‌
33‌ ‌ 
 ‌6.2‌ ‌Exclusion‌ ‌criteria‌
33‌ ‌ 
 ‌6.3.‌ ‌Inclusion‌ ‌of‌ ‌subjects‌
35‌ ‌ 
 ‌6.4‌  ‌Treatment‌ ‌assignment‌
35‌ ‌ 
 ‌7.‌ ‌TREATMENT‌ ‌PROCEDURES‌
36‌ ‌ 
 ‌7.1.‌ ‌Dosage,‌ ‌Administration,‌ ‌and‌ ‌Biweekly‌ ‌Cetuximab‌ ‌Schedule‌
36‌ ‌ 
 ‌7.2.‌ ‌FOLFOX6‌ ‌(m)‌
44‌ ‌ 
 ‌7.3‌ ‌FOLFIRI‌ ‌(m)‌
50‌ ‌ 
 ‌7.4‌ ‌Concomitant‌ ‌treatments‌
54‌ ‌ 
 ‌7.5‌ ‌Prohibited‌ ‌treatments‌ ‌during‌ ‌the‌ ‌study‌ ‌period‌
55‌ ‌ 
 ‌8.‌ ‌STUDY‌ ‌PROCEDURES‌
56‌ ‌ 
 ‌8.1‌ ‌Selection‌
56‌ ‌ 
 ‌8.2‌ ‌Inclusion‌‌ 
57‌ ‌ 
 ‌8.3‌ ‌Treatment‌ ‌phase‌
57‌ ‌ 
 ‌8.4‌ ‌Safety‌ ‌follow-up‌ ‌visit‌
58‌ ‌ 
 ‌8.5.‌ ‌Visitas‌ ‌de‌ ‌seguimiento‌ ‌desde‌ ‌fin‌ ‌de‌ ‌tratamiento‌ ‌sin‌ ‌progresión‌ ‌hasta‌ ‌progresión‌ ‌de‌ ‌la‌‌ 
enfermedad.‌
59‌ ‌ 
 ‌8.6‌ ‌Long-term‌ ‌Follow-up‌ ‌visit‌
59‌ ‌ 
 ‌8.6‌ ‌Tumor‌ ‌response‌ ‌evaluation‌
60‌ ‌ 
 ‌8.7‌ ‌Subject‌ ‌withdrawal‌ ‌and‌ ‌replacement‌
61‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
9‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
 ‌9.‌ ‌Collection,‌ ‌registration‌ ‌and‌ ‌notification‌ ‌of‌ ‌security‌ ‌data‌
63‌ ‌ 
 ‌9.1‌ ‌Definitions‌
63‌ ‌ 
 ‌9.2‌ ‌Reporting‌ ‌procedures‌ ‌for‌ ‌all‌ ‌adverse‌ ‌events‌
64‌ ‌ 
 ‌9.3‌ ‌Reporting‌ ‌procedures‌ ‌for‌ ‌serious‌ ‌adverse‌ ‌events‌‌ 
65‌ ‌ 
 ‌9.4‌ ‌Notification‌ ‌of‌ ‌adverse‌ ‌events‌ ‌to‌ ‌the‌ ‌regulatory‌ ‌agencies‌ ‌and‌ ‌the‌ ‌CEICs‌ ‌involved.‌
66‌ ‌ 
 ‌10.‌ ‌STATISTICAL‌ ‌CONSIDERATIONS‌
68‌ ‌ 
 ‌10.1‌ ‌Study‌ ‌design‌‌ 
68‌ ‌ 
 ‌10.2.‌ ‌Study‌ ‌variables,‌ ‌subgroups‌ ‌and‌ ‌covariates‌
68‌ ‌ 
 ‌10.3‌ ‌General‌ ‌approaches‌ ‌/‌ ‌considerations‌
70‌ ‌ 
 ‌10.4‌ ‌Study‌ ‌principal‌ ‌endpoints‌ ‌analysis‌
71‌ ‌ 
 ‌11.‌ ‌ETHICS‌ ‌AND‌ ‌LEGAL‌ ‌CONSIDERATIONS‌
72‌ ‌ 
 ‌11.1‌ ‌Ethics‌ ‌committee‌
72‌ ‌ 
 ‌11.2‌ ‌Authorities‌
73‌ ‌ 
 ‌11.3‌ ‌Protocol‌ ‌amendment‌ ‌/‌ ‌Deviations‌
73‌ ‌ 
 ‌11.4‌ ‌Informed‌ ‌consent‌
73‌ ‌ 
 ‌11.5‌ ‌Confidentiality‌
74‌ ‌ 
 ‌11.6‌ ‌Insurance‌
74‌ ‌ 
 ‌12.‌ ‌ETHICAL‌ ‌CONSIDERATIONS‌‌ 
75‌ ‌ 
 ‌12.1‌ ‌Investigational‌ ‌product‌
75‌ ‌ 
 ‌12.2‌ ‌Associated‌ ‌diseases‌
75‌ ‌ 
 ‌12.3.‌ ‌Responsibilities‌ ‌from‌ ‌GCPs‌
75‌ ‌ 
 ‌12.4.‌ ‌Report‌ ‌and‌ ‌publishing‌ ‌of‌ ‌the‌ ‌study‌
76‌ ‌ 
 ‌12.5‌ ‌Monitoring‌ ‌and‌ ‌audit‌
77‌ ‌ 
 ‌12.6‌ ‌Protocol‌ ‌amendment‌
77‌ ‌ 
 ‌12.7‌ ‌Data‌ ‌Management‌
77‌ ‌ 
 ‌12.8‌ ‌Documentation‌
77‌ ‌ 
 ‌12.9.Finances‌
78‌ ‌ 
 ‌13.‌ ‌REFERENCES‌
79‌ ‌ 
‌ 
‌
 
‌ 
‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
10‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
3.‌ ‌GENERAL‌ ‌INFORMATION‌‌ ‌
  
3.1‌ ‌Clinical‌ ‌Trial‌ ‌Identification‌ ‌
 
Protocol‌ ‌Code:‌ ‌GEMCAD-1002‌ ‌ 
Title:‌ ‌Single-arm,‌ ‌multicenter,‌ ‌prospective‌ ‌phase‌ ‌II‌ ‌clinical‌ ‌trial‌ ‌for‌ ‌biomarker‌ ‌validation‌ ‌in‌ ‌patients‌‌ 
with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌ ‌with‌‌ 
chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy.‌ ‌ 
N‌ ‌EudraCT:‌ ‌2010-019236-12‌ ‌ 
3.2‌ ‌Clinical‌ ‌Trial‌ ‌Type‌ ‌
 
Single-arm‌ ‌prospective‌ ‌phase‌ ‌II‌ ‌clinical‌ ‌trial.‌ ‌ 
3.3‌ ‌Description‌ ‌of‌ ‌the‌ ‌Products‌ ‌under‌ ‌Study‌ ‌
 
FOLFOX6‌ ‌(m)‌ ‌ 
Oxaliplatin‌ ‌5‌ ‌mg‌ ‌/‌ ‌ml‌ ‌powder‌ ‌for‌ ‌solution‌ ‌for‌ ‌infusion.‌ ‌ 
Leucovorin‌ ‌(CALCIUM‌ ‌FOLINATE).‌ ‌Powder‌ ‌for‌ ‌solution‌ ‌for‌ ‌injection‌ ‌(350‌ ‌mg‌ ‌of‌ ‌folinic‌ ‌acid).‌ ‌ 
Fluorouracil‌ ‌(5-FU)‌ ‌solution‌ ‌for‌ ‌injection‌ ‌50‌ ‌mg‌ ‌/‌ ‌ml.‌ ‌ 
‌ 
FOLFIRI‌ ‌(m)‌ ‌ 
Irinotecan‌ ‌20‌ ‌mg‌ ‌/‌ ‌ml‌ ‌(irinotecan‌ ‌hydrochloride‌ ‌trihydrate)‌ ‌concentrate‌ ‌for‌ ‌solution‌ ‌for‌ ‌infusion‌‌ 
(equivalent‌ ‌to‌ ‌17.33‌ ‌mg‌ ‌/‌ ‌ml‌ ‌irinotecan).‌ ‌ 
Leucovorin‌ ‌(CALCIUM‌ ‌FOLINATE).‌ ‌Powder‌ ‌for‌ ‌solution‌ ‌for‌ ‌injection‌ ‌(350‌ ‌mg‌ ‌of‌ ‌folinic‌ ‌acid).‌ ‌ 
Fluorouracil‌ ‌(5-FU)‌ ‌solution‌ ‌for‌ ‌injection‌ ‌50‌ ‌mg‌ ‌/‌ ‌ml.‌ ‌ 
‌ 
CETUXIMAB‌ ‌ 
Cetuximab‌ ‌(Erbitux®)‌ ‌2‌ ‌mg‌ ‌/‌ ‌ml‌ ‌solution‌ ‌for‌ ‌infusion‌ ‌ 
‌ 
3.4‌ ‌Sponsor‌‌ ‌
  
Grupo‌ ‌Español‌ ‌Multidisciplinar‌ ‌en‌ ‌Cáncer‌ ‌Digestivo‌ ‌(GEMCAD)‌ ‌ 
Ronda‌ ‌Gral.‌ ‌Mitre,‌ ‌200‌ ‌entresuelo‌ ‌3ª‌ ‌
 
08006‌ ‌Barcelona‌‌ ‌
  
Correo‌ ‌electrónico:‌ ‌secretaria@gemcad.org‌ ‌ 
Teléfono:‌ ‌+‌ ‌34‌ ‌93‌ ‌434‌ ‌44‌ ‌12‌ ‌ 
Fax:‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68‌ ‌ 
3.5‌ ‌Coordinating‌ ‌Investigator:‌ ‌
 
Nombre:‌ ‌Dr.‌ ‌Jesús‌ ‌García‌ ‌Foncillas‌ ‌ 
Servicio‌ ‌de‌ ‌Oncología‌‌ ‌
  
Clínica‌ ‌Universitaria‌ ‌de‌ ‌Navarra‌ ‌ 
Dirección:‌ ‌Avda.‌ ‌Pio‌ ‌XII‌ ‌36‌ ‌ 
31008‌ ‌–‌ ‌Pamplona‌‌ ‌
  
Teléfono:+‌ ‌34‌ ‌94‌ ‌825‌ ‌54‌ ‌00‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
11‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Fax:‌ ‌+‌ ‌34‌  ‌94‌ ‌825‌ ‌55‌ ‌00‌ ‌ 
Correo‌ ‌electrónico:‌ ‌jgfoncillas@unav.es‌ ‌ 
3.6‌ ‌Co-coordinating‌ ‌Investigator:‌ ‌
 
Nombre:‌ ‌Dr.‌ ‌Xabier‌ ‌García‌ ‌Albeniz‌ ‌ 
Servicio‌ ‌de‌ ‌Oncología‌‌ ‌
  
Hospital‌ ‌Clínic‌ ‌de‌ ‌Barcelona‌‌ ‌
  
Dirección:‌ ‌Villarroel‌ ‌170‌‌ ‌
  
08036‌ ‌-‌ ‌Barcelona‌‌ ‌
  
Teléfono:+‌ ‌34‌ ‌93‌ ‌227‌ ‌54‌ ‌02‌ ‌ 
Fax:‌ ‌+‌ ‌34‌  ‌93‌ ‌227‌ ‌65‌ ‌20‌ ‌ 
Correo‌ ‌electrónico:‌ ‌xagarcia@clinic.ub.es‌ ‌ 
3.7‌ ‌Monitor‌‌ ‌
  
Secretaría‌ ‌Técnica‌ ‌GEMCAD‌ ‌ 
Secretari‌ ‌Coloma,‌ ‌64-68,‌ ‌esc.‌ ‌B‌ ‌entlo.‌ ‌5ª‌ ‌ 
08024‌ ‌Barcelona‌ ‌
 
Correo‌ ‌electrónico:‌ ‌secretaria@gemcad.org‌ ‌ 
Teléfono:‌ ‌+‌ ‌34‌ ‌93‌  ‌434‌ ‌44‌ ‌12‌ ‌ 
Fax:‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68‌ ‌ 
3.8‌ ‌Sites‌ ‌
 
Attachment‌ ‌ 
3.9‌ ‌Schedule‌ ‌and‌ ‌expected‌ ‌completion‌ ‌date‌ ‌ 
‌ 
Start‌ ‌date:‌ ‌Second‌ ‌quarter‌ ‌2010‌ ‌ 
First‌ ‌Inclusion‌ ‌Date:‌ ‌Fourth‌ ‌quarter‌ ‌2010‌ ‌ 
Recruitment‌ ‌period:‌ ‌24‌ ‌months‌ ‌ 
End‌ ‌of‌ ‌Trial‌ ‌Period:‌ ‌Year‌ ‌2014‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
12‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
4.‌ ‌RATIONALE‌ ‌AND‌ ‌OBJECTIVES‌ ‌
 
4.1‌ ‌Colorrectal‌ ‌Cancer‌ ‌(CRC)‌ ‌
 
Colorectal‌‌carcinoma‌‌is‌‌one‌‌of‌‌the‌‌most‌‌common‌‌neoplasms‌‌in‌‌Western‌‌countries‌‌and‌‌is‌‌the‌‌second‌‌
 
   
 
 
 
 
 
   
 
 
   
 
 
most‌‌common‌‌cancer-related‌‌cause‌‌of‌‌death‌‌after‌‌lung‌‌cancer‌‌in‌‌men‌‌and‌‌breast‌‌cancer‌‌in‌‌women.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In‌‌2009,‌‌CRC‌‌caused‌‌an‌‌estimated‌‌49,920‌‌cancer‌‌deaths‌‌in‌‌the‌‌U.S.‌‌American‌‌Cancer‌‌Society‌‌.:‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Cancer‌‌Facts‌‌and‌‌Figures‌‌2009.‌‌(Atlanta,‌‌Ga:‌‌American‌‌Cancer‌‌Society,‌‌2009.‌‌Also‌‌available‌‌online‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.‌ ‌Last‌ ‌accessed‌ ‌January‌ ‌6,‌ ‌2010)‌ ‌and‌ ‌approximately‌ ‌251,000‌ ‌in‌ ‌Europe‌ ‌in‌ ‌2008;‌ ‌ 
(http://www.who.int/healthinfo/global_burden_disease/projections/en/index.html)‌.‌‌Of‌‌the‌‌newly‌‌diagnosed‌‌cases,‌‌
 
 
 
 
 
 
15-25%‌‌correspond‌‌to‌‌patients‌‌who‌‌present‌‌metastatic‌‌disease‌‌at‌‌the‌‌time‌‌of‌‌diagnosis‌‌(Kindler‌‌and‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
Shulman,‌ ‌2001)‌ ‌and‌ ‌up‌ ‌to‌ ‌50%‌ ‌of‌ ‌all‌ ‌patients‌ ‌finally‌ ‌present‌ ‌metastatic‌ ‌disease‌ ‌(Kindler‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shulman,‌‌2001;‌‌McLeod‌‌et‌‌al,‌‌2000).‌‌In‌‌general,‌‌CRC‌‌is‌‌curable‌‌if‌‌the‌‌diagnosis‌‌is‌‌made‌‌early‌‌and‌‌
 
 
   
 
 
 
 
   
   
 
   
 
 
 
is‌‌localized‌‌to‌‌the‌‌intestinal‌‌mucosa,‌‌with‌‌a‌‌5-year‌‌survival‌‌of‌‌93%‌‌(Pazdur‌‌et‌‌al,‌‌1999).‌‌However,‌‌
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
the‌‌5-year‌‌survival‌‌rate‌‌falls‌‌to‌‌67%‌‌after‌‌adjacent‌‌organ‌‌and‌‌lymph‌‌node‌‌involvement‌‌and‌‌is‌‌only‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
8%‌ ‌in‌ ‌patients‌ ‌with‌ ‌disseminated‌ ‌metastatic‌ ‌disease‌ ‌(Pazdur‌ ‌et‌ ‌al,‌ ‌1999;‌ ‌Kindler‌‌and‌‌Shulman,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2001).‌ ‌ 
‌ 
Analyzing‌ ‌the‌ ‌situation‌ ‌in‌ ‌Spain‌ ‌in‌ ‌more‌ ‌detail,‌ ‌according‌ ‌to‌ ‌data‌ ‌from‌ ‌the‌ ‌National‌ ‌Statistics‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institute‌‌(INE,‌‌2006‌‌data‌‌published‌‌in‌‌January‌‌2008),‌‌the‌‌second‌‌most‌‌significant‌‌type‌‌of‌‌cancer‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
men‌ ‌was‌ ‌colon‌ ‌cancer‌ ‌with‌ ‌5,642‌ ‌deaths.‌ ‌This‌ ‌tumor‌ ‌accounted‌ ‌for‌ ‌4,284‌ ‌deaths‌ ‌in‌ ‌women‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(http://www.ine.es/jaxi/tabla.do‌ ‌http://www.ine.es/prensa/np490.pdf).‌ ‌ 
‌ 
Taking‌‌SEOM‌‌as‌‌a‌‌source,‌‌in‌‌Spain‌‌more‌‌than‌‌25,000‌‌new‌‌cases‌‌of‌‌CRC‌‌are‌‌diagnosed‌‌each‌‌year‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(15%‌‌of‌‌the‌‌incidence‌‌of‌‌all‌‌tumors).‌‌In‌‌addition,‌‌it‌‌is‌‌the‌‌second‌‌leading‌‌cause‌‌of‌‌death‌‌from‌‌cancer‌‌
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
in‌‌our‌‌country,‌‌after‌‌lung‌‌cancer,‌‌with‌‌more‌‌than‌‌13,000‌‌deaths‌‌per‌‌year.‌‌A‌‌figure‌‌that‌‌is‌‌well‌‌above‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
the‌‌data‌‌for‌‌deaths‌‌from‌‌AIDS,‌‌with‌‌more‌‌than‌‌1,300‌‌a‌‌year,‌‌and‌‌from‌‌traffic‌‌accidents,‌‌with‌‌more‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
than‌ ‌4,000‌ ‌ 
 ‌(http://www.seom.org/seomcms/images/stories/recursos/home/2009/Dossier_Prensa.pdf).‌ ‌ 
‌ 
‌ 
Colorectal‌ ‌Cancer‌ ‌Treatment‌ ‌ 
‌ 
Historically,‌ ‌the‌‌median‌‌survival‌‌of‌‌patients‌‌with‌‌metastatic‌‌disease‌‌has‌‌been‌‌11-13‌‌months‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
modulation‌ ‌with‌ ‌fluoropyrimidine,‌ ‌5-fluorouracil‌ ‌and‌ ‌leucovorin‌ ‌(LV)‌ ‌(Advanced‌ ‌Colorectal‌‌
 
 
 
 
 
 
 
 
 
Cancer‌ ‌Meta-Analysis‌ ‌Project‌ ‌1992).‌ ‌The‌ ‌introduction‌‌of‌‌oxaliplatin‌‌and‌‌irinotecan‌‌in‌‌advanced‌‌
 
 
 
 
 
 
 
 
 
 
 
 
colorectal‌ ‌cancer‌ ‌chemotherapy‌ ‌has‌ ‌increased‌ ‌the‌ ‌frequency‌ ‌and‌ ‌magnitude‌‌of‌‌clinical‌‌response‌‌
 
 
 
 
 
 
 
 
 
 
 
 
compared‌‌to‌‌that‌‌achieved‌‌with‌‌5-FU‌‌/‌‌LV‌‌alone,‌‌and‌‌has‌‌increased‌‌progression-free‌‌survival‌‌and‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
overall‌ ‌survival.‌ ‌Research‌ ‌is‌ ‌currently‌ ‌underway‌‌to‌‌determine‌‌how‌‌this‌‌systemic‌‌therapy‌‌can‌‌be‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
optimized.‌ ‌ 
‌ 
Irinotecan,‌ ‌a‌ ‌specific‌ ‌DNA‌ ‌topoisomerase‌ ‌I‌ ‌inhibitor,‌ ‌has‌ ‌shown‌ ‌significant‌ ‌activity‌‌as‌‌a‌‌single‌‌
   
 
 
   
 
 
 
 
 
   
 
agent‌‌in‌‌the‌‌treatment‌‌of‌‌patients‌‌with‌‌CRC‌‌refractory‌‌to‌‌5-FU‌‌(Rougier‌‌et‌‌al‌‌1998;‌‌Cunningham‌‌et‌‌
 
 
 
 
 
 
 
 
   
 
     
 
   
al‌ ‌1998).‌ ‌Furthermore,‌ ‌the‌ ‌addition‌ ‌of‌ ‌irinotecan‌ ‌to‌ ‌5-FU‌ ‌/‌ ‌LV‌ ‌combination‌ ‌therapy‌ ‌(FOLFIRI‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
regimen)‌‌produced‌‌a‌‌significant‌‌improvement‌‌over‌‌5-FU‌‌/‌‌LV‌‌alone‌‌in‌‌overall‌‌survival,‌‌response‌‌
 
   
 
 
 
   
 
 
 
 
 
 
rate,‌ ‌and‌ ‌time‌ ‌to‌ ‌progression‌ ‌in‌ ‌the‌ ‌treatment‌ ‌of‌ ‌patients‌ ‌with‌ ‌previously‌ ‌untreated‌ ‌mCRC‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Douillard‌ ‌et‌ ‌al,‌ ‌2000).‌ ‌ 
‌ 
Oxaliplatin,‌ ‌a‌ ‌platinum‌ ‌analog,‌ ‌forms‌ ‌cross-linked‌ ‌adducts‌ ‌and‌ ‌blocks‌ ‌deoxyribonucleic‌ ‌acid‌‌
   
 
 
 
 
 
 
 
 
 
replication.‌ ‌Oxaliplatin‌ ‌has‌ ‌been‌ ‌shown‌ ‌to‌ ‌be‌ ‌effective‌ ‌and‌ ‌well‌ ‌tolerated‌ ‌when‌ ‌given‌ ‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
leucovorin‌‌bolus‌‌and‌‌infusion‌‌(FOLFOX‌‌regimen),‌‌although‌‌neutropenia‌‌and‌‌sensory‌‌neuropathies‌‌
 
 
 
 
 
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
13‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
occur‌‌more‌‌frequently‌‌than‌‌when‌‌5-FU‌‌and‌‌LV‌‌are‌‌given‌‌alone‌‌(Maindrault-Goebel‌‌et‌‌al,‌‌1999;‌‌de‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
Gramont‌ ‌et‌ ‌al,‌ ‌2000;‌ ‌Rothenberg‌ ‌et‌ ‌al,‌ ‌2003;‌ ‌Goldberg‌ ‌RM‌ ‌et‌ ‌al,‌ ‌2004;‌ ‌Tournigand‌ ‌et‌ ‌al,‌ ‌2004).‌ ‌ 
‌ 
The‌ ‌last‌ ‌few‌ ‌years‌ ‌have‌ ‌been‌ ‌accompanied‌ ‌by‌ ‌advances‌ ‌in‌ ‌the‌ ‌treatment‌ ‌of‌ ‌mCRC‌ ‌that‌ ‌have‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
improved‌ ‌the‌ ‌life‌ ‌expectancy‌ ‌of‌ ‌patients.‌ ‌ 
‌ 
Among‌‌the‌‌latest‌‌additions‌‌to‌‌mCRC‌‌therapy‌‌are‌‌biological‌‌therapies‌‌or‌‌targeted‌‌therapies,‌‌of‌‌which‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
we‌ ‌could‌ ‌highlight‌‌drugs‌‌directed‌‌against‌‌the‌‌vascular‌‌growth‌‌factor‌‌receptor‌‌(VEGF)‌‌and‌‌those‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
directed‌ ‌against‌ ‌the‌ ‌epidermal‌ ‌growth‌ ‌factor‌ ‌receptor‌ ‌(EGFR).‌ ‌).‌ ‌ 
‌ 
Target‌ ‌biological‌ ‌agents,‌ ‌specifically‌ ‌designed‌ ‌to‌ ‌inhibit‌ ‌the‌ ‌biochemical‌ ‌processes‌ ‌of‌
 
 
 
 
 
 
 
 
 
 
 
carcinogenesis,‌ ‌have‌ ‌been‌ ‌shown‌ ‌to‌ ‌be‌ ‌effective‌ ‌in‌ ‌treating‌ ‌mCRC.‌ ‌Cetuximab‌ ‌(Erbitux®),‌ ‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
   
chimeric‌ ‌monoclonal‌ ‌antibody‌ ‌directed‌ ‌against‌ ‌the‌ ‌epidermal‌ ‌growth‌ ‌factor‌ ‌receptor‌ ‌(EGFr),‌ ‌is‌‌
 
 
 
 
 
 
 
 
 
 
 
 
cleared‌‌by‌‌the‌‌FDA‌‌for‌‌use‌‌in‌‌combination‌‌with‌‌irinotecan‌‌for‌‌the‌‌treatment‌‌of‌‌patients‌‌with‌‌mCRC‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
who‌ ‌have‌ ‌tumors‌ ‌that‌ ‌express‌ ‌EGFr‌ ‌that‌ ‌are‌ ‌resistant‌ ‌to‌ ‌irinotecan-based‌ ‌treatment‌ ‌or‌ ‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
monotherapy‌ ‌in‌ ‌irinotecan-intolerant‌ ‌patients‌ ‌with‌ ‌tumors‌ ‌that‌ ‌express‌ ‌EGFr‌ ‌(Baselga‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
Mendelson,‌ ‌1994;‌ ‌Herbst‌ ‌et‌ ‌al,‌ ‌2002;‌ ‌Cunningham‌ ‌et‌ ‌al,‌ ‌2004;‌ ‌Saltz‌ ‌et‌ ‌al,‌ ‌2004).‌ ‌Within‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
European‌‌Union,‌‌the‌‌authorization‌‌allows‌‌patients‌‌with‌‌metastatic‌‌colorectal‌‌cancer‌‌to‌‌be‌‌treated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
with‌ ‌non-mutated‌ ‌KRAS‌ ‌with‌ ‌expression‌ ‌of‌ ‌the‌ ‌epidermal‌ ‌growth‌ ‌factor‌ ‌receptor‌ ‌(EGFr)‌ ‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
combination‌‌with‌‌chemotherapy‌‌or‌‌as‌‌monotherapy‌‌in‌‌patients‌‌whose‌‌treatment‌‌based‌‌on‌‌irinotecan‌‌
 
 
 
 
 
   
 
 
 
 
 
 
and‌ ‌oxaliplatin‌ ‌failed‌ ‌and‌ ‌they‌ ‌do‌ ‌not‌ ‌tolerate‌ ‌irinotecan‌ ‌(Erbitux®‌ ‌SmPC,‌ ‌2009).‌ ‌ 
‌ 
Another‌‌selective‌‌product‌‌is‌‌bevacizumab‌‌(Avastin®),‌‌which‌‌binds‌‌and‌‌inhibits‌‌endothelial‌‌growth‌‌
 
 
   
 
 
 
 
 
 
 
 
factor‌ ‌A‌ ‌(VEGF-A),‌ ‌a‌ ‌protein‌ ‌that‌ ‌plays‌ ‌a‌ ‌crucial‌ ‌role‌ ‌in‌ ‌tumor‌ ‌angiogenesis.‌ ‌Bevacizumab‌‌in‌‌
 
 
   
 
 
   
 
 
 
 
 
 
 
combination‌ ‌with‌‌fluoropyrimidine-based‌‌chemotherapy‌‌is‌‌indicated‌‌for‌‌the‌‌treatment‌‌of‌‌patients‌‌
 
 
 
   
 
 
 
 
 
 
with‌ ‌metastatic‌ ‌carcinoma‌ ‌of‌ ‌the‌ ‌colon‌ ‌or‌ ‌rectum‌ ‌(Avastin®‌ ‌SmPC,‌ ‌2009).‌ ‌ 
‌ 
There‌ ‌are‌ ‌two‌ ‌monoclonal‌ ‌antibodies‌ ‌directed‌ ‌against‌ ‌EGFR:‌ ‌panitumumab‌ ‌and‌ ‌cetuximab.‌ ‌ 
‌ 
Panitumumab‌ ‌currently‌ ‌has‌ ‌an‌ ‌indication‌ ‌“as‌ ‌monotherapy‌ ‌for‌ ‌the‌ ‌treatment‌ ‌of‌ ‌patients‌ ‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic‌ ‌colorectal‌ ‌carcinoma‌ ‌expressing‌ ‌EGFR‌ ‌with‌ ‌wild-type‌ ‌KRAS,‌ ‌after‌ ‌the‌ ‌failure‌ ‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
chemotherapy‌ ‌regimens‌ ‌containing‌ ‌fluoropyrimidine,‌ ‌oxaliplatin‌ ‌and‌ ‌irinotecan‌ ‌(Vectibix‌ ‌SmPC‌ ‌)‌ ‌".‌ ‌ 
‌ 
The‌‌monoclonal‌‌antibody‌‌cetuximab‌‌has,‌‌since‌‌July‌‌2008,‌‌in‌‌light‌‌of‌‌the‌‌information‌‌provided‌‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌health‌‌authorities,‌‌authorization‌‌by‌‌the‌‌EMEA‌‌to‌‌be‌‌used‌‌in‌‌the‌‌first‌‌line‌‌in‌‌patients‌‌with‌‌mCRC‌‌
 
 
 
 
 
 
   
 
   
 
 
   
 
 
 
who‌ ‌meet‌ ‌the‌ ‌requirements‌ ‌reflected‌ ‌in‌ ‌the‌ ‌approved‌ ‌indication‌ ‌(Technical‌ ‌Sheet‌ ‌by‌ ‌Erbitux)‌ ‌ 
‌ 
Cetuximab‌‌is‌‌indicated‌‌for‌‌the‌‌treatment‌‌of‌‌patients‌‌with‌‌mCRC,‌‌with‌‌expression‌‌of‌‌the‌‌epidermal‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
growth‌ ‌factor‌ ‌receptor‌ ‌(EFGR),‌ ‌with‌ ‌a‌ ‌native-type‌ ‌KRAS‌ ‌gene:‌ ‌ 
in‌ ‌combination‌ ‌with‌ ‌chemotherapy,‌ ‌ 
as‌‌monotherapy‌‌in‌‌those‌‌patients‌‌in‌‌whom‌‌treatment‌‌with‌‌oxaliplatin‌‌and‌‌irinotecan‌‌has‌‌failed‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
who‌ ‌cannot‌ ‌tolerate‌ ‌irinotecan‌ ‌(Erbitux‌ ‌SmPC).‌ ‌ 
‌ 
Thus,‌‌the‌‌current‌‌indication‌‌for‌‌the‌‌first‌‌line‌‌of‌‌treatment‌‌in‌‌patients‌‌with‌‌mCRC‌‌with‌‌expression‌‌of‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
the‌ ‌epidermal‌ ‌growth‌ ‌factor‌ ‌receptor‌ ‌(EFGR),‌ ‌with‌ ‌the‌ ‌KRAS‌ ‌gene‌ ‌of‌ ‌the‌ ‌non-mutated‌ ‌type,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
included‌‌in‌‌the‌‌technical‌‌data‌‌sheet,‌‌is‌‌achieved‌‌after‌‌a‌‌complete‌‌clinical‌‌development‌‌of‌‌the‌‌drug.‌‌,‌‌
 
 
 
 
 
   
 
   
 
 
 
 
 
   
culminating‌‌in‌‌the‌‌CRYSTAL‌‌and‌‌OPUS‌‌trials,‌‌clear‌‌exponents‌‌of‌‌the‌‌use‌‌of‌‌cetuximab‌‌in‌‌regimens‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
with‌‌irinotecan‌‌and‌‌oxaliplatin,‌‌in‌‌the‌‌first‌‌line‌‌of‌‌treatment,‌‌common‌‌guidelines‌‌in‌‌daily‌‌clinical‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
practice.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
14‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
CRYSTAL‌ ‌study‌ ‌ 
‌ 
The‌‌CRYSTAL‌‌study‌‌was‌‌designed‌‌to‌‌assess‌‌the‌‌efficacy‌‌of‌‌adding‌‌cetuximab‌‌to‌‌FOLFIRI‌‌in‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
first-line‌‌treatment‌‌of‌‌metastatic‌‌colorectal‌‌cancer.‌‌This‌‌is‌‌a‌‌phase‌‌III‌‌study‌‌comparing‌‌FOLFIRI‌‌vs.‌‌
 
 
 
 
 
 
     
 
 
 
 
 
 
FOLFIRI‌‌+‌‌cetuximab.‌‌The‌‌sample‌‌size‌‌was‌‌1198‌‌patients,‌‌randomized‌‌1:‌‌1‌‌by‌‌region‌‌of‌‌origin‌‌and‌‌
   
 
 
 
 
 
 
 
     
 
 
 
 
 
ECOG‌‌status.‌‌Its‌‌design‌‌considered‌‌progression-free‌‌survival‌‌as‌‌the‌‌primary‌‌endpoint‌‌and‌‌overall‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
survival,‌ ‌response,‌ ‌and‌ ‌safety‌‌as‌‌secondary‌‌endpoints.‌‌The‌‌efficacy‌‌analysis‌‌according‌‌to‌‌KRAS‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
status‌ ‌was‌ ‌retrospective.‌ ‌ 
‌ 
At‌‌the‌‌last‌‌ECCO‌‌/‌‌ESMO‌‌congress‌‌(Berlin,‌‌2009),‌‌updated‌‌survival‌‌data‌‌were‌‌presented‌‌for‌‌these‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
native‌ ‌KRAS‌ ‌patients,‌ ‌treated‌ ‌with‌ ‌the‌ ‌combination‌ ‌of‌ ‌FOLFIRI-cetuximab,‌ ‌after‌ ‌a‌ ‌longer‌‌
 
 
 
 
 
 
 
 
 
   
 
follow-up‌‌time‌‌and‌‌a‌‌greater‌‌number‌‌of‌‌KRAS‌‌determinations.‌‌The‌‌number‌‌of‌‌patients‌‌with‌‌KRAS‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
status‌ ‌determination‌ ‌increased‌ ‌from‌ ‌45%‌ ‌to‌ ‌89%‌ ‌in‌ ‌this‌ ‌update.‌ ‌In‌ ‌these‌ ‌patients,‌ ‌a‌‌significant‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
increase‌‌was‌‌demonstrated‌‌both‌‌in‌‌the‌‌OR‌‌(57.3‌‌vs‌‌39.7,‌‌p‌‌<0.0001),‌‌as‌‌well‌‌as‌‌in‌‌the‌‌SPL‌‌(9.9‌‌vs‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
8.4‌‌months,‌‌p‌‌=‌‌0.012)‌‌and‌‌the‌‌overall‌‌survival,‌‌until‌‌now‌‌not‌‌reached‌‌(23.5‌‌vs‌‌20‌‌months‌‌,‌‌p‌‌=‌‌
 
     
 
 
 
 
 
 
 
 
 
 
 
 
       
0.0094,‌‌HR:‌‌0.8,‌‌95%‌‌CI:‌‌0.67-0.95).‌‌(Lang‌‌I,‌‌Könhe‌‌CH,‌‌Folprecht‌‌G‌‌et‌‌al.‌‌Cetuximab‌‌plus‌‌Folfiri‌‌
 
 
 
 
 
 
   
 
 
     
 
 
 
 
in‌‌1st‌‌line‌‌treatment‌‌of‌‌mCCR:‌‌quality‌‌of‌‌life‌‌analysis‌‌of‌‌patients‌‌with‌‌KRAS‌‌WT‌‌tumors‌‌in‌‌Crystal‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
trial.‌ ‌Presented‌ ‌at:‌ ‌ASCO‌ ‌gastrointestinal‌ ‌Cancers‌ ‌Symposium.‌ ‌January‌ ‌2010‌ ‌(Abstract‌ ‌281)‌ ‌ 
‌ 
‌ 
In‌ ‌a‌ ‌recent‌ ‌update‌ ‌of‌ ‌the‌ ‌data‌ ‌at‌ ‌the‌ ‌ASCO‌ ‌GI‌ ‌2010‌ ‌congress,‌ ‌the‌ ‌results‌ ‌are‌ ‌reported‌ ‌after‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
determining‌‌the‌‌KRAS‌‌status‌‌of‌‌89%‌‌of‌‌the‌‌sample‌‌(in‌‌the‌‌original‌‌publication‌‌it‌‌was‌‌only‌‌45%).‌‌A‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
benefit‌‌of‌‌the‌‌addition‌‌of‌‌cetuximab‌‌to‌‌FOLFIRI‌‌in‌‌KRAS‌‌WT‌‌patients‌‌was‌‌confirmed‌‌in‌‌terms‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression-free‌ ‌survival‌ ‌(HR‌ ‌0.70;‌ ‌95%‌ ‌CI‌ ‌0.56-0.87),‌ ‌overall‌ ‌survival‌ ‌(HR‌ ‌0.80;‌ ‌95%‌ ‌CI‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
0.67-0.95)‌‌and‌‌response‌‌(‌‌OR‌‌2.07‌‌95%‌‌CI‌‌1.52-2.83).‌‌(Van‌‌Cutsem‌‌E,‌‌et‌‌al.‌‌ASCO‌‌GI‌‌Congress‌‌
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
2010.‌ ‌Abstract‌ ‌No:‌ ‌281.)‌ ‌ 
‌ 
These‌‌data‌‌were‌‌presented‌‌together‌‌with‌‌their‌‌update‌‌according‌‌to‌‌the‌‌mutational‌‌status‌‌of‌‌KRAS‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌‌BRAF‌‌(determined‌‌in‌‌83%‌‌of‌‌patients),‌‌in‌‌the‌‌past‌‌ASCO‌‌GI‌‌(Van‌‌Cutsem‌‌E,‌‌Lang‌‌I,‌‌Folprecht‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
G,‌ ‌et‌ ‌al.‌ ‌Cetuximab‌ ‌plus‌ ‌Folfiri‌ ‌in‌ ‌the‌ ‌treatment‌ ‌of‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌(mCRC):‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
influence‌ ‌of‌ ‌KRAS‌ ‌and‌ ‌BRAF‌ ‌biomarkers‌ ‌on‌ ‌outcome:‌ ‌updated‌ ‌data‌ ‌from‌ ‌the‌ ‌Crystal‌ ‌trial.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presented‌‌at:‌‌ASCO‌‌gastrointestinal‌‌Cancers‌‌Symposium.‌‌January‌‌2010‌‌(Abstract‌‌281),‌‌maintaining‌‌
 
 
 
 
 
 
 
 
 
 
 
superiority‌‌in‌‌terms‌‌efficacy‌‌of‌‌the‌‌combination‌‌of‌‌QT‌‌with‌‌cetuximab‌‌in‌‌native‌‌KRAS‌‌patients.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These‌‌results‌‌were‌‌superior‌‌in‌‌patients‌‌with‌‌native‌‌KRAS‌‌and‌‌native‌‌BRAF,‌‌and‌‌the‌‌presence‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mutated‌‌BRAF‌‌worsened‌‌the‌‌results,‌‌regardless‌‌of‌‌the‌‌treatment‌‌used,‌‌the‌‌authors‌‌concluding‌‌that‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌BRAF‌ ‌mutation‌ ‌is‌ ‌a‌ ‌negative‌ ‌prognostic‌ ‌factor‌ ‌in‌ ‌mCRC.‌ ‌ 
‌ 
OPUS‌ ‌20‌ ‌study‌ ‌ 
‌ 
The‌‌OPUS‌‌20‌‌study‌‌is‌‌a‌‌randomized‌‌phase‌‌II‌‌trial,‌‌comparing‌‌FOLFOX‌‌vs.‌‌FOLFOX‌‌+‌‌cetuximab‌‌
 
 
 
     
 
   
 
 
 
 
   
 
in‌ ‌the‌ ‌first‌ ‌line‌ ‌of‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌treatment.‌ ‌The‌ ‌sample‌ ‌size‌ ‌was‌ ‌292‌ ‌patients,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
randomized‌ ‌1:‌ ‌1‌ ‌by‌ ‌ECOG‌ ‌status.‌ ‌ 
Its‌‌design‌‌considered‌‌superiority‌‌in‌‌the‌‌percentage‌‌of‌‌response‌‌in‌‌the‌‌experimental‌‌arm‌‌as‌‌a‌‌primary‌‌
 
 
 
   
 
 
 
   
 
 
 
   
 
objective.‌ ‌The‌ ‌efficacy‌ ‌analysis‌ ‌according‌ ‌to‌ ‌KRAS‌ ‌status‌ ‌was,‌ ‌as‌ ‌in‌ ‌CRYSTAL,‌ ‌retrospective.‌ ‌ 
‌ 
In‌ ‌the‌ ‌past‌ ‌ECCO‌ ‌/‌ ‌ESMO‌ ‌(Berlin,‌ ‌2009),‌ ‌updated‌ ‌efficacy‌ ‌data‌ ‌of‌ ‌the‌ ‌combination‌ ‌of‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
FOLFOX-4-cetuximab‌‌in‌‌patients‌‌with‌‌native‌‌KRAS‌‌was‌‌presented,‌‌after‌‌increasing‌‌the‌‌number‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌‌in‌‌whom‌‌the‌‌determination‌‌of‌‌mutational‌‌status‌‌was‌‌performed.‌‌(93.5%)‌‌(Bokemeyer‌‌C,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Bondarenko‌‌I,‌‌Hartmenn‌‌JT,‌‌et‌‌al.‌‌Overall‌‌survival‌‌of‌‌patients‌‌with‌‌KRAS‌‌wild-type‌‌tumors‌‌treated‌‌
   
 
   
 
 
 
 
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
15‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
with‌‌FOLFOX-4‌‌±‌‌cetuximab‌‌as‌‌1st‌‌line‌‌treatment‌‌of‌‌metastatic‌‌colorectal‌‌cancer:‌‌the‌‌OPUS‌‌study.‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
Updated‌ ‌information‌‌presented‌‌at‌‌the‌‌15th‌‌Congress‌‌of‌‌the‌‌European‌‌cancer‌‌Oragnization‌‌/‌‌34th‌
 
 
 
 
 
 
 
 
 
 
 
   
 
Congress‌‌of‌‌the‌‌European‌‌Society‌‌of‌‌Medical‌‌Oncology.‌‌Abstr.‌‌6079).‌‌In‌‌these‌‌patients,‌‌the‌‌median‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
overall‌‌survival‌‌was‌‌22.8‌‌months‌‌in‌‌the‌‌cetuximab‌‌arm,‌‌compared‌‌to‌‌18.5‌‌months‌‌in‌‌the‌‌QT‌‌alone‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
arm‌‌(p‌‌=‌‌0.38).‌‌The‌‌updated‌‌global‌‌response‌‌data‌‌was‌‌57.3%‌‌in‌‌the‌‌patients‌‌treated‌‌with‌‌cetuximab‌‌
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
vs‌‌34%‌‌in‌‌the‌‌other‌‌arm‌‌(p‌‌=‌‌0.027)‌‌and‌‌progression-free‌‌survival‌‌was‌‌8.3‌‌months‌‌in‌‌the‌‌arm‌‌that‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
associated‌ ‌cetuximab,‌ ‌maintaining‌ ‌7.2‌ ‌months‌ ‌achieved‌ ‌in‌ ‌patients‌ ‌treated‌‌only‌‌with‌‌CT‌‌(HR‌‌=‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
0.57,‌ ‌95%‌ ‌CI‌ ‌(0.38-0.86),‌ ‌p‌ ‌=‌ ‌0.0064),‌‌which‌‌represents‌‌a‌‌43%‌‌reduction‌‌in‌‌the‌‌risk‌‌of‌‌disease‌‌
 
 
 
     
 
 
   
 
 
 
 
 
 
 
progression.‌ ‌ 
‌ 
‌ 
In‌‌a‌‌recent‌‌update‌‌of‌‌the‌‌data‌‌at‌‌the‌‌2010‌‌ASCO‌‌GI‌‌symposium,‌‌the‌‌results‌‌are‌‌reported‌‌reaffirming‌‌
   
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
the‌‌efficacy‌‌of‌‌the‌‌combination‌‌of‌‌cetuximab‌‌and‌‌FOLFOX-4‌‌in‌‌patients‌‌with‌‌native‌‌KRAS,‌‌after‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
determining‌ ‌the‌ ‌KRAS‌ ‌status‌ ‌of‌ ‌93.5%‌ ‌of‌ ‌the‌ ‌sample‌ ‌(in‌ ‌the‌ ‌original‌‌publication‌‌was‌‌made‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
69.1%).‌‌The‌‌OPUS‌‌study‌‌confirms,‌‌once‌‌again,‌‌a‌‌benefit‌‌of‌‌the‌‌addition‌‌of‌‌cetuximab‌‌to‌‌FOLFOX‌‌
 
 
 
 
 
 
   
 
 
 
 
 
   
 
in‌ ‌KRAS‌ ‌WT‌ ‌patients‌ ‌in‌ ‌terms‌ ‌of‌ ‌progression-free‌ ‌survival‌ ‌(HR‌ ‌0.57;‌ ‌95%‌ ‌CI‌ ‌0.38-0.86)‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
response‌‌(OR‌‌2.55‌‌95%‌‌CI‌‌1.38‌‌-4.72).‌‌No‌‌benefit‌‌in‌‌overall‌‌survival‌‌was‌‌shown.‌‌(Bokemeyer‌‌C,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bondarenko‌‌I,‌‌Hatmann‌‌JT,‌‌De‌‌Braud‌‌FG,‌‌et‌‌al.‌‌Biomarkers‌‌predictive‌‌for‌‌outcome‌‌in‌‌patients‌‌with‌‌
   
 
 
 
 
   
 
 
 
 
   
 
 
mCRC‌‌tretaed‌‌with‌‌first-line‌‌FOLFOX-4‌‌plus‌‌or‌‌minus‌‌cetuximab:‌‌Updated‌‌data‌‌from‌‌the‌‌OPUS‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study.‌ ‌Presented‌ ‌at:‌ ‌ASCO‌ ‌gastrointestinal‌ ‌Cancers‌ ‌Symposium.‌ ‌January‌ ‌2010‌ ‌(Abstract‌ ‌428).‌ ‌ 
‌ 
A‌ ‌meta-analysis‌ ‌performed‌ ‌with‌ ‌individual‌ ‌data‌ ‌from‌ ‌both‌ ‌studies‌ ‌(n‌ ‌=‌ ‌845,‌ ‌absence‌ ‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
heterogeneity‌‌for‌‌progression-free‌‌survival,‌‌overall‌‌survival,‌‌and‌‌response)‌‌was‌‌also‌‌reported‌‌at‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
   
 
2010‌ ‌ASCO‌‌GI‌‌symposium,‌‌confirming‌‌the‌‌benefit‌‌of‌‌adding‌‌cetuximab‌‌first-line‌‌to‌‌KRAS‌‌WT‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌‌both‌‌in‌‌terms‌‌of‌‌progression-free‌‌survival‌‌(HR‌‌0.66,‌‌95%‌‌CI‌‌0.55-0.80),‌‌overall‌‌survival‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(HR‌‌0.81,‌‌95%‌‌CI‌‌0.69-0.94)‌‌and‌‌response‌‌percentage‌‌(OR‌‌0.81,‌‌95%‌‌CI‌‌0.69-0.94‌‌)‌‌(Koehne‌‌C,‌‌et‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
al.‌ ‌ASCO‌ ‌GI‌ ‌Congress‌ ‌2010.‌ ‌Abstract‌ ‌No:‌ ‌406).‌ ‌ 
‌ 
‌ 
At‌‌these‌‌same‌‌congresses,‌‌a‌‌meta-analysis‌‌has‌‌been‌‌presented‌‌that‌‌collects‌‌the‌‌efficacy‌‌data‌‌of‌‌the‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
addition‌ ‌of‌ ‌cetuximab‌ ‌to‌ ‌the‌ ‌1st-line‌ ‌QT‌ ‌of‌ ‌mCRC‌ ‌in‌ ‌the‌ ‌CRYSTAL‌ ‌and‌ ‌OPUS‌ ‌studies‌ ‌(Van‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cutsem‌‌E,‌‌Rougier‌‌P,‌‌Köhne‌‌C,‌‌et‌‌al.‌‌.‌‌A‌‌meta-analysis‌‌of‌‌the‌‌Crystal‌‌and‌‌Opus‌‌trials.‌‌Eur‌‌J‌‌Cancer‌‌
 
 
   
 
   
     
 
 
 
 
 
 
 
   
 
Suppl.‌‌2009;‌‌7:‌‌354.‌‌Updated‌‌information‌‌presented‌‌at‌‌the‌‌15th‌‌Congress‌‌of‌‌the‌‌European‌‌cancer‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oragnization‌‌/‌‌34th‌‌Congress‌‌of‌‌the‌‌European‌‌Society‌‌of‌‌Medical‌‌Oncology.‌‌Abstr.‌‌6077)‌‌.‌‌This‌‌
   
 
 
 
 
 
 
 
 
 
 
   
 
study‌‌collected‌‌independent‌‌data‌‌from‌‌a‌‌total‌‌of‌‌845‌‌patients‌‌with‌‌mCRC‌‌and‌‌native‌‌KRAS‌‌(666‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
from‌ ‌the‌ ‌Crystal‌ ‌study‌ ‌and‌ ‌179‌ ‌from‌ ‌the‌ ‌Opus).‌ ‌This‌ ‌analysis‌ ‌showed‌ ‌that‌ ‌adding‌ ‌cetuximab‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
provides‌‌a‌‌clear‌‌benefit‌‌in‌‌the‌‌global‌‌response,‌‌doubling‌‌the‌‌possibility‌‌of‌‌obtaining‌‌a‌‌response,‌‌and‌‌
   
 
 
 
 
 
 
 
 
 
 
   
 
 
an‌‌increase‌‌in‌‌PFS‌‌of‌‌patients‌‌with‌‌native‌‌KRAS:‌‌it‌‌reduces‌‌the‌‌risk‌‌of‌‌disease‌‌progression‌‌by‌‌34%‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
(HR‌‌:‌‌0.66;‌‌p‌‌<0.001).‌‌Furthermore,‌‌it‌‌also‌‌demonstrated‌‌a‌‌significant‌‌increase‌‌in‌‌survival‌‌in‌‌native‌‌
   
   
 
   
 
   
 
   
   
 
KRAS‌‌patients‌‌receiving‌‌cetuximab‌‌(HR:‌‌0.81;‌‌p‌‌=‌‌0.0062)‌‌(Table‌‌6)‌‌(Kohne‌‌C,‌‌Rougier‌‌P,‌‌Stroh‌‌C,‌‌
 
 
 
 
 
     
 
 
 
 
 
   
 
 
et‌‌al.‌‌Cetuximab‌‌with‌‌chemotherapy‌‌as‌‌first-line‌‌treatment‌‌for‌‌metastatic‌‌mCRC:‌‌A‌‌meta-analysis‌‌
 
 
 
 
 
 
 
 
 
 
   
 
of‌‌the‌‌CRYSTAL‌‌and‌‌OPUS‌‌studies‌‌according‌‌to‌‌KRAS‌‌and‌‌BRAF‌‌mutation‌‌status.‌‌Presented‌‌at:‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASCO‌ ‌gastrointestinal‌ ‌Cancers‌ ‌Symposium.‌ ‌January‌ ‌2010‌ ‌(Abstract‌ ‌406).‌ ‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
‌ ‌
  
HR/odds‌ ‌ratio‌ ‌ ‌ ‌ ‌ ‌ 95%‌ ‌ CI‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ p‌ ‌value‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ Heterogeneity‌ ‌
 
 ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ p‌ ‌value‌ ‌ 
‌ ‌
  


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
16‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
Conclusion‌ ‌ 
‌ 
The‌‌NCCN‌‌21‌‌guidelines‌‌propose‌‌the‌‌use‌‌of‌‌cetuximab‌‌in‌‌combination‌‌with‌‌chemotherapy‌‌drugs‌‌in‌‌
 
 
 
 
 
 
 
 
   
 
 
 
   
the‌ ‌first‌ ‌line‌ ‌in‌ ‌patients‌ ‌with‌ ‌mCRC‌ ‌and‌ ‌Kras‌ ‌mutational‌ ‌status‌ ‌not‌ ‌mutated.‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
OS‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌      ‌0.81‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ 0.69-0.94‌ ‌ ‌ ‌ ‌ ‌ ‌   ‌ ‌ ‌0.0062‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ 0.6696‌‌ ‌
  
PFS‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌  ‌0.66‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ 0.55-0.80‌ ‌ ‌ ‌ ‌ ‌ ‌  ‌ <0.0001‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌    ‌0.3332‌‌ ‌
  
ORR‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ 2.16‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ 1.64-2.86‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌<0.0001‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌    ‌0.5568‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
17‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
4.3.‌ ‌Previous‌ ‌experience‌ ‌and‌ ‌justification‌ ‌for‌ ‌the‌ ‌biweekly‌ ‌cetuximab‌ ‌regimen‌‌ ‌
  
‌ 
The‌‌standard‌‌administration‌‌schedule‌‌for‌‌cetuximab‌‌involves‌‌a‌‌weekly‌‌infusion‌‌of‌‌the‌‌drug.‌‌The‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
biweekly‌‌form‌‌of‌‌administration‌‌(ie‌‌every‌‌14‌‌days)‌‌has‌‌two‌‌advantages:‌‌it‌‌is‌‌more‌‌comfortable‌‌for‌‌
 
 
 
 
 
 
 
 
 
 
     
 
 
 
patients‌ ‌and‌ ‌represents‌ ‌a‌ ‌saving‌ ‌of‌ ‌resources‌ ‌for‌ ‌health‌ ‌systems.‌ ‌ 
However,‌‌this‌‌benefit‌‌would‌‌be‌‌greater‌‌in‌‌the‌‌case‌‌of‌‌treatment‌‌of‌‌CRC‌‌with‌‌cetuximab,‌‌because‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
most‌ ‌chemotherapy‌ ‌regimens‌ ‌with‌ ‌which‌ ‌cetuximab‌ ‌is‌ ‌combined‌ ‌are‌ ‌administered‌ ‌every‌ ‌14‌ ‌days.‌ ‌ 
‌ 
This‌ ‌possibility‌ ‌has‌ ‌been‌ ‌studied‌ ‌in‌ ‌clinical‌ ‌trials‌ ‌based‌ ‌on‌ ‌a‌ ‌previous‌ ‌demonstration‌ ‌that‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
pharmacokinetics‌ ‌and‌ ‌pharmacodynamics‌ ‌of‌ ‌the‌ ‌weekly‌ ‌and‌ ‌biweekly‌ ‌regimens‌ ‌are‌ ‌equivalent.‌‌
 
 
 
 
 
 
 
 
 
 
 
Phase‌‌II‌‌clinical‌‌trials‌‌of‌‌combination‌‌of‌‌cetuximab‌‌with‌‌chemotherapy‌‌provide‌‌data‌‌that‌‌support‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌hypothesis‌ ‌that‌ ‌the‌ ‌toxicity‌ ‌and‌ ‌efficacy‌ ‌of‌ ‌the‌ ‌biweekly‌ ‌regimen‌ ‌is‌ ‌similar‌ ‌to‌ ‌the‌ ‌weekly‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
regimen.‌ ‌ 
‌ 
The‌‌evidence‌‌behind‌‌the‌‌decision‌‌to‌‌use‌‌the‌‌biweekly‌‌cetuximab‌‌regimen‌‌in‌‌this‌‌trial‌‌is‌‌detailed‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
below:‌ ‌ 
A‌‌prospective,‌‌multicenter,‌‌uncontrolled‌‌clinical‌‌trial‌‌presented‌‌at‌‌the‌‌ASCO‌‌2008‌‌GI‌‌Symposium,‌‌
 
 
 
 
 
 
   
 
 
 
 
 
evaluating‌ ‌the‌ ‌safety‌ ‌profile‌ ‌of‌ ‌70‌ ‌patients‌ ‌treated‌‌with‌‌irinotecan‌‌plus‌‌cetuximab‌‌500‌‌mg‌‌/‌‌m2‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
every‌‌2‌‌weeks.‌‌Grade‌‌3‌‌and‌‌4‌‌toxicities‌‌included‌‌neutropenia‌‌(6%),‌‌diarrhea‌‌(6%),‌‌asthenia‌‌(7%),‌‌
   
 
   
   
 
 
 
 
 
 
 
 
and‌ ‌acne-like‌ ‌skin‌ ‌rash‌ ‌(11.4%).‌ ‌The‌ ‌primary‌ ‌endpoint‌ ‌of‌ ‌the‌ ‌study‌ ‌was‌ ‌PFS‌ ‌at‌ ‌12‌ ‌weeks.‌ ‌29‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌ ‌were‌ ‌evaluable,‌ ‌and‌ ‌the‌ ‌12-month‌ ‌PFS‌ ‌rate‌ ‌was‌ ‌52%.‌ ‌The‌ ‌authors‌ ‌concluded‌ ‌that‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab‌‌every‌‌2‌‌weeks‌‌is‌‌as‌‌active‌‌and‌‌as‌‌safe‌‌an‌‌option‌‌as‌‌standard‌‌weekly‌‌therapy.‌‌(J.M.‌‌Roca,‌‌
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
V.‌‌Alonso,‌‌C.‌‌Pericay‌‌et‌‌al.‌‌Cetuximab‌‌given‌‌every‌‌2‌‌weeks‌‌plus‌‌irinotecan‌‌is‌‌an‌‌active‌‌and‌‌safe‌‌
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
 
option‌ ‌for‌ ‌previously‌ ‌treated‌ ‌patients‌ ‌with‌ ‌metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌ASCO‌ ‌Gastrointestinal‌‌
 
 
 
 
 
 
 
 
 
 
 
Cancers‌ ‌Symposium‌ ‌2008;‌ ‌388).‌ ‌ 
‌ 
An‌ ‌exploratory‌ ‌trial‌ ‌of‌ ‌the‌ ‌biweekly‌ ‌treatment‌ ‌of‌ ‌irinotecan‌ ‌and‌ ‌cetuximab‌ ‌in‌ ‌patients‌ ‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic‌‌colorectal‌‌cancer‌‌who‌‌had‌‌progressed‌‌to‌‌at‌‌least‌‌one‌‌prior‌‌chemotherapy.‌‌In‌‌this‌‌trial‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
total‌‌of‌‌40‌‌patients‌‌were‌‌treated‌‌with‌‌Irinotecan‌‌180‌‌mg‌‌/‌‌m2‌‌and‌‌cetuximab‌‌500‌‌mg‌‌/‌‌m2‌‌every‌‌2‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
   
 
   
weeks‌‌in‌‌21-day‌‌cycles‌‌until‌‌unacceptable‌‌toxicity‌‌or‌‌disease‌‌progression.‌‌The‌‌overall‌‌response‌‌rate‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
was‌‌22.5%‌‌(2‌‌complete‌‌responses‌‌and‌‌7‌‌partial‌‌responses).‌‌The‌‌disease‌‌control‌‌rate‌‌was‌‌60%.‌‌Time‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
to‌‌progression‌‌was‌‌3.4‌‌months‌‌and‌‌overall‌‌survival‌‌was‌‌8‌‌months.‌‌The‌‌biweekly‌‌regimen‌‌proved‌‌to‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
   
be‌‌well‌‌tolerated.‌‌Grade‌‌3‌‌and‌‌4‌‌adverse‌‌effects‌‌were‌‌observed‌‌in‌‌12‌‌patients.‌‌The‌‌results‌‌of‌‌this‌‌
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
study‌ ‌show‌ ‌that‌ ‌the‌ ‌biweekly‌ ‌regimen‌‌in‌‌terms‌‌of‌‌toxicity‌‌and‌‌efficacy‌‌is‌‌similar‌‌to‌‌the‌‌weekly‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
administration‌‌regimen.‌‌(Martín-Martorell‌‌P,‌‌Roselló‌‌s,‌‌Rodriguez‌‌Braun‌‌E,‌‌Chirivella‌‌I,‌‌Bosch‌‌A,‌‌
 
 
   
   
 
 
 
   
 
 
Cervantes‌‌A.‌‌Biweekly‌‌cetuximab‌‌and‌‌irinotecan‌‌in‌‌advanced‌‌colorectal‌‌cancer‌‌patients‌‌progressing‌‌
 
 
 
 
 
   
 
 
 
 
 
after‌‌at‌‌least‌‌one‌‌previous‌‌line‌‌of‌‌chemotherapy:‌‌results‌‌of‌‌a‌‌phase‌‌II‌‌single‌‌institution‌‌trial.‌‌Br‌‌J‌‌
 
 
 
 
 
 
 
 
 
   
   
 
 
 
   
Cancer‌ ‌2008;‌ ‌99:‌ ‌455-8).‌ ‌ 
‌ 
A‌ ‌single-center‌ ‌clinical‌ ‌trial‌ ‌of‌ ‌74‌ ‌refractory‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌patients‌ ‌treated‌ ‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
irinotecan‌‌and‌‌cetuximab‌‌500‌‌mg‌‌/‌‌m2‌‌every‌‌2‌‌weeks.‌‌Duration‌‌of‌‌treatment,‌‌ORR,‌‌median‌‌time‌‌to‌‌
 
 
 
 
   
 
   
 
 
 
 
 
 
   
progression,‌ ‌and‌ ‌median‌ ‌overall‌ ‌survival‌ ‌were‌ ‌4.3‌ ‌months,‌ ‌25%,‌ ‌5.4‌ ‌months,‌ ‌and‌ ‌8.9‌ ‌months,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
respectively.‌‌Treatment‌‌was‌‌well‌‌tolerated.‌‌(Pfeiffer‌‌P,‌‌Nielsen‌‌D,‌‌Bjerregaard‌‌J,‌‌QvortupC,‌‌Yilmaz‌‌
 
 
 
 
 
   
 
 
   
 
 
M,‌ ‌Jensen‌‌B.‌‌Biweekly‌‌cetuximab‌‌and‌‌irinotecan‌‌as‌‌third-line‌‌therapy‌‌in‌‌patients‌‌with‌‌advanced‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
colorectal‌ ‌cancer‌ ‌after‌ ‌failure‌ ‌to‌ ‌irinotecan,‌ ‌oxaliplatin‌ ‌and‌ ‌5-fluoracil.‌ ‌Ann‌ ‌Oncol‌ ‌2008;‌ ‌19:‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
1141-5)‌ ‌ 
‌ 
‌ ‌
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
18‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
A‌‌study‌‌has‌‌been‌‌published‌‌retrospectively‌‌comparing‌‌the‌‌efficacy‌‌and‌‌safety‌‌of‌‌the‌‌administration‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of‌‌cetuximab‌‌in‌‌association‌‌with‌‌irinotecan‌‌in‌‌two‌‌treatment‌‌schedules,‌‌once‌‌a‌‌week‌‌or‌‌every‌‌two‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
weeks‌ ‌in‌ ‌patients‌ ‌with‌ ‌metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌The‌ ‌clinical‌ ‌data‌ ‌of‌ ‌50‌ ‌patients‌ ‌who‌ ‌had‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
received‌‌treatment‌‌with‌‌cetuximab‌‌separated‌‌into‌‌two‌‌groups‌‌were‌‌studied.‌‌The‌‌patients‌‌in‌‌the‌‌first‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
group‌‌(N‌‌=‌‌32)‌‌had‌‌been‌‌treated‌‌with‌‌an‌‌initial‌‌dose‌‌of‌‌400‌‌mg‌‌/‌‌m2,‌‌followed‌‌by‌‌a‌‌weekly‌‌infusion‌‌
 
   
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
of‌‌250‌‌mg‌‌/‌‌m2‌‌of‌‌cetuximab.‌‌The‌‌patients‌‌in‌‌the‌‌second‌‌group‌‌(N‌‌=‌‌18)‌‌had‌‌received‌‌cetuximab‌‌
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
every‌‌two‌‌weeks‌‌at‌‌a‌‌dose‌‌of‌‌500‌‌mg‌‌/‌‌m2.‌‌Tumor‌‌response,‌‌time‌‌to‌‌progression,‌‌overall‌‌survival,‌‌
 
 
     
 
 
 
   
 
 
 
 
 
 
 
 
and‌‌toxicity‌‌were‌‌compared‌‌in‌‌both‌‌groups.‌‌All‌‌patients‌‌had‌‌received‌‌irinotecan‌‌and‌‌5-fluorouracil‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌most‌ ‌had‌ ‌previously‌ ‌received‌ ‌oxaliplatin.‌ ‌The‌ ‌median‌ ‌follow-up‌ ‌for‌ ‌all‌ ‌patients‌ ‌was‌ ‌34.2‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
months.‌‌The‌‌rates‌‌of‌‌time‌‌to‌‌progression‌‌and‌‌7-month‌‌overall‌‌survival‌‌were‌‌similar‌‌in‌‌both‌‌groups.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
Although‌‌the‌‌result‌‌of‌‌the‌‌trial‌‌taking‌‌into‌‌account‌‌the‌‌variable‌‌"disease‌‌control‌‌(partial‌‌response‌‌+‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
stable‌ ‌disease)"‌ ‌was‌ ‌not‌ ‌statistically‌ ‌significant‌ ‌(56.3%‌ ‌of‌ ‌the‌ ‌patients‌ ‌who‌ ‌received‌‌cetuximab‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
weekly,‌‌compared‌‌to‌‌77.8%‌‌in‌‌the‌‌other‌‌group‌‌(P‌‌=‌‌0.21‌‌)),‌‌it‌‌is‌‌important‌‌to‌‌note‌‌that‌‌the‌‌most‌‌
 
 
 
 
 
 
 
 
   
 
     
 
 
 
 
 
 
relevant‌‌adverse‌‌event‌‌was‌‌dermatological‌‌toxicity‌‌and‌‌only‌‌one‌‌patient‌‌in‌‌each‌‌group‌‌had‌‌a‌‌grade‌‌3‌‌
 
 
 
 
 
 
 
 
 
   
 
 
   
   
adverse‌ ‌reaction.‌ ‌The‌ ‌results‌ ‌of‌ ‌this‌ ‌study‌ ‌indicate‌ ‌that‌ ‌the‌ ‌efficacy‌ ‌between‌ ‌the‌ ‌weekly‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biweekly‌‌regimen‌‌of‌‌cetuximab‌‌is‌‌similar‌‌without‌‌increasing‌‌toxicity‌‌in‌‌association‌‌with‌‌irinotecan.‌‌
 
 
 
   
 
 
 
   
 
 
 
(Mrabti‌ ‌H,‌ ‌De‌ ‌la‌ ‌Fouchardiere‌ ‌C,‌ ‌Desseigne‌ ‌F,‌ ‌Dussart‌ ‌S,‌ ‌Negrier‌ ‌S,‌ ‌Errihani‌ ‌H.‌ ‌Irinotecan‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
associated‌‌with‌‌cetuximab‌‌given‌‌every‌‌2‌‌weeks‌‌versus‌‌cetuximab‌‌weekly‌‌in‌‌metastatic‌‌colorectal‌‌
 
 
 
 
   
 
 
 
 
 
 
 
cancer.‌ ‌J‌ ‌Cancer‌ ‌Res‌ ‌Ther.‌ ‌2009‌ ‌Oct-Dec;‌ ‌5‌ ‌(4‌ ‌):‌ ‌272-6)‌ ‌ 
‌ 
A‌‌phase‌‌I‌‌clinical‌‌trial‌‌reported‌‌that‌‌cetuximab‌‌500‌‌mg‌‌/‌‌m2‌‌administered‌‌every‌‌2‌‌weeks‌‌exhibits‌‌
 
   
 
 
 
 
 
 
   
 
 
   
 
 
the‌ ‌same‌ ‌pharmacokinetic‌ ‌profile‌ ‌as‌ ‌the‌ ‌approved‌ ‌weekly‌ ‌regimen‌ ‌and‌ ‌that‌ ‌it‌ ‌can‌ ‌be‌ ‌safely‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
administered‌ ‌every‌ ‌2‌ ‌weeks‌ ‌at‌ ‌500‌ ‌mg‌ ‌/‌ ‌m2‌ ‌without‌ ‌major‌ ‌differences‌ ‌in‌ ‌pharmacodynamic‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
profiles.‌‌Concluding‌‌that‌‌the‌‌biweekly‌‌alternative‌‌seems‌‌to‌‌be‌‌an‌‌adequate‌‌alternative‌‌to‌‌the‌‌weekly‌‌
 
 
 
 
 
 
   
 
 
 
   
 
 
regimen.‌‌(J.Tabernero,‌‌A.‌‌Cervantes,‌‌E.‌‌Martinelli‌‌et‌‌al.‌‌Optimal‌‌dose‌‌of‌‌cetuximab‌‌(C)‌‌given‌‌every‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
2‌‌weeks‌‌(q2w):‌‌A‌‌phase‌‌I‌‌pharmacokinetic‌‌(PK)‌‌and‌‌pharmacodynamic‌‌(PD)‌‌study‌‌of‌‌weekly‌‌and‌‌
 
 
   
   
 
 
 
 
 
 
 
 
 
q2w‌‌schedules‌‌in‌‌patients‌‌with‌‌metastatic‌‌colorectal‌‌cancer.‌‌Ann‌‌Oncol.‌‌2009‌‌Nov‌‌25,‌‌J‌‌Clin‌‌Oncol.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
2010‌ ‌Mar‌ ‌1;‌ ‌28‌ ‌(7):‌ ‌1181-9.‌ ‌ 
‌ 
‌ 
These‌‌publications‌‌strongly‌‌support‌‌the‌‌concept‌‌of‌‌equivalence,‌‌in‌‌terms‌‌of‌‌efficacy‌‌and‌‌toxicity‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab,‌ ‌between‌ ‌the‌ ‌biweekly‌ ‌and‌ ‌weekly‌ ‌form‌ ‌of‌ ‌administration‌ ‌of‌ ‌this‌ ‌drug.‌ ‌ 
‌ 
After‌ ‌the‌ ‌demonstration‌ ‌of‌ ‌differences‌ ‌in‌ ‌the‌ ‌clinical‌ ‌benefit‌ ‌obtained‌‌in‌‌treatment‌‌with‌‌weekly‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab,‌‌among‌‌patients‌‌with‌‌metastatic‌‌CRC,‌‌taking‌‌into‌‌account‌‌the‌‌KRAS‌‌mutational‌‌status,‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
clinical‌ ‌trial‌ ‌with‌ ‌the‌ ‌secondary‌ ‌objective‌ ‌of‌ ‌discerning‌ ‌the‌ ‌toxicity‌ ‌profile‌ ‌is‌ ‌justified.‌ ‌when‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab‌ ‌is‌ ‌given‌ ‌biweekly.‌ ‌ 
‌ 
4.4‌ ‌Justification‌ ‌of‌ ‌the‌ ‌biomarkers‌ ‌under‌ ‌study‌ ‌
 
‌ 
4.4.1‌ ‌Role‌ ‌of‌ ‌the‌ ‌IGFR‌ ‌pathway‌ ‌in‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌ 
‌ 
IGFR‌‌is‌‌hyper-expressed‌‌in‌‌CRC.‌‌However,‌‌no‌‌IGFR‌‌amplification‌‌or‌‌mutations‌‌have‌‌been‌‌found‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
in‌ ‌CCR,‌ ‌so‌ ‌it‌ ‌is‌ ‌likely‌ ‌that‌ ‌IGFR‌ ‌transcription‌ ‌activation‌ ‌mechanisms‌ ‌are‌ ‌involved‌ ‌in‌ ‌tumor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
oncogenesis.‌‌IGFR‌‌activation‌‌leads‌‌to‌‌phosphorylation‌‌of‌‌r‌‌EGF‌‌through‌‌the‌‌autocrine‌‌/‌‌paracrine‌‌
 
 
 
 
 
 
   
 
 
 
   
 
pathway‌ ‌through‌ ‌a‌ ‌metalloproteinase‌ ‌cleavage‌ ‌mechanism‌ ‌of‌‌different‌‌EGF-like‌‌ligands‌‌such‌‌as‌‌
 
   
 
 
 
 
 
 
 
 
 
heparin-binding‌ ‌EGF,‌ ‌ampheregulin,‌ ‌or‌ ‌tumor‌ ‌necrosis‌ ‌factor‌ ‌alpha‌‌(Roudabush‌‌et‌‌al.‌‌al.,‌‌2000;‌
 
 
 
 
 
 
 
 
 
 
 
 
 
El-Shewy‌ ‌et‌ ‌al.,‌ ‌2004).‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
19‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
4.4.2‌ ‌MMP-7‌ ‌and‌ ‌its‌ ‌relationship‌ ‌with‌ ‌the‌ ‌IGF‌ ‌system‌ ‌ 
‌ 
MMP-7‌‌is‌‌a‌‌metalloproteinase‌‌secreted‌‌in‌‌the‌‌tumor‌‌microenvironment‌‌by‌‌neoplastic‌‌cells‌‌that‌‌acts,‌‌
     
 
   
 
 
 
 
 
 
 
 
normally‌ ‌promoting‌ ‌invasion,‌ ‌tumor‌ ‌progression‌ ‌and‌ ‌the‌ ‌generation‌ ‌of‌ ‌metastases.‌ ‌This‌‌
 
 
 
 
 
 
 
 
 
 
 
metalloproteinase‌‌can‌‌degrade‌‌proteins‌‌of‌‌the‌‌IGRF‌‌pathway‌‌with‌‌a‌‌pro-apoptotic‌‌function‌‌such‌‌as‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
IGFBP-3‌‌(Miyamoto‌‌et‌‌al.,‌‌2004)‌‌and‌‌also‌‌activate‌‌EGFr‌‌(Tan‌‌et‌‌al.,‌‌2005).‌‌EGFr‌‌can‌‌also‌‌stimulate‌‌
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
the‌‌expression‌‌of‌‌MMP-7.‌‌Several‌‌in‌‌vitro‌‌studies‌‌correlate‌‌activation‌‌of‌‌the‌‌IGFR‌‌pathway‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
resistance‌ ‌to‌ ‌EGFr‌ ‌inhibitors‌ ‌(Chakravarti‌ ‌et‌ ‌al.,‌ ‌2002;‌ ‌Desbois-Mouthon‌ ‌et‌ ‌al.,‌ ‌2006).‌ ‌ 
‌ 
It‌‌has‌‌been‌‌observed‌‌in‌‌vitro‌‌that,‌‌in‌‌the‌‌native‌‌cell‌‌line‌‌HT-29,‌‌MMP-7‌‌increases‌‌after‌‌48‌‌hours‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment‌‌with‌‌oxaliplatin‌‌and‌‌that‌‌the‌‌basal‌‌levels‌‌of‌‌MMP-7‌‌in‌‌HT-29‌‌cells‌‌resistant‌‌to‌‌oxaliplatin‌‌
 
 
 
 
 
 
 
 
 
   
 
 
   
 
(HT-20‌‌OXL‌‌-R)‌‌are‌‌4‌‌times‌‌higher‌‌than‌‌in‌‌native‌‌HT-29‌‌cells‌‌(Almendro‌‌et‌‌al.,‌‌Plos‌‌One‌‌2009).‌‌
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
We‌ ‌hypothesized‌ ‌that‌ ‌chemotherapy‌ ‌or‌ ‌hypoxia‌ ‌might‌ ‌increase‌ ‌MMP-7.‌ ‌In‌ ‌fact,‌ ‌under‌‌hypoxic‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
conditions,‌ ‌one‌ ‌of‌ ‌the‌ ‌most‌ ‌induced‌ ‌genes‌ ‌was‌ ‌MMP-7‌ ‌(Burke‌ ‌et‌ ‌al.,‌ ‌2003).‌ ‌ 
We‌ ‌have‌ ‌observed‌ ‌in‌ ‌untreated‌ ‌colorectal‌ ‌cancer‌ ‌patients‌ ‌that‌ ‌MMP-7‌ ‌increases‌ ‌with‌ ‌disease‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
progression,‌‌and‌‌that‌‌this‌‌increase‌‌is‌‌associated‌‌with‌‌a‌‌reduction‌‌in‌‌IGFBP-3‌‌levels‌‌(Gallego‌‌et‌‌al.,‌‌
 
 
 
 
   
 
   
 
 
 
 
   
 
2009).‌ ‌In‌ ‌HT-29‌ ‌OXL-R‌ ‌cells,‌‌IGFBP-2‌‌has‌‌higher‌‌levels‌‌compared‌‌to‌‌native‌‌HT-29‌‌cells.‌‌This‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
increase‌‌in‌‌the‌‌level‌‌of‌‌IGFBP-2‌‌can‌‌cause‌‌apoptosis‌‌due‌‌to‌‌the‌‌down‌‌regulation‌‌of‌‌pIGF-1R‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pAKT,‌ ‌although‌ ‌this‌ ‌will‌ ‌not‌ ‌be‌ ‌the‌ ‌case‌ ‌in‌ ‌HT-29-R‌ ‌cells‌ ‌that‌ ‌express‌ ‌the‌ ‌double‌ ‌positivity‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
condition‌ ‌(pIGF-1R‌ ‌+‌ ‌and‌ ‌MMP-‌ ‌7‌ ‌+).‌ ‌Recently,‌ ‌this‌ ‌resistant‌ ‌phenotype‌ ‌related‌ ‌to‌ ‌increased‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
IGF-1R‌‌phosphorylation‌‌has‌‌been‌‌reported‌‌by‌‌Dallas‌‌et‌‌al.‌‌(2009).‌‌We‌‌propose‌‌that‌‌after‌‌treatment‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
with‌‌OXL,‌‌IGFBP‌‌induces‌‌apoptosis‌‌by‌‌inhibiting‌‌phosphorylation‌‌of‌‌pIGF-1R‌‌in‌‌HT-29‌‌cell‌‌lines‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
but‌ ‌not‌ ‌in‌ ‌HT-29R,‌ ‌by‌ ‌constitutive‌ ‌activation‌ ‌of‌ ‌MMP-7.‌ ‌ 
‌ 
In‌ ‌the‌ ‌clinical‌ ‌context,‌ ‌our‌ ‌group‌ ‌retrospectively‌ ‌investigated‌‌the‌‌role‌‌of‌‌IGFRp‌‌and‌‌MMP-7‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastases‌ ‌or‌ ‌primary‌ ‌CRC‌ ‌in‌ ‌a‌ ‌group‌ ‌of‌ ‌patients‌‌with‌‌advanced‌‌colorectal‌‌cancer‌‌treated‌‌with‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
cetuximab‌‌or‌‌panitumumab‌‌as‌‌second‌‌or‌‌third‌‌line‌‌treatment‌‌(Horndler‌‌et‌‌al.‌‌al.,‌‌2009).‌‌A‌‌total‌‌of‌‌
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
104‌‌patients‌‌with‌‌available‌‌tissue‌‌from‌‌168‌‌patients‌‌were‌‌taken‌‌to‌‌analyze‌‌the‌‌mutational‌‌status‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RAS‌‌and‌‌BRAF‌‌and‌‌the‌‌expression‌‌of‌‌MMP-7‌‌and‌‌IGFRp.‌‌There‌‌were‌‌no‌‌significant‌‌differences‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
response‌‌rate‌‌(18.8%‌‌vs.‌‌15%),‌‌PFS‌‌(3.3‌‌vs.‌‌3‌‌m),‌‌and‌‌OS‌‌(7.76‌‌vs.‌‌7‌‌m)‌‌between‌‌the‌‌total‌‌and‌‌
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
selected‌ ‌cohorts.‌ ‌Expression‌ ‌of‌ ‌MMP-7‌ ‌and‌ ‌IGFRp‌ ‌was‌ ‌observed‌ ‌in‌‌49%‌‌and‌‌52%‌‌of‌‌patients,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
respectively.‌‌Co-expression‌‌of‌‌MMP-7‌‌and‌‌IGFRp‌‌(double‌‌positive‌‌group‌‌[IGFRp‌‌+‌‌/‌‌MMP-7‌‌+])‌‌
 
 
 
 
 
 
 
 
 
     
 
 
was‌‌observed‌‌in‌‌27/104‌‌patients‌‌(26%)‌‌and‌‌in‌‌15/71‌‌patients‌‌(24%)‌‌in‌‌patients‌‌with‌‌RAS‌‌and‌‌BRAF‌‌
 
   
 
 
 
   
 
 
   
 
 
 
 
 
not‌‌mutated.‌‌There‌‌was‌‌no‌‌correlation‌‌between‌‌RAS‌‌and‌‌BRAF‌‌mutational‌‌status‌‌and‌‌the‌‌double‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
positive‌ ‌group‌ ‌(IGFRp‌ ‌+‌ ‌/‌ ‌MMP-7‌ ‌+)‌ ‌(p‌ ‌=‌ ‌0.52).‌ ‌In‌ ‌the‌ ‌subgroup‌ ‌of‌ ‌patients‌ ‌with‌ ‌RAS‌ ‌and‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
non-mutated‌ ‌BRAF,‌ ‌the‌ ‌group‌ ‌with‌ ‌double‌ ‌positivity‌ ‌(IGFRp‌ ‌+‌ ‌/‌ ‌MMP-7‌‌+)‌‌presented‌‌a‌‌lower‌‌
 
 
 
 
 
 
 
     
 
 
   
 
response‌ ‌than‌ ‌patients‌ ‌without‌ ‌double‌ ‌positivity‌ ‌(p‌ ‌=‌ ‌0.002)‌ ‌and‌ ‌showed‌ ‌a‌ ‌trend‌ ‌towards‌ ‌a‌‌
 
 
 
 
 
 
 
 
 
 
   
 
   
disappointing‌ ‌PFS‌ ‌of‌ ‌91‌ ‌days‌‌versus‌‌121‌‌days‌‌(p‌‌=‌‌0.09)‌‌and‌‌a‌‌poor‌‌OS‌‌of‌‌196‌‌days‌‌(95%‌‌CI:‌‌
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
175-215)‌ ‌versus‌ ‌294‌ ‌days‌ ‌(95%‌ ‌CI:‌ ‌182-344)‌ ‌(p‌ ‌=‌ ‌0.002).‌ ‌ 
‌ 
4.4.3‌ ‌BRAF‌ ‌ 
‌ 
Different‌‌publications‌‌have‌‌established‌‌the‌‌prognostic‌‌and‌‌predictive‌‌role‌‌of‌‌the‌‌BRAF‌‌mutation‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
metastatic‌‌colon‌‌cancer.‌‌The‌‌BRAF‌‌mutation‌‌is‌‌present‌‌in‌‌5‌‌to‌‌8%‌‌of‌‌cases.‌‌In‌‌the‌‌OPUS‌‌study‌
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
(discussed‌‌above),‌‌a‌‌retrospective‌‌analysis‌‌was‌‌made‌‌of‌‌the‌‌prognostic‌‌and‌‌predictive‌‌value‌‌of‌‌this‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
mutation‌‌in‌‌the‌‌patients‌‌included‌‌in‌‌the‌‌study.‌‌The‌‌percentage‌‌of‌‌patients‌‌with‌‌mutated‌‌BRAF‌‌was‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.9%,‌‌and‌‌this‌‌mutation‌‌was‌‌associated‌‌with‌‌both‌‌overall‌‌survival‌‌(HR‌‌1.82,‌‌95%‌‌CI‌‌1.36-2.43)‌‌but‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
not‌‌with‌‌progression-free‌‌survival‌‌(HR‌‌1.14,‌‌95%‌‌CI‌‌0.86-1.52).‌‌.‌‌There‌‌are‌‌other‌‌studies,‌‌such‌‌as‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
20‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
those‌‌of‌‌Di‌‌Nicolantonio‌‌et‌‌al.‌‌(JCO‌‌2008)‌‌and‌‌Laurent-Puig‌‌et‌‌al.‌‌(JCO‌‌2009)‌‌who‌‌also‌‌evaluate‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
the‌ ‌prognostic‌ ‌and‌‌predictive‌‌role‌‌of‌‌BRAF.‌‌In‌‌both‌‌studies,‌‌the‌‌BRAF‌‌mutation‌‌was‌‌associated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with‌‌poorer‌‌overall‌‌survival‌‌and‌‌worse‌‌progression-free‌‌survival.‌‌Own‌‌data‌‌(under‌‌review,‌‌pending‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
publication)‌‌confirm‌‌these‌‌results.‌‌The‌‌interest‌‌of‌‌studying‌‌this‌‌marker,‌‌rather‌‌than‌‌identifying‌‌it‌‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
a‌ ‌new‌ ‌prognostic‌ ‌marker,‌ ‌lies‌ ‌in‌ ‌establishing‌ ‌its‌ ‌magnitude‌ ‌in‌ ‌the‌ ‌context‌ ‌of‌ ‌other‌ ‌prognostic‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
markers‌ ‌(creation‌ ‌of‌ ‌a‌ ‌score),‌ ‌as‌ ‌proposed‌ ‌in‌ ‌this‌ ‌protocol.‌‌ ‌
  
‌ 
4.4.4‌ ‌PTEN‌ ‌ 
‌ 
PTEN,‌ ‌like‌ ‌BRAF,‌ ‌is‌ ‌another‌ ‌component‌ ‌of‌ ‌the‌ ‌MAPK‌ ‌signaling‌ ‌pathway‌ ‌and‌ ‌therefore‌ ‌its‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mutational‌‌status‌‌could‌‌affect‌‌the‌‌efficacy‌‌of‌‌cetuximab.‌‌In‌‌the‌‌Laurent-Puig‌‌study‌‌discussed‌‌above‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(JCO‌‌2009)‌‌they‌‌also‌‌evaluate‌‌this‌‌marker.‌‌PTEN‌‌expression‌‌was‌‌absent‌‌in‌‌19.9%‌‌​of‌‌KRAS‌‌WT‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌ ‌and‌ ‌was‌ ‌associated‌ ‌with‌ ‌both‌ ‌progression-free‌ ‌survival‌ ‌and‌ ‌overall‌ ‌survival.‌ ‌Similarly,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
another‌‌study‌‌(Loupakis‌‌et‌‌al.‌‌JCO‌‌2009)‌‌evaluated‌‌the‌‌predictive‌‌role‌‌of‌‌loss‌‌of‌‌PTEN‌‌expression‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
in‌‌metastases‌‌in‌‌patients‌‌with‌‌colorectal‌‌cancer‌‌in‌‌progression‌‌to‌‌irinotecan‌‌treated‌‌with‌‌irinotecan‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
plus‌‌cetuximab.‌‌In‌‌this‌‌study,‌‌the‌‌loss‌‌of‌‌PTEN‌‌expression‌‌in‌‌metastases‌‌was‌‌shown‌‌to‌‌be‌‌associated‌‌
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
with‌ ‌worse‌ ‌progression-free‌ ‌survival‌ ‌(p‌ ‌=‌ ‌0.005).‌ ‌ 
For‌ ‌all‌ ‌this,‌ ‌we‌ ‌consider‌ ‌that‌ ‌the‌ ‌expression‌ ‌of‌ ‌PTEN,‌ ‌together‌ ‌with‌ ‌BRAF,‌ ‌is‌ ‌another‌ ‌of‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
markers‌ ‌that‌ ‌we‌ ‌must‌ ‌include‌ ‌in‌ ‌the‌ ‌characterization‌ ‌of‌ ‌the‌ ‌MAPK‌ ‌pathway‌ ‌in‌ ‌this‌ ‌protocol.‌‌ ‌
  
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
21‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
4.5‌  ‌Rationale‌ ‌for‌ ‌this‌ ‌trial‌ ‌
 
‌ 
Advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌(CCRA)‌ ‌is‌ ‌a‌ ‌heterogeneous‌ ‌disease‌ ‌and‌ ‌the‌‌
 
   
 
 
 
 
 
   
 
 
 
 
classification‌‌of‌‌patients‌‌is‌‌currently‌‌poor.‌‌Approximately‌‌twenty‌‌percent‌‌of‌‌patients‌‌have‌‌favorable‌‌
 
 
   
 
 
 
 
 
 
 
 
 
stages‌ ‌(less‌ ‌than‌ ‌4‌‌nodules‌‌in‌‌the‌‌liver‌‌and‌‌less‌‌than‌‌5‌‌cm)‌‌and‌‌are‌‌suitable‌‌for‌‌local‌‌treatments‌‌
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
(surgery‌‌or‌‌local‌‌ablative‌‌therapies).‌‌Additionally,‌‌10-15%‌‌of‌‌patients‌‌have‌‌a‌‌poor‌‌functional‌‌status‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
(ECOG>‌ ‌2)‌ ‌or‌ ‌are‌ ‌impaired‌‌due‌‌to‌‌geriatric‌‌syndromes‌‌and‌‌/‌‌or‌‌co-morbidity‌‌with‌‌diseases‌‌that‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
oppose‌ ‌any‌ ‌strategy‌ ‌other‌ ‌than‌ ‌the‌ ‌best‌ ‌supportive‌ ‌therapy.‌ ‌.‌ ‌The‌ ‌rest‌ ‌of‌ ‌the‌ ‌patients‌ ‌(suitable‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
patients‌‌not‌‌suitable‌‌for‌‌radical‌‌surgery)‌‌constitute‌‌the‌‌population‌‌of‌‌patients‌‌treated‌‌with‌‌palliative‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapies.‌‌Despite‌‌this,‌‌not‌‌all‌‌patients‌‌have‌‌the‌‌same‌‌prognosis.‌‌Patients‌‌with‌‌ECOG‌‌0.1‌‌and‌‌LDH‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
levels‌ ‌<ULN‌ ‌(intermediate-risk‌ ‌patients)‌ ‌have‌ ‌better‌ ‌PFS‌ ‌and‌ ‌OS‌ ‌regardless‌ ‌of‌ ‌therapy‌ ‌in‌ ‌all‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
randomized‌‌clinical‌‌trials‌‌(de‌‌Gramont‌‌et‌‌al,‌‌JCO‌‌2000;‌‌Douillard‌‌et‌‌al,‌‌Lancet‌‌2000;‌‌Koopman‌‌et‌‌
 
 
 
 
   
 
 
 
   
 
 
 
   
al,‌ ‌2007).‌ ‌ 
‌ 
The‌‌CRYSTAL‌‌study‌‌shows‌‌a‌‌benefit‌‌in‌‌PFS‌‌(1.5‌‌months)‌‌in‌‌non-mutated‌‌KRAS‌‌from‌‌FOLFIRI‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
plus‌‌cetuximab‌‌compared‌‌to‌‌FOLFIRI‌‌alone.‌‌Currently,‌‌the‌‌selection‌‌of‌‌patients‌‌for‌‌treatment‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab‌‌is‌‌based‌‌on‌‌the‌‌KRAS‌‌mutational‌‌status,‌‌which‌‌allows‌‌selecting‌‌those‌‌patients‌‌who‌‌will‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
not‌ ‌respond‌ ‌to‌ ‌therapy.‌ ‌Other‌ ‌activity‌ ‌markers‌ ‌should‌ ‌be‌ ‌evaluated.‌ ‌ 
‌ 
PTEN‌ ‌ 
The‌‌cytoplasmic‌‌expression‌‌of‌‌PTEN‌‌is‌‌inversely‌‌associated‌‌with‌‌PFS‌‌in‌‌colorectal‌‌cancer.‌‌There‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
are‌‌two‌‌main‌‌retrospective‌‌studies‌‌evaluating‌‌PTEN‌‌expression‌‌in‌‌patients‌‌treated‌‌with‌‌cetuximanb.‌‌
 
 
 
 
 
 
 
   
 
 
 
 
Prospective‌ ‌validation‌ ‌of‌ ‌this‌ ‌marker‌ ‌has‌ ‌not‌ ‌yet‌ ‌been‌ ‌developed.‌ ‌ 
‌ 
‌ 
 ‌Clinical‌ ‌Hypothesis‌ ‌ 
‌ 
Our‌‌hypothesis‌‌is‌‌that‌‌the‌‌proposed‌‌markers‌‌will‌‌make‌‌it‌‌possible‌‌to‌‌select‌‌those‌‌patients‌‌who‌‌will‌‌
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
benefit‌ ‌the‌ ‌most‌ ‌from‌ ‌biweekly‌ ‌cetuximab‌ ‌treatment.‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
22‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
4.6‌ ‌OBJECTIVES‌ ‌
 
4.6.1‌ ‌Principal‌ ‌Objective‌ ‌
 
Validation‌ ‌of‌ ‌the‌ ‌biomarkers‌ ‌BRAF,‌ ‌IGF1P‌ ‌/‌ ‌MMp7‌ ‌(DP)‌ ‌and‌ ‌PI3K-PTEN‌ ‌to‌ ‌predict‌ ‌PFS‌ ‌in‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌non-mutated‌‌KRAS‌‌treated‌‌with‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
standard‌ ‌chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy.‌ ‌ 
To‌‌identify‌‌new‌‌biomarkers‌‌that‌‌can‌‌predict‌‌progression-free‌‌survival‌‌(PFS)‌‌in‌‌non-mutated‌‌KRAS‌‌
 
 
 
 
 
 
 
 
 
   
 
 
patients‌ ‌treated‌ ‌with‌ ‌biweekly‌ ‌chemotherapy‌ ‌(QT)‌ ‌and‌ ‌cetuximab‌ ‌in‌ ‌first-line‌ ‌therapy.‌ ‌ 
The‌‌need‌‌to‌‌identify‌‌additional‌‌biomarkers‌‌of‌‌cetuximab‌‌efficacy‌‌stems‌‌from‌‌the‌‌small‌‌predictive‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
value‌‌of‌‌the‌‌current‌‌classification,‌‌based‌‌on‌‌KRAS‌‌mutational‌‌status,‌‌of‌‌the‌‌efficacy‌‌of‌‌biweekly‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab‌ ‌administration‌ ‌in‌ ‌the‌ ‌group‌ ‌of‌ ‌patients‌ ‌with‌ ‌the‌ ‌disease‌ ‌under‌ ‌study.‌ ‌ 
The‌ ‌proposed‌ ‌biomarkers‌ ‌are:‌ ‌ 
1‌ ‌BRAF‌ ‌mutations‌ ‌ 
2.IGF-1Rp‌ ‌/‌ ‌MMP-7‌ ‌(DP)‌ ‌ 
3.PIK3CA-PTEN.‌ ‌ 
Identifying‌ ‌additional‌‌factors‌‌that‌‌determine‌‌the‌‌efficacy‌‌of‌‌biweekly‌‌cetuximab‌‌will‌‌provide‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
scientific‌‌community‌‌with‌‌additional‌‌stratification‌‌factors‌‌for‌‌clinical‌‌trial‌‌design‌‌and‌‌better‌‌patient‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
selection‌ ‌for‌ ‌biweekly‌ ‌cetuximab‌ ‌treatment.‌ ‌ 
4.6.2‌ ‌Secondary‌ ‌Objectives‌‌ ‌
  
Secondary‌‌biological‌‌markers‌‌(MMP-7,‌‌IGF-1‌‌and‌‌IGFBP3)‌‌will‌‌be‌‌analyzed‌‌in‌‌serum‌‌and‌‌tumor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tissue‌ ‌to‌ ‌predict‌ ‌acquired‌ ‌resistance.‌ ‌ 
SG‌ ‌based‌ ‌on‌ ‌proposed‌ ‌classification‌ ‌ 
Objective‌ ‌response‌ ‌according‌ ‌to‌ ‌RECIST‌ ‌1.1‌ ‌(E.J.‌ ‌Cáncer‌ ‌2009;‌ ‌228-47)‌ ‌ 
Describe‌‌the‌‌safety‌‌profile‌‌of‌‌the‌‌Cetuximab‌‌500‌‌mg‌‌/‌‌m2‌‌every‌‌2‌‌weeks‌‌administration‌‌regimen‌‌in‌‌
 
 
 
 
 
 
 
 
   
 
   
 
 
   
the‌ ‌first-line‌ ‌setting‌ ‌including‌ ‌the‌ ‌incidence‌ ‌of‌ ‌AE‌ ‌and‌ ‌significant‌ ‌changes‌ ‌in‌ ‌laboratory‌ ‌parameters.‌ ‌ 
‌ 
To‌ ‌assess‌ ‌the‌ ‌objective‌‌response‌‌rate‌‌(ORR)‌‌and‌‌duration‌‌of‌‌response‌‌(RD)‌‌and‌‌overall‌‌survival‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(OS)‌‌in‌‌subjects‌‌treated‌‌with‌‌biweekly‌‌cetuximab‌‌in‌‌combination‌‌with‌‌FOLFOX6‌‌(m)‌‌or‌‌FOLFIRI‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(m)‌ ‌as‌ ‌a‌ ‌first-line‌ ‌chemotherapy‌ ‌regimen.‌ ‌for‌ ‌subjects‌ ‌with‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌with‌‌
 
   
 
 
 
 
 
 
 
 
 
 
non-mutated‌ ‌KRAS,‌ ‌according‌ ‌to‌ ‌the‌ ‌expression‌ ‌of‌ ‌the‌ ‌different‌ ‌proposed‌ ‌biomarkers.‌ ‌ 
‌ 
‌
 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
23‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
5.‌ ‌EXPERIMENTAL‌ ‌PLAN‌ ‌
 
5.1‌ ‌Study‌ ‌Design‌ ‌
 
‌ 
Single-arm,‌ ‌multicenter,‌ ‌and‌ ‌prospective‌ ‌phase‌ ‌II‌ ‌clinical‌ ‌trial‌ ‌for‌ ‌validation‌ ‌of‌ ‌biomarkers‌ ‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌non-mutated‌‌KRAS‌‌gene‌‌treated‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
with‌ ‌chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy.‌ ‌Patients‌ ‌with‌ ‌non-mutated‌‌
 
 
 
 
 
 
 
 
 
 
 
CCRAyM‌ ‌and‌ ‌KRAS‌ ‌will‌ ‌be‌ ‌eligible.‌ ‌ 
‌ 
Patients‌ ‌will‌ ‌be‌ ‌recruited‌ ‌over‌ ‌a‌ ‌24-month‌ ‌period.‌ ‌ 
‌ 
Before‌ ‌inclusion‌ ‌in‌ ‌the‌ ‌study‌ ‌and‌ ‌to‌‌confirm‌‌eligibility,‌‌the‌‌investigator‌‌or‌‌designee‌‌will‌‌send‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
sample‌‌of‌‌the‌‌primary‌‌tumor‌‌to‌‌the‌‌CUN,‌‌which‌‌will‌‌centrally‌‌review‌‌the‌‌status‌‌of‌‌KRAS‌‌(if‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patient‌‌already‌‌has‌‌a‌‌prior‌‌determination‌‌of‌‌the‌‌status‌‌of‌‌the‌‌KRAS‌‌gene,‌‌it‌‌can‌‌be‌‌included‌‌in‌‌the‌‌
 
 
   
 
 
 
 
 
 
 
 
   
 
 
 
 
 
assay‌‌without‌‌the‌‌need‌‌to‌‌re-determine‌‌K-RAS).‌‌At‌‌the‌‌same‌‌time,‌‌the‌‌investigator‌‌or‌‌designee‌‌will‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
review‌‌existing‌‌radiological‌‌images‌‌in‌‌addition‌‌to‌‌any‌‌other‌‌relevant‌‌clinical‌‌documents‌‌(reports,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
notes,‌ ‌etc.)‌ ‌to‌ ‌confirm‌ ‌that‌ ‌the‌ ‌subject‌ ‌has‌ ‌previously‌ ‌untreated‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
colorectal‌ ‌cancer.‌ ‌ 
‌ 
The‌ ‌proposed‌ ‌biomarkers‌‌will‌‌be‌‌measured‌‌at‌‌the‌‌beginning‌‌of‌‌the‌‌study.‌‌Investigators‌‌can‌‌treat‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌‌with‌‌CCRAyM‌‌and‌‌non-mutated‌‌KRAS‌‌with‌‌biweekly‌‌FOLFOX6‌‌(m)‌‌or‌‌FOLFIRI‌‌(m)‌‌+‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
cetuximab.‌ ‌Other‌ ‌investigative‌ ‌agents‌ ‌will‌ ‌be‌ ‌excluded.‌ ‌ 
‌ 
FOLFIRI‌ ‌(m)‌ ‌/‌ ‌FOLFOX6‌ ‌(m)‌ ‌will‌ ‌be‌ ‌administered‌ ‌once‌ ‌every‌ ‌2‌ ‌weeks‌ ‌until‌ ‌6‌ ‌months‌ ‌of‌‌
 
   
 
 
 
 
 
 
   
 
   
 
 
treatment,‌‌disease‌‌progression‌‌(PE),‌‌or‌‌unacceptable‌‌toxicity.‌‌Cetuximab‌‌will‌‌be‌‌administered‌‌every‌‌
 
 
 
 
 
 
 
 
 
 
 
 
2‌‌weeks‌‌as‌‌stipulated‌‌in‌‌this‌‌protocol‌‌until‌‌disease‌‌progression.‌‌If‌‌patients‌‌do‌‌not‌‌show‌‌progression‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
after‌‌6‌‌months‌‌of‌‌treatment‌‌with‌‌FOLFIRI‌‌(m)‌‌and‌‌FOLFOX6‌‌(m),‌‌they‌‌will‌‌continue‌‌to‌‌receive‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌monotherapy‌ ‌until‌ ‌progression.‌ ‌ 
‌ 
Subjects‌ ‌who‌ ‌stop‌ ‌receiving‌ ‌FOLFOX6‌ ‌(m)‌ ‌/‌ ‌FOLFIRI‌ ‌(m),‌ ‌for‌ ‌example‌ ‌due‌ ‌to‌ ‌toxicity,‌ ‌may‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
receive‌‌biweekly‌‌cetuximab‌‌as‌‌monotherapy‌‌until‌‌disease‌‌progression.‌‌Following‌‌discontinuation‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
biweekly‌‌cetuximab,‌‌the‌‌treatment‌‌period‌‌will‌‌end‌‌and‌‌subjects‌‌will‌‌attend‌‌a‌‌follow-up‌‌safety‌‌visit‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
30‌ ‌±‌ ‌3‌ ‌days‌ ‌later.‌ ‌ 
Throughout‌ ‌the‌ ‌trial,‌ ‌subjects‌ ‌will‌ ‌be‌ ‌assessed‌ ‌for‌ ‌tumor‌ ‌response‌ ‌using‌ ‌Response‌ ‌Assessment‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria‌‌for‌‌Solid‌‌Tumors‌‌(RECIST‌‌1.1).‌‌The‌‌tumor‌‌response‌‌of‌‌the‌‌subjects‌‌will‌‌be‌‌evaluated‌‌by‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT‌‌(helical‌‌or‌‌conventional)‌‌thoracic‌‌and‌‌abdominal‌‌performed‌‌in‌‌the‌‌baseline‌‌phase‌‌and‌‌every‌‌12‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks‌‌(three‌‌months)‌‌until‌‌the‌‌progression‌‌of‌‌the‌‌disease.‌‌In‌‌subjects‌‌with‌‌symptoms‌‌that‌‌indicate‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
disease‌ ‌progression,‌ ‌tumor‌ ‌response‌ ‌should‌ ‌be‌ ‌assessed‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌ ‌symptoms.‌ ‌ 
‌ 
Serum‌‌biomarker‌‌measurements‌‌will‌‌be‌‌performed:‌‌until‌‌disease‌‌progression‌‌is‌‌documented‌‌(every‌‌
 
 
 
 
 
 
 
 
   
 
 
12‌ ‌weeks‌ ‌+/-‌ ‌1‌ ‌week).‌ ‌ 
‌ 
All‌ ‌subjects‌ ‌who‌ ‌discontinue‌ ‌treatment‌ ‌before‌ ‌disease‌ ‌progression‌ ‌(eg,‌ ‌due‌ ‌to‌ ‌unacceptable‌‌
 
 
 
 
 
 
 
 
 
 
 
 
toxicities)‌ ‌will‌ ‌be‌ ‌followed‌ ‌for‌ ‌PFS‌ ‌(eg,‌ ‌radiographic‌ ‌tumor‌ ‌evaluations)‌ ‌every‌ ‌12‌ ‌weeks‌ ‌until‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression‌‌of‌‌the‌‌disease‌‌or‌‌the‌‌end‌‌of‌‌the‌‌study‌‌(unless‌‌the‌‌reason‌‌for‌‌abandoning‌‌the‌‌study‌‌is‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
total‌ ‌withdrawal‌ ‌of‌ ‌consent).‌ ‌ 
‌ 
Once‌‌the‌‌patient‌‌has‌‌progressed,‌‌the‌‌long-term‌‌follow-up‌‌period‌‌of‌‌24‌‌months‌‌will‌‌begin‌‌from‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
date‌ ‌of‌ ‌progression‌ ‌(every‌ ‌3‌ ‌months).‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
24‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
K-RAS,‌‌in‌‌patients‌‌who‌‌do‌‌not‌‌have‌‌a‌‌previous‌‌determination,‌‌and‌‌other‌‌markers‌‌of‌‌tumor‌‌tissue‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
will‌‌be‌‌measured‌‌at‌‌the‌‌University‌‌Clinic‌‌of‌‌Navarra‌‌(CUN)‌‌and‌‌the‌‌markers‌‌of‌‌the‌‌blood‌‌samples‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
will‌ ‌be‌ ‌measured‌ ‌at‌ ‌the‌ ‌Hospital‌ ‌Clínic‌ ‌de‌ ‌Barcelona‌ ‌(HCB)‌ ‌.‌ ‌ 
Biomarkers‌ ‌will‌ ‌be‌ ‌measured‌ ‌prior‌ ‌to‌ ‌patient‌ ‌enrollment.‌ ‌In‌ ‌addition,‌ ‌blood‌ ‌samples‌ ‌will‌ ‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
collected‌ ‌every‌ ‌3‌ ‌months‌ ‌until‌ ‌disease‌ ‌progression.‌ ‌ 
‌ 
The‌‌proposed‌‌biomarkers‌‌(BRAF,‌‌MMP7‌‌/‌‌IGF-1RP‌‌/‌‌MMP-7‌‌(DP),‌‌PIK3CA-PTEN)‌‌will‌‌be‌‌used‌‌
 
 
 
 
   
   
 
 
 
 
 
 
as‌‌independent‌‌variables‌‌in‌‌a‌‌multivariate‌‌model‌‌containing‌‌other‌‌established‌‌prognostic‌‌variables‌‌
 
 
 
   
 
 
 
 
 
 
 
to‌‌predict‌‌PFS.‌‌A‌‌classification‌‌will‌‌be‌‌constructed‌‌based‌‌on‌‌the‌‌ability‌‌to‌‌predict‌‌the‌‌response‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌biomarkers.‌‌ ‌
  
‌ 
‌ 
5.1.1‌ ‌Premature‌ ‌withdrawal‌ ‌of‌ ‌treatment:‌ ‌ 
‌ 
Treatment‌ ‌will‌ ‌be‌ ‌interrupted‌ ‌in‌ ‌case‌ ‌of:‌ ‌ 
Withdrawal‌ ‌of‌ ‌consent‌ ‌from‌ ‌the‌ ‌patient‌ ‌ 
Progressive‌ ‌disease‌ ‌ 
Intolerable‌ ‌toxicity‌ ‌ 
Investigator's‌ ‌decision‌ ‌based‌ ‌on‌ ‌what‌ ‌he‌ ‌considers‌ ‌best‌ ‌for‌ ‌the‌ ‌patient‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
25‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Study‌ ‌Schema‌‌ ‌
  
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
a‌ ‌Day‌ ‌1‌ ‌=‌ ‌day‌ ‌of‌ ‌the‌ ‌first‌ ‌treatment‌ ‌administration.‌ ‌ 
b‌‌Subjects'‌‌tumor‌‌response‌‌will‌‌be‌‌assessed‌‌every‌‌12‌‌weeks,‌‌throughout‌‌the‌‌trial‌‌until‌‌PE‌‌(per‌‌revised‌‌RECIST‌‌1.1‌‌criteria)‌‌or‌‌withdrawal‌‌from‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study.‌ ‌ 
c‌ ‌Subsequent‌ ‌cycles‌ ‌could‌ ‌be‌ ‌delayed‌ ‌due‌ ‌to‌ ‌toxicities‌ ‌associated‌ ‌with‌ ‌cetuximab‌ ‌or‌ ‌chemotherapy.‌ ‌ 
d‌ ‌All‌ ‌subjects‌ ‌who‌ ‌permanently‌ ‌discontinue‌ ‌treatment‌ ‌(discontinuation‌ ‌is‌ ‌considered‌ ‌completion‌ ‌of‌ ‌all‌‌treatment)‌‌for‌‌any‌‌reason‌‌will‌‌undergo‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
follow-up‌‌safety‌‌assessment‌‌30‌‌days‌‌±‌‌3‌‌days‌‌after‌‌the‌‌last‌‌dose‌‌of‌‌treatment.‌‌After‌‌the‌‌safety‌‌follow-up‌‌visit,‌‌subjects‌‌who‌‌have‌‌not‌‌progressed‌‌will‌‌
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be‌‌followed‌‌up‌‌every‌‌12‌‌weeks‌‌as‌‌defined‌‌in‌‌the‌‌study.‌‌Subjects‌‌who‌‌undergo‌‌surgery‌‌for‌‌metastases‌‌should‌‌follow‌‌the‌‌controls‌‌every‌‌12‌‌weeks‌‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
established‌ ‌in‌ ‌the‌ ‌protocol.‌ ‌In‌ ‌case‌ ‌of‌ ‌progression‌ ‌by‌ ‌RECIST‌ ‌1.1‌ ‌criteria‌ ‌,.‌ ‌Subjects‌ ‌will‌ ‌be‌ ‌monitored‌ ‌for‌ ‌disease‌ ‌status,‌ ‌subsequent‌ ‌cancer‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
treatment,‌ ‌and‌ ‌survival‌ ‌(long-term‌ ‌follow-up).‌ ‌ 
e‌ ‌All‌ ‌subjects‌ ‌who‌ ‌discontinue‌ ‌treatment‌ ‌prior‌ ‌to‌ ‌disease‌ ‌progression‌ ‌(eg,‌ ‌due‌ ‌to‌ ‌unacceptable‌ ‌toxicities)‌ ‌will‌ ‌be‌ ‌followed‌ ‌up‌ ‌for‌ ‌PFS‌ ‌(eg,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
radiographic‌‌tumor‌‌assessments)‌‌every‌‌12‌‌weeks‌‌until‌‌the‌‌progression‌‌of‌‌the‌‌disease‌‌or‌‌the‌‌end‌‌of‌‌the‌‌study‌‌(unless‌‌the‌‌reason‌‌for‌‌abandoning‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌ ‌was‌ ‌the‌ ‌total‌ ‌withdrawal‌ ‌of‌ ‌consent).‌ ‌ 
F.‌‌The‌‌end‌‌of‌‌treatment‌‌is‌‌understood‌‌to‌‌be‌‌the‌‌last‌‌day‌‌the‌‌patient‌‌has‌‌received‌‌the‌‌last‌‌drug‌‌of‌‌the‌‌combination‌‌under‌‌test‌‌(FOLFOX6‌‌(m)‌‌/‌‌FOLFIRI‌‌
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
(m)‌‌/‌‌Cetuximab).‌‌The‌‌safety‌‌visit‌‌should‌‌be‌‌carried‌‌out‌‌30‌‌±‌‌3‌‌days‌‌after‌‌the‌‌end‌‌of‌‌the‌‌treatment,‌‌regardless‌‌of‌‌the‌‌cause‌‌that‌‌caused‌‌it.‌‌If‌‌the‌‌patient‌‌
   
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
has‌ ‌not‌ ‌progressed,‌ ‌imaging‌ ‌and‌ ‌biomarker‌ ‌determinations‌ ‌should‌ ‌continue‌ ‌every‌ ‌12‌ ‌weeks‌ ‌until‌ ‌progression‌ ‌as‌ ‌specified‌ ‌in‌ ‌this‌ ‌protocol.‌ ‌ 
g.‌ ‌In‌ ‌order‌ ‌to‌ ‌mobilize‌ ‌any‌ ‌biological‌ ‌sample,‌ ‌the‌ ‌signing‌ ‌of‌ ‌the‌ ‌informed‌ ‌consent‌ ‌will‌ ‌be‌ ‌mandatory.‌ ‌If‌ ‌the‌ ‌patient‌ ‌already‌ ‌has‌ ‌a‌ ‌previous‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
determination‌ ‌of‌ ‌the‌ ‌status‌ ‌of‌ ‌the‌ ‌KRAS‌ ‌gene,‌ ‌he‌ ‌can‌‌be‌‌included‌‌in‌‌the‌‌test‌‌without‌‌it‌‌being‌‌necessary‌‌to‌‌re-determine‌‌the‌‌mutational‌‌status‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
K-RAS.‌ ‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
26‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
5.2‌ ‌Number‌ ‌of‌ ‌sites‌ ‌
 
Approximately‌ ‌30‌ ‌centers‌ ‌in‌ ‌Spain‌ ‌will‌ ‌participate‌ ‌(see‌ ‌attached‌ ‌list)‌ ‌ 
‌ 
5.3‌ ‌Number‌ ‌of‌ ‌subjects‌ ‌
 
‌ 
The‌ ‌participants‌ ‌in‌ ‌this‌ ‌clinical‌ ‌investigation‌ ‌will‌ ‌be‌ ‌called‌ ‌subjects.‌ ‌ 
The‌‌expected‌‌sample‌‌size‌‌is‌‌170‌‌subjects‌‌enrolled‌‌to‌‌receive‌‌chemotherapy.‌‌The‌‌justification‌‌for‌‌the‌‌
 
 
 
   
 
 
   
 
 
 
 
 
 
sample‌ ‌size‌ ‌can‌ ‌be‌ ‌found‌ ‌in‌ ‌section‌ ‌10.2.5.‌ ‌ 
‌ 
5.4‌ ‌Estimated‌ ‌study‌ ‌duration‌ ‌
 
‌ 
5.4.1‌ ‌Study‌ ‌duration‌ ‌for‌ ‌the‌ ‌participants‌ ‌ 
‌ 
The‌ ‌inclusion‌ ‌period‌ ‌is‌ ‌expected‌ ‌to‌ ‌last‌ ‌approximately‌ ‌24‌ ‌months.‌ ‌ 
‌ 
Throughout‌ ‌the‌ ‌trial,‌ ‌subjects‌ ‌will‌ ‌be‌ ‌assessed‌ ‌for‌ ‌tumor‌ ‌response‌ ‌using‌ ‌Response‌ ‌Assessment‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria‌‌for‌‌Solid‌‌Tumors‌‌(RECIST‌‌1.1).‌‌The‌‌tumor‌‌response‌‌of‌‌the‌‌subjects‌‌will‌‌be‌‌evaluated‌‌by‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT‌‌(helical‌‌or‌‌conventional)‌‌thoracic‌‌and‌‌abdominal‌‌performed‌‌in‌‌the‌‌baseline‌‌phase‌‌and‌‌every‌‌12‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks‌‌(three‌‌months)‌‌until‌‌the‌‌progression‌‌of‌‌the‌‌disease.‌‌In‌‌subjects‌‌with‌‌symptoms‌‌that‌‌indicate‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
disease‌ ‌progression,‌ ‌tumor‌ ‌response‌ ‌should‌ ‌be‌ ‌assessed‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌ ‌symptoms.‌ ‌ 
‌ 
To‌‌assess‌‌overall‌‌survival,‌‌all‌‌patients‌‌will‌‌be‌‌followed‌‌up‌‌by‌‌visits‌‌to‌‌the‌‌center‌‌or‌‌by‌‌telephone‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
contact‌‌every‌‌12‌‌weeks‌‌±‌‌4‌‌weeks‌‌from‌‌the‌‌date‌‌of‌‌progression‌‌up‌‌to‌‌24‌‌months‌‌after‌‌inclusion‌‌or‌‌
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
death‌ ‌of‌ ‌the‌ ‌last‌ ‌subject,‌ ‌which‌ ‌happen‌ ‌first.‌ ‌ 
‌ 
Therefore,‌ ‌the‌ ‌estimated‌ ‌maximum‌ ‌duration‌ ‌of‌ ‌the‌ ‌study‌ ‌is‌ ‌about‌ ‌48‌ ‌months‌ ‌(4‌ ‌years).‌ ‌ 
‌ 
‌ 
5.4.2‌ ‌End‌ ‌of‌ ‌study‌ ‌ 
‌ 
Subjects‌ ‌will‌ ‌follow‌ ‌study‌ ‌procedures‌ ‌until‌ ‌the‌ ‌end‌ ‌of‌ ‌the‌ ‌clinical‌ ‌study,‌ ‌death,‌ ‌withdrawal‌ ‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consent‌ ‌from‌‌the‌‌study,‌‌and‌‌/‌‌or‌‌loss‌‌to‌‌follow-up.‌‌The‌‌study‌‌will‌‌end‌‌when‌‌the‌‌last‌‌subject‌‌has‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
completed‌ ‌the‌ ‌long-term‌ ‌follow-up‌ ‌period‌ ‌or‌ ‌has‌ ‌died,‌ ‌whichever‌ ‌occurs‌ ‌first.‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
27‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
6.‌ ‌SUBJECT‌ ‌ELIGIBILITY‌ ‌
 
Subjects‌‌who‌‌meet‌‌all‌‌the‌‌inclusion‌‌criteria‌‌and‌‌none‌‌of‌‌the‌‌exclusion‌‌criteria‌‌will‌‌be‌‌included‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
this‌ ‌study:‌ ‌ 
6.1‌ ‌Inclusion‌ ‌criteria‌ ‌
 
Male‌ ‌or‌ ‌female‌ ‌≥‌ ‌18‌ ‌years‌ ‌old.‌ ‌ 
Able‌ ‌to‌ ‌understand,‌ ‌sign‌ ‌and‌ ‌date‌ ‌an‌ ‌informed‌ ‌consent‌ ‌form‌ ‌approved‌ ‌by‌ ‌the‌ ‌CEIC.‌ ‌ 
Advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌ ‌confirmed‌ ‌histologically‌ ‌or‌‌cytologically‌‌by‌‌the‌‌
 
   
 
 
 
 
 
 
 
 
 
 
investigator.‌ ‌ 
KRAS‌ ‌non-mutated‌ ‌colorectal‌ ‌cancer.‌ ‌ 
At‌ ‌least‌ ‌1‌ ‌unidimensionally‌ ‌measurable‌ ‌lesion>‌ ‌10‌ ‌mm‌ ‌with‌ ‌helical‌ ‌CT‌ ‌or>‌ ‌20‌ ‌mm‌ ‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
conventional‌ ‌CT‌ ‌according‌ ‌to‌ ‌the‌ ‌revised‌ ‌RECIST‌ ‌1.1‌ ‌criteria.‌ ‌(All‌ ‌disease‌ ‌sites‌ ‌should‌ ‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluated‌ ‌≤‌ ‌28‌ ‌days‌ ‌before‌ ‌the‌ ‌start‌ ‌of‌ ‌treatment).‌ ‌ 
Patients‌ ‌with‌ ‌the‌ ‌following‌ ‌characteristics‌ ‌will‌ ‌be‌ ‌included:‌ ‌ 
1.‌‌Recurrence‌‌after‌‌adjuvant‌‌treatment‌‌+/-‌‌radiotherapy‌‌with‌‌a‌‌disease-free‌‌interval>‌‌6‌‌months‌‌after‌‌
 
 
 
 
 
 
 
   
 
   
 
 
completion.‌ ‌ 
2.‌ ‌De‌ ‌novo‌ ‌diagnosis‌ ‌of‌ ‌the‌ ‌disease.‌ ‌ 
ECOG‌‌(Eastern‌‌Cooperative‌‌Oncology‌‌Group)‌‌performance‌‌status‌‌of‌‌0,‌‌1‌‌or‌‌2.‌‌(recommended‌‌only‌‌
 
 
 
 
 
 
 
     
   
 
 
0-1)‌ ‌ 
Life‌ ‌expectancy‌ ‌≥‌ ‌3‌ ‌months.‌ ‌ 
Adequate‌‌bone‌‌marrow‌‌function:‌‌neutrophils‌‌≥1.5‌‌x‌‌109‌‌/‌‌L;‌‌platelets‌‌≥‌‌100‌‌x‌‌109‌‌/‌‌L;‌‌hemoglobin‌‌
 
 
 
 
 
   
   
 
   
   
   
 
 
≥9‌ ‌g‌ ‌/‌ ‌dL.‌ ‌ 
Liver,‌ ‌kidney‌ ‌and‌ ‌metabolic‌ ‌functions‌ ‌as‌ ‌follows:‌ ‌ 
‌ 
Adequate‌‌liver‌‌function:‌‌ASAT‌‌(SGOT)‌‌and‌‌ALAT‌‌(SGPT)‌‌2.5‌‌x‌‌ULN‌‌(5‌‌x‌‌ULN‌‌if‌‌there‌‌are‌‌liver‌‌
 
 
 
 
 
 
 
 
   
 
   
   
 
 
 
metastases).‌‌Total‌‌bilirubin‌‌<1.5‌‌x‌‌ULN.‌‌Alkaline‌‌phosphatase‌‌2.5‌‌x‌‌ULN‌‌(5‌‌x‌‌ULN‌‌in‌‌case‌‌of‌‌liver‌‌
 
 
 
   
 
 
 
   
 
   
   
 
 
 
metastases‌ ‌or‌ ‌10‌ ‌x‌ ‌ULN‌ ‌in‌ ‌case‌ ‌of‌ ‌bone‌ ‌metastases).‌ ‌ 
Renal‌‌function,‌‌calculated‌‌as‌‌creatinine‌‌clearance‌‌or‌‌creatinine‌‌clearance‌‌for‌‌24‌‌hours‌‌≥‌‌50‌‌mL‌‌/‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
   
min.‌ ‌ 
Magnesium‌ ‌≥‌ ‌ULN,‌ ‌calcium‌ ‌≥‌ ‌ULN.‌ ‌ 
‌ 
6.2‌ ‌Exclusion‌ ‌criteria‌ ‌
 
PS>‌ ‌2‌ ‌or‌ ‌elderly‌ ‌patients‌ ‌with‌ ‌frailty‌ ‌criteria,‌ ‌according‌ ‌to‌ ‌the‌ ‌investigator's‌ ‌criteria.‌ ‌ 
Previous‌ ‌surgery‌ ‌for‌ ‌metastases‌ ‌(liver,‌ ‌lung‌ ‌or‌ ‌other).‌ ‌ 
Patients‌ ‌who‌ ‌have‌ ‌received‌ ‌previous‌ ‌systemic‌ ‌treatment‌ ‌for‌ ‌metastatic‌ ‌colorectal‌ ‌carcinoma.‌ ‌ 
Pretreatment‌‌with‌‌anti-EGFr‌‌antibodies‌‌(eg,‌‌panitumumab)‌‌or‌‌treatment‌‌with‌‌small‌‌molecule‌‌EGFr‌‌
 
 
 
 
 
 
 
 
 
 
 
 
tyrosine‌ ‌kinase‌ ‌inhibitors‌ ‌(eg,‌ ‌erlotinib)‌ ‌or‌ ‌EGFr‌ ‌signal‌ ‌transduction‌ ‌inhibitors.‌ ‌Subjects‌ ‌who‌‌
 
 
 
 
 
 
 
 
 
 
 
 
discontinue‌‌their‌‌first‌‌dose‌‌of‌‌anti-EGFr‌‌therapy‌‌(panitumumab)‌‌due‌‌to‌‌an‌‌infusion‌‌reaction‌‌may‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
participate‌ ‌in‌ ‌this‌ ‌clinical‌ ‌trial.‌ ‌ 
Metastases‌‌in‌‌the‌‌brain‌‌/‌‌central‌‌nervous‌‌system‌‌(exception:‌‌subjects‌‌who‌‌have‌‌been‌‌treated,‌‌have‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
asymptomatic‌‌metastases‌‌in‌‌the‌‌central‌‌nervous‌‌system‌‌and‌‌have‌‌not‌‌received‌‌steroids‌‌for‌‌at‌‌least‌‌30‌‌
 
   
 
 
 
 
 
 
 
 
 
   
 
 
days‌ ‌prior‌ ‌to‌ ‌study‌ ‌inclusion).‌ ‌ 
Previous‌‌malignant‌‌tumor‌‌within‌‌the‌‌last‌‌5‌‌years,‌‌except‌‌for‌‌a‌‌history‌‌of‌‌basal‌‌cell‌‌carcinoma‌‌of‌‌the‌‌
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
skin‌ ‌or‌ ‌preinvasive‌ ‌cervical‌ ‌cancer.‌ ‌ 
Unresolved‌‌toxicities‌‌from‌‌prior‌‌systemic‌‌treatment‌‌that,‌‌in‌‌the‌‌opinion‌‌of‌‌the‌‌investigator,‌‌render‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌patient‌ ‌ineligible‌ ‌for‌ ‌inclusion.‌ ‌ 
Presence‌‌of‌‌peripheral‌‌neuropathy‌‌(grade>‌‌1‌‌of‌‌version‌‌3.0‌‌of‌‌the‌‌common‌‌toxicity‌‌criteria‌‌(CCT)),‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
and‌ ‌of‌ ‌serious‌ ‌wound‌ ‌or‌ ‌ulcer‌ ‌without‌ ‌healing‌ ‌or‌ ‌open‌ ‌bone‌ ‌fracture.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
28‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Hormone‌ ‌therapy,‌ ‌immunotherapy,‌ ‌or‌ ‌experimental‌ ‌or‌ ‌approved‌ ‌antibodies‌ ‌/‌ ‌proteins‌ ‌(eg,‌‌
 
 
 
 
 
 
 
   
 
 
bevacizumab)‌ ‌≤‌ ‌30‌ ‌days‌ ‌prior‌ ‌to‌ ‌enrollment.‌ ‌ 
Significant‌ ‌cardiovascular‌ ‌disease,‌ ‌including‌ ‌unstable‌ ‌angina‌ ‌or‌ ‌myocardial‌‌infarction‌‌within‌‌12‌‌
 
 
 
 
 
 
 
 
 
 
 
months‌ ‌prior‌ ‌to‌ ‌the‌ ‌start‌ ‌of‌ ‌study‌ ‌treatment‌ ‌or‌ ‌a‌ ‌history‌ ‌of‌ ‌ventricular‌ ‌arrhythmia.‌ ‌ 
History‌‌of‌‌interstitial‌‌pneumonitis‌‌or‌‌pulmonary‌‌fibrosis‌‌or‌‌evidence‌‌of‌‌interstitial‌‌pneumonitis‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
pulmonary‌ ‌fibrosis‌ ‌on‌ ‌baseline‌ ‌chest‌ ‌CT‌ ‌scan.‌ ‌ 
Treatment‌ ‌for‌ ‌systemic‌ ‌infection‌ ‌within‌ ‌14‌ ‌days‌ ‌prior‌ ‌to‌ ‌the‌ ‌start‌ ‌of‌ ‌study‌ ‌treatment.‌ ‌ 
Acute‌ ‌or‌ ‌subacute‌ ‌bowel‌ ‌occlusion‌ ‌and‌ ‌/‌ ‌or‌ ‌active‌ ‌inflammatory‌ ‌bowel‌ ‌disease‌ ‌or‌ ‌other‌‌bowel‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
disease‌ ‌causing‌ ‌chronic‌ ‌diarrhea‌ ‌(defined‌ ‌as>‌ ‌4‌ ‌loose‌ ‌stools‌ ‌per‌ ‌day).‌ ‌ 
History‌ ‌of‌ ‌Gilbert's‌ ‌syndrome‌ ‌or‌ ‌dihydropyrimidine‌ ‌deficiency.‌ ‌ 
History‌ ‌of‌ ‌any‌ ‌illness‌ ‌that‌ ‌may‌ ‌increase‌ ‌the‌ ‌risks‌ ‌associated‌ ‌with‌ ‌study‌ ‌participation‌ ‌or‌ ‌may‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
interfere‌ ‌with‌ ‌the‌ ‌interpretation‌ ‌of‌ ‌the‌ ‌study‌ ‌results.‌ ‌ 
Known‌‌positive‌‌test‌‌for‌‌human‌‌immunodeficiency‌‌virus‌‌infection,‌‌hepatitis‌‌C‌‌virus‌‌with‌‌abnormal‌‌
 
 
 
 
 
 
 
 
   
 
 
 
liver‌ ‌enzyme‌ ‌values,‌ ‌chronic‌ ‌active‌ ‌hepatitis‌ ‌B‌ ‌infection.‌ ‌Hepatitis‌ ‌C‌ ‌seropositive‌‌patients‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
normal‌ ‌liver‌ ‌enzyme‌ ‌values‌ ‌​may‌ ‌be‌ ‌included.‌ ‌ 
Any‌ ‌concurrent‌ ‌illness‌ ‌that‌ ‌may‌ ‌increase‌ ‌the‌ ‌risk‌ ‌of‌ ‌toxicity.‌ ‌ 
The‌‌subject‌‌has‌‌a‌‌disorder‌‌of‌‌any‌‌kind‌‌that‌‌compromises‌‌their‌‌ability‌‌to‌‌provide‌‌written‌‌informed‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
consent‌ ‌and‌ ‌/‌ ‌or‌ ‌comply‌ ‌with‌ ‌study‌ ‌procedures‌ ‌ 
Have‌ ‌received‌ ‌any‌ ‌investigating‌ ‌agent‌ ‌within‌ ‌30‌ ‌days‌ ‌prior‌ ‌to‌ ‌listing.‌ ‌ 
Pregnant‌ ‌or‌ ‌lactating‌ ‌woman,‌ ‌or‌ ‌planning‌ ‌to‌ ‌become‌‌pregnant‌‌within‌‌6‌‌months‌‌after‌‌the‌‌end‌‌of‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
treatment.‌ ‌ 
Surgery‌‌(not‌‌including‌‌diagnostic‌‌biopsy‌‌or‌‌central‌‌venous‌‌catheter‌‌placement)‌‌and‌‌/‌‌or‌‌radiation‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
therapy‌ ‌within‌ ‌28‌ ‌days‌ ‌prior‌ ‌to‌ ‌study‌ ‌enrollment.‌ ‌ 
Woman‌ ‌or‌ ‌man‌ ‌of‌ ‌childbearing‌ ‌potential‌ ‌who‌ ‌does‌ ‌not‌ ‌agree‌ ‌to‌ ‌take‌ ‌adequate‌ ‌contraceptive‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
precautions,‌ ‌that‌ ‌is,‌ ‌to‌ ‌use‌ ‌2‌ ‌contraceptive‌ ‌methods‌ ‌together,‌ ‌at‌ ‌least‌ ‌1‌ ‌of‌ ‌them‌ ‌barrier‌ ‌(eg,‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
contraceptive‌‌pills‌‌plus‌‌condom)‌‌or‌‌abstinence‌‌during‌‌over‌‌the‌‌course‌‌of‌‌the‌‌study‌‌and‌‌for‌‌6‌‌months‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
after‌ ‌the‌ ‌last‌ ‌study‌ ‌drug‌ ‌administration‌ ‌for‌ ‌women‌ ‌and‌ ‌1‌ ‌month‌ ‌for‌ ‌men.‌ ‌ 
The‌ ‌subject‌ ‌is‌ ‌unwilling‌ ‌or‌ ‌unable‌ ‌to‌ ‌meet‌ ‌the‌ ‌requirements‌ ‌of‌ ‌the‌ ‌study.‌ ‌ 
Psychological,‌‌family,‌‌sociological‌‌or‌‌geographical‌‌conditions‌‌that‌‌potentially‌‌prevent‌‌compliance‌‌
 
 
 
 
 
 
 
 
 
 
with‌‌the‌‌study‌‌protocol‌‌and‌‌the‌‌follow-up‌‌calendar.‌‌These‌‌conditions‌‌should‌‌be‌‌discussed‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patient‌ ‌before‌ ‌registering‌ ‌for‌ ‌the‌ ‌clinical‌ ‌trial.‌ ‌ 
6.3.‌ ‌Subject‌ ‌inclusions‌ ‌
 
Before‌‌the‌‌subjects‌‌can‌‌be‌‌included‌‌in‌‌the‌‌study,‌‌the‌‌sponsor‌‌needs‌‌to‌‌have‌‌a‌‌copy‌‌of‌‌the‌‌written‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
approval‌ ‌of‌ ‌the‌ ‌protocol,‌‌the‌‌informed‌‌consent‌‌and‌‌the‌‌rest‌‌of‌‌the‌‌subject's‌‌information‌‌and‌‌/‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
inclusion‌ ‌material‌ ‌that‌ ‌may‌ ‌come‌ ‌from‌ ‌the‌ ‌Ethics‌ ‌Committee.‌ ‌Clinical‌ ‌Research‌ ‌Committee‌ ‌/‌‌
 
 
 
 
 
 
 
 
 
 
 
   
Institutional‌ ‌Review‌ ‌Committee‌ ‌(CEIC‌ ‌/‌ ‌CRI)‌ ‌of‌ ‌the‌ ‌center‌ ‌and‌ ‌the‌ ‌AEMPS‌ ‌Approval.‌ ‌ 
‌ 
Any‌‌subject‌‌who‌‌passes‌‌the‌‌selection‌‌period‌‌(defined‌‌as‌‌the‌‌moment‌‌the‌‌subject‌‌signs‌‌the‌‌informed‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consent)‌‌will‌‌be‌‌registered‌‌and‌‌will‌‌receive‌‌a‌‌unique‌‌identification‌‌number‌‌of‌‌the‌‌subject‌‌before‌‌any‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
study‌ ‌procedure‌ ‌is‌ ‌performed.‌ ‌This‌ ‌number‌ ‌will‌ ‌be‌ ‌used‌ ‌to‌ ‌identify‌ ‌the‌ ‌subject‌ ‌throughout‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical‌ ‌study‌ ‌and‌ ‌should‌ ‌be‌ ‌used‌ ‌in‌ ‌all‌ ‌study‌ ‌documentation‌ ‌related‌ ‌to‌ ‌that‌ ‌subject.‌ ‌ 
‌ 
Study‌ ‌treatment‌ ‌should‌ ‌begin‌ ‌within‌ ‌28‌ ‌days‌ ‌of‌ ‌baseline‌ ‌CT.‌‌ ‌
  
6.4‌  ‌Treatment‌ ‌assignment‌ ‌
 
The‌ ‌selection‌ ‌of‌ ‌treatment‌ ‌between‌ ‌FOLFOX-6‌ ‌(m)‌ ‌+‌ ‌biweekly‌ ‌cetuximab‌ ‌or‌ ‌FOLFIRI‌ ‌(m)‌ ‌+‌‌
 
 
 
 
 
 
   
 
 
 
 
   
biweekly‌ ‌cetuximab‌ ‌will‌ ‌be‌ ‌made‌ ‌by‌ ‌the‌ ‌Principal‌ ‌Investigator,‌ ‌according‌ ‌to‌ ‌the‌ ‌usual‌ ‌clinical‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
practice‌ ‌of‌ ‌his‌ ‌center.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
29‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
After‌‌confirmation‌‌of‌‌eligibility,‌‌the‌‌center's‌‌staff‌‌will‌‌fax‌‌an‌‌inclusion‌‌request‌‌form‌‌to‌‌the‌‌Sponsor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
(GEMCAD‌ ‌Technical‌ ‌Secretariat‌ ‌at‌ ‌FAX‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68‌)‌ ‌in‌ ‌which‌ ‌they‌ ‌must‌ ‌record‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment‌ ‌chosen‌ ‌by‌ ‌the‌ ‌Principal‌ ‌Investigator‌ ‌for‌ ‌the‌ ‌patient.‌ ‌ 
‌ 
The‌‌GEMCAD‌‌Technical‌‌Secretariat‌‌will‌‌return‌‌a‌‌communication‌‌to‌‌the‌‌center‌‌to‌‌confirm‌‌that‌‌a‌‌
 
 
 
 
 
   
 
 
 
 
 
 
   
new‌ ‌patient‌ ‌has‌ ‌been‌ ‌registered‌ ‌in‌ ‌the‌ ‌study.‌ ‌ 
‌ 
‌ 
‌
 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
30‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
7.‌ ‌TREATMENT‌ ‌PROCEDURES‌ ‌
 
7.1.‌ ‌Dosage,‌ ‌Administration,‌ ‌and‌ ‌Biweekly‌ ‌Cetuximab‌ ‌Schedule‌ ‌
 
‌ 
Cetuximab‌‌is‌‌commercially‌‌available.‌‌This‌‌drug‌‌will‌‌be‌‌formulated,‌‌packaged,‌‌labeled‌‌and‌‌stored‌‌
   
 
 
 
 
 
 
 
 
 
 
 
according‌ ‌to‌ ‌the‌ ‌procedures‌ ‌indicated‌ ‌by‌ ‌the‌ ‌local‌ ‌manufacturer,‌ ‌the‌ ‌supplier‌ ‌and‌ ‌the‌ ‌center.‌ ‌ 
‌ 
As‌‌it‌‌is‌‌a‌‌commercialized‌‌drug‌‌of‌‌habitual‌‌use‌‌in‌‌the‌‌study‌‌pathology,‌‌the‌‌supply‌‌will‌‌be‌‌carried‌‌out‌‌
       
 
 
 
 
   
 
 
 
 
 
 
 
 
 
through‌‌the‌‌usual‌‌channels‌‌of‌‌the‌‌National‌‌Health‌‌System,‌‌with‌‌the‌‌prior‌‌favorable‌‌opinion‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CEIC‌ ‌and‌ ‌the‌ ‌approval‌ ‌of‌ ‌the‌ ‌Center's‌ ‌Directorate.‌ ‌ 
‌ 
Cetuximab‌‌(Erbitux)‌‌should‌‌be‌‌administered‌‌under‌‌the‌‌supervision‌‌of‌‌a‌‌physician‌‌experienced‌‌in‌‌the‌‌
 
 
 
 
 
 
 
 
   
 
   
 
use‌‌of‌‌antineoplastic‌‌pharmaceuticals.‌‌Close‌‌monitoring‌‌is‌‌required‌‌during‌‌the‌‌infusion‌‌and‌‌for‌‌at‌‌
 
 
 
 
 
   
 
 
 
 
 
   
least‌ ‌1‌ ‌hour‌ ‌after‌ ‌the‌ ‌end‌ ‌of‌ ‌the‌ ‌infusion.‌ ‌Availability‌ ‌of‌ ‌resuscitation‌ ‌equipment‌ ‌must‌ ‌be‌ ‌ensured.‌ ‌ 
‌ 
7.1.1.‌ ‌Dosage‌ ‌ 
‌ 
Before‌ ‌the‌ ‌first‌ ‌infusion,‌ ‌the‌ ‌patient‌ ‌should‌ ‌be‌ ‌administered‌ ‌an‌ ‌antihistamine‌ ‌and‌ ‌a‌ ‌corticosteroid.‌ ‌ 
‌ 
This‌ ‌premedication‌ ‌is‌ ‌recommended‌ ‌for‌ ‌all‌ ‌subsequent‌ ‌infusions.‌ ‌ 
‌ 
Cetuximab‌ ‌will‌ ‌be‌ ‌administered‌ ‌every‌ ‌2‌ ‌weeks,‌ ‌the‌ ‌dose‌ ‌is‌ ‌500‌ ‌mg‌ ‌/‌ ‌m2.‌ ‌ 
‌ 
In‌ ‌reference‌ ‌to‌ ‌the‌ ‌dosage‌ ‌or‌ ‌modifications‌ ‌of‌ ‌the‌ ‌recommended‌ ‌dose‌ ‌of‌ ‌concomitantly‌ ‌used‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
chemotherapeutic‌‌agents,‌‌consult‌‌the‌‌SmPC‌‌of‌‌these‌‌drugs.‌‌They‌‌should‌‌not‌‌be‌‌administered‌‌until‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
one‌ ‌hour‌ ‌after‌ ‌the‌ ‌end‌ ‌of‌ ‌the‌ ‌cetuximab‌ ‌infusion.‌ ‌ 
Biweekly‌ ‌cetuximab‌ ‌treatment‌ ‌should‌ ‌be‌ ‌continued‌ ‌until‌ ‌underlying‌ ‌disease‌ ‌progresses.‌ ‌ 
‌ 
Once‌ ‌a‌ ‌dose‌ ‌reduction‌ ‌has‌ ‌been‌ ‌made,‌ ‌a‌ ‌dose‌ ‌escalation‌ ‌will‌ ‌not‌ ‌be‌ ‌allowed‌ ‌in‌ ‌subsequent‌ ‌cycles.‌ ‌ 
‌ 
In‌‌no‌‌case‌‌can‌‌the‌‌patient‌‌be‌‌kept‌‌in‌‌the‌‌study‌‌with‌‌Oxaliplatin‌‌or‌‌Irinotecan‌‌in‌‌monotherapy,‌‌or‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
combination‌ ‌with‌ ‌cetuximab‌ ‌without‌ ‌5-FU.‌ ‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
31‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
7.1.2.‌ ‌Administration‌ ‌ 
‌ 
Erbitux‌ ‌5‌ ‌mg‌ ‌/‌ ‌ml‌ ‌ 
‌ 
Erbitux‌‌5‌‌mg‌‌/‌‌ml‌‌is‌‌administered‌‌intravenously‌‌via‌‌an‌‌infusion‌‌pump,‌‌gravity‌‌drip‌‌or‌‌syringe‌‌pump‌‌
   
   
   
 
 
 
 
 
 
 
 
 
 
 
(for‌ ‌instructions‌ ‌for‌ ‌use‌ ‌and‌ ‌handling,‌ ‌see‌ ‌section‌ ‌6.6‌ ‌product‌ ‌data‌ ‌sheet).‌ ‌ 
‌The‌‌duration‌‌of‌‌the‌‌cetuximab‌‌infusion‌‌will‌‌be‌‌120‌‌minutes‌‌in‌‌the‌‌first‌‌cycle,‌‌90‌‌minutes‌‌in‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
second‌‌and‌‌60‌‌minutes‌‌from‌‌the‌‌third‌‌and‌‌later.‌‌The‌‌maximum‌‌infusion‌‌rate‌‌should‌‌not‌‌exceed‌‌10‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mg‌ ‌/‌ ‌min.‌ ‌ 
Prior‌ ‌to‌ ‌all‌ ‌cetuximab‌ ‌infusions,‌ ‌appropriate‌ ‌medication‌ ‌will‌ ‌be‌ ‌administered‌ ‌as‌ ‌a‌ ‌prophylaxis‌‌
 
 
 
 
 
 
 
 
 
 
   
 
against‌‌the‌‌onset‌‌of‌‌acute‌‌hypersensitivity‌‌reaction.‌‌The‌‌patient‌‌should‌‌be‌‌given‌‌an‌‌antihistamine‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌a‌ ‌corticosteroid.‌ ‌ 
During‌‌the‌‌first‌‌infusion‌‌it‌‌is‌‌advisable‌‌for‌‌the‌‌doctor‌‌to‌‌be‌‌present‌‌or‌‌close‌‌to‌‌the‌‌treatment‌‌area.‌‌
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients‌‌will‌‌receive‌‌treatment‌‌in‌‌an‌‌area‌‌of‌‌​the‌‌hospital‌‌where‌‌resuscitation‌‌equipment‌‌and‌‌other‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
drugs‌ ‌are‌ ‌available‌ ‌for‌ ‌the‌ ‌treatment‌ ‌of‌ ‌acute‌ ‌hypersensitivity‌ ‌reactions,‌ ‌such‌ ‌as‌ ‌adrenaline‌ ‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steroids.‌ ‌If‌‌an‌‌allergic‌‌reaction‌‌occurs‌‌to‌‌the‌‌infusion‌‌with‌‌cetuximab,‌‌the‌‌patient‌‌will‌‌be‌‌treated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
according‌‌to‌‌the‌‌best‌‌available‌‌medical‌‌practice.‌‌Patients‌‌will‌‌be‌‌asked‌‌to‌‌report‌‌delayed‌‌reactions‌‌to‌‌
   
 
 
 
 
 
 
 
 
   
 
 
   
their‌‌physician‌‌immediately.‌‌Although‌‌it‌‌is‌‌not‌‌necessary‌‌to‌‌check‌‌vital‌‌signs,‌‌careful‌‌observation‌‌of‌‌
 
 
 
     
 
   
 
 
 
 
 
 
the‌‌patient‌‌(up‌‌to‌‌one‌‌hour‌‌after‌‌the‌‌infusion)‌‌is‌‌required‌‌to‌‌monitor‌‌the‌‌possible‌‌appearance‌‌of‌‌AAs‌‌
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
(specifically‌ ‌allergic‌ ‌reactions).‌ ‌ 
‌ 
Erbitux‌ ‌can‌ ‌be‌ ‌given‌ ‌by‌ ‌gravity‌ ‌drip,‌ ‌infusion‌ ‌pump,‌ ‌or‌ ‌syringe‌ ‌pump.‌ ‌The‌ ‌infusion‌ ‌must‌ ‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
performed‌ ‌with‌ ‌a‌ ‌separate‌ ‌infusion‌‌line,‌‌which‌‌must‌‌be‌‌flushed‌‌with‌‌a‌‌sterile‌‌0.9%‌‌(9‌‌mg‌‌/‌‌ml)‌‌
 
   
 
 
 
 
 
 
 
   
 
 
 
   
 
sodium‌ ‌chloride‌ ‌solution‌ ‌for‌ ‌injection‌ ‌at‌ ‌the‌ ‌end‌ ‌of‌ ‌the‌ ‌infusion.‌ ‌ 
‌ 
Erbitux‌ ‌5‌ ‌mg‌ ‌/‌ ‌ml‌ ‌is‌ ‌supported‌ ‌ 
‌ 
•‌ ‌with‌ ‌polyethylene‌ ‌(PE),‌ ‌ethyl‌ ‌vinyl‌ ‌acetate‌ ‌(EVA)‌ ‌or‌ ‌polyvinyl‌ ‌chloride‌ ‌(PVC)‌ ‌bags,‌ ‌ 
•‌ ‌with‌ ‌infusion‌ ‌sets‌ ‌made‌ ‌of‌ ‌polyethylene‌ ‌(PE),‌ ‌polyurethane‌ ‌(PUR),‌ ‌ethyl‌ ‌vinyl‌ ‌acetate‌ ‌(EVA),‌ ‌ 
thermoplastic‌ ‌polyolefin‌ ‌(TP)‌ ‌or‌ ‌polyvinyl‌ ‌chloride‌ ‌(PVC),‌ ‌ 
•‌ ‌with‌ ‌polypropylene‌ ‌(PP)‌ ‌syringes‌ ‌for‌ ‌syringe‌ ‌pump.‌ ‌ 
‌ 
Care‌ ‌should‌ ‌be‌ ‌taken‌ ‌to‌ ‌ensure‌ ‌aseptic‌ ‌conditions‌ ‌when‌ ‌preparing‌ ‌the‌ ‌infusion.‌ ‌ 
‌ 
Erbitux‌ ‌5‌ ‌mg‌ ‌/‌ ‌ml‌ ‌should‌ ‌be‌ ‌prepared‌ ‌as‌ ‌follows:‌ ‌ 
‌ 
•‌‌For‌‌administration‌‌with‌‌an‌‌infusion‌‌pump‌‌or‌‌gravity‌‌drip‌‌(diluted‌‌with‌‌sterile‌‌sodium‌‌chloride‌‌9‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
mg‌‌/‌‌ml‌‌[0.9%]‌‌solution):‌‌Take‌‌one‌‌infusion‌‌bag‌‌of‌‌sodium‌‌chloride‌‌9‌‌mg‌‌/‌‌ml‌‌(0.9‌‌%)‌‌sterile‌‌of‌‌the‌‌
   
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
appropriate‌‌size.‌‌Calculate‌‌the‌‌required‌‌volume‌‌of‌‌Erbitux.‌‌Withdraw‌‌the‌‌appropriate‌‌volume‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sodium‌‌chloride‌‌solution‌‌from‌‌the‌‌infusion‌‌bag,‌‌using‌‌an‌‌appropriate‌‌sterile‌‌syringe‌‌with‌‌a‌‌suitable‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
needle.‌ ‌Take‌ ‌an‌ ‌appropriate‌ ‌sterile‌ ‌syringe‌ ‌and‌ ‌attach‌ ‌a‌ ‌suitable‌ ‌needle.‌ ‌Withdraw‌ ‌the‌ ‌required‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
volume‌ ‌of‌ ‌Erbitux‌ ‌from‌ ‌one‌ ‌vial.‌ ‌Transfer‌ ‌Erbitux‌ ‌to‌ ‌the‌ ‌prepared‌ ‌infusion‌ ‌bag.‌ ‌Repeat‌ ‌this‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
procedure‌ ‌until‌ ‌the‌ ‌calculated‌ ‌volume‌ ‌is‌ ‌reached.‌ ‌ 
Connect‌‌the‌‌infusion‌‌line‌‌and‌‌prime‌‌with‌‌diluted‌‌Erbitux‌‌before‌‌starting‌‌the‌‌infusion.‌‌Use‌‌a‌‌gravity‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
drip‌ ‌system‌ ‌or‌ ‌an‌ ‌infusion‌ ‌pump‌ ‌for‌ ‌administration.‌ ‌Set‌ ‌and‌ ‌control‌ ‌the‌ ‌speed‌ ‌as‌ ‌previously‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
explained.‌ ‌ 
‌ 
•‌ ‌For‌ ‌administration‌ ‌with‌ ‌an‌ ‌infusion‌ ‌pump‌ ‌or‌ ‌gravity‌ ‌drip‌ ‌(undiluted):‌ ‌Calculate‌ ‌the‌ ‌required‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
volume‌ ‌of‌ ‌Erbitux.‌ ‌Take‌ ‌an‌ ‌appropriate‌ ‌sterile‌ ‌syringe‌ ‌(minimum‌ ‌50‌ ‌ml)‌ ‌and‌ ‌attach‌ ‌a‌ ‌suitable‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
needle.‌‌Withdraw‌‌the‌‌required‌‌volume‌‌of‌‌Erbitux‌‌from‌‌one‌‌vial.‌‌Transfer‌‌Erbitux‌‌to‌‌an‌‌empty‌‌sterile‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
32‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
bag‌‌or‌‌container.‌‌Repeat‌‌this‌‌procedure‌‌until‌‌the‌‌calculated‌‌volume‌‌is‌‌reached.‌‌Connect‌‌the‌‌infusion‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
line‌ ‌and‌ ‌prime‌ ‌with‌ ‌Erbitux‌ ‌before‌ ‌starting‌ ‌the‌ ‌infusion.‌ ‌ 
Set‌ ‌and‌ ‌control‌ ‌the‌ ‌speed‌ ‌as‌ ‌previously‌ ‌explained.‌ ‌ 
‌ 
•‌ ‌For‌ ‌administration‌ ‌with‌ ‌a‌ ‌syringe‌ ‌pump:‌ ‌Calculate‌ ‌the‌ ‌required‌ ‌volume‌ ‌of‌ ‌Erbitux.‌ ‌Take‌ ‌an‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
appropriate‌‌sterile‌‌syringe‌‌and‌‌attach‌‌a‌‌suitable‌‌needle.‌‌Withdraw‌‌the‌‌required‌‌volume‌‌of‌‌Erbitux‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
from‌ ‌one‌ ‌vial.‌ ‌Remove‌ ‌the‌ ‌needle‌ ‌and‌ ‌insert‌ ‌the‌ ‌syringe‌ ‌into‌ ‌the‌ ‌syringe‌ ‌pump.‌ ‌ 
Connect‌‌the‌‌infusion‌‌line‌‌to‌‌the‌‌syringe,‌‌set‌‌and‌‌control‌‌the‌‌infusion‌‌rate‌‌as‌‌previously‌‌explained,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌‌start‌‌the‌‌infusion‌‌after‌‌priming‌‌the‌‌line‌‌with‌‌Erbitux‌‌or‌‌sterile‌‌sodium‌‌chloride‌‌9‌‌mg‌‌/‌‌ml‌‌(0.9%)‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
solution.‌ ‌.‌ ‌If‌ ‌necessary,‌ ‌repeat‌ ‌this‌ ‌procedure‌ ‌until‌ ‌the‌ ‌calculated‌ ‌volume‌ ‌has‌ ‌been‌ ‌infused.‌ ‌ 
‌ 
7.1.3.‌ ‌Special‌ ‌populations‌ ‌ 
‌ 
To‌‌date,‌‌only‌‌patients‌‌with‌‌adequate‌‌renal‌‌and‌‌hepatic‌‌function‌‌have‌‌been‌‌studied‌‌(see‌‌section‌‌4.4‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
product‌ ‌data‌ ‌sheet).‌ ‌ 
Cetuximab‌ ‌has‌ ‌not‌ ‌been‌ ‌studied‌ ‌in‌ ‌patients‌ ‌with‌ ‌pre-existing‌ ‌haematological‌ ‌disorders‌ ‌(see‌ ‌ 
section‌ ‌4.4‌ ‌product‌ ‌data‌ ‌sheet).‌ ‌ 
‌ 
No‌‌dose‌‌adjustment‌‌is‌‌necessary‌‌in‌‌the‌‌elderly,‌‌although‌‌the‌‌experience‌‌in‌‌patients‌‌aged‌‌75‌‌years‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌over‌ ‌is‌ ‌limited.‌ ‌ 
‌ 
7.1.4‌ ‌Contraindications‌ ‌ 
‌ 
Erbitux‌‌is‌‌contraindicated‌‌in‌‌patients‌‌with‌‌known‌‌severe‌‌(Grade‌‌3‌‌or‌‌4)‌‌hypersensitivity‌‌reactions‌‌to‌‌
   
   
 
 
 
 
   
 
 
 
   
cetuximab.‌ ‌ 
Before‌ ‌starting‌ ‌a‌ ‌combination‌ ‌treatment,‌ ‌the‌ ‌contraindications‌ ‌of‌ ‌the‌ ‌concomitantly‌ ‌used‌‌
 
 
 
 
 
 
 
 
 
 
 
chemotherapy‌ ‌agents‌ ‌should‌ ‌be‌ ‌taken‌ ‌into‌ ‌account.‌ ‌ 
‌ 
7.1.5.‌ ‌Warnings‌ ‌and‌ ‌precautions‌ ‌ 
‌ 
Respiratory‌ ‌disorders‌ ‌ 
‌ 
Individual‌‌cases‌‌of‌‌interstitial‌‌lung‌‌disease‌‌have‌‌been‌‌reported‌‌in‌‌which‌‌the‌‌causal‌‌relationship‌‌with‌‌
 
   
 
 
 
 
 
   
 
 
 
 
 
cetuximab‌‌is‌‌unknown.‌‌If‌‌interstitial‌‌lung‌‌disease‌‌is‌‌diagnosed,‌‌cetuximab‌‌should‌‌be‌‌discontinued‌‌
   
   
 
 
   
 
 
 
 
 
and‌ ‌the‌ ‌patient‌ ‌treated‌ ‌appropriately.‌ ‌ 
‌ 
‌ 
Skin‌ ‌reactions‌ ‌ 
‌ 
If‌‌a‌‌patient‌‌develops‌‌a‌‌severe‌‌skin‌‌reaction‌‌(grade‌‌≥‌‌3;‌‌US‌‌National‌‌Cancer‌‌Institute‌‌-‌‌Common‌‌
   
 
   
 
 
 
   
 
 
 
 
   
 
Toxicity‌‌Criteria,‌‌NCI-CTC,‌‌v3.0),‌‌cetuximab‌‌treatment‌‌should‌‌be‌‌discontinued.‌‌Treatment‌‌can‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
resumed‌ ‌only‌ ‌if‌ ‌the‌ ‌reaction‌ ‌subsides‌ ‌to‌ ‌grade‌ ‌2‌ ‌(see‌ ‌section‌ ‌4.8‌ ‌of‌ ‌the‌ ‌product‌ ‌data‌ ‌sheet).‌ ‌ 
If‌‌the‌‌severe‌‌skin‌‌reaction‌‌has‌‌occurred‌‌for‌‌the‌‌first‌‌time,‌‌treatment‌‌can‌‌be‌‌resumed‌‌without‌‌change‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in‌ ‌dose.‌ ‌ 
If‌ ‌severe‌ ‌skin‌ ‌reactions‌ ‌occur‌ ‌for‌ ‌the‌ ‌second‌ ‌or‌‌third‌‌time,‌‌cetuximab‌‌should‌‌be‌‌stopped‌‌again.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment‌‌can‌‌be‌‌resumed‌‌at‌‌a‌‌lower‌‌dose‌‌(400‌‌mg‌‌/‌‌m²‌‌after‌‌the‌‌second‌‌time,‌‌and‌‌300‌‌mg‌‌/‌‌m²‌‌after‌‌
 
 
 
     
 
 
 
   
 
 
 
 
 
 
 
   
 
 
the‌ ‌third‌ ‌time)‌ ‌only‌ ‌if‌ ‌the‌ ‌reaction‌ ‌has‌ ‌subsided‌ ‌to‌ ‌grade‌ ‌2.‌ ‌ 
If‌ ‌severe‌ ‌skin‌ ‌reactions‌ ‌appear‌ ‌for‌ ‌the‌ ‌fourth‌ ‌time,‌ ‌or‌ ‌they‌ ‌do‌ ‌not‌ ‌subside‌ ‌to‌ ‌grade‌ ‌2‌ ‌during‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
treatment‌ ‌interruption,‌ ‌permanent‌ ‌discontinuation‌ ‌of‌ ‌cetuximab‌ ‌treatment‌ ‌is‌ ‌required.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
33‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Electrolyte‌ ‌disturbances‌ ‌ 
‌ 
Progressive‌ ‌decreases‌ ‌in‌ ‌serum‌ ‌magnesium‌ ‌levels‌ ‌occur‌ ‌frequently,‌ ‌which‌ ‌can‌ ‌lead‌ ‌to‌ ‌severe‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
hypomagnesemia.‌‌Hypomagnesemia‌‌is‌‌reversible‌‌after‌‌stopping‌‌cetuximab‌‌treatment.‌‌In‌‌addition,‌‌
 
   
 
 
 
 
 
 
 
hypokalemia‌ ‌may‌ ‌occur‌ ‌as‌ ‌a‌ ‌result‌ ‌of‌ ‌diarrhea.‌ ‌ 
Hypocalcemia‌ ‌can‌ ‌also‌ ‌occur;‌ ‌in‌ ‌particular‌ ‌the‌ ‌frequency‌ ‌of‌ ‌severe‌ ‌hypocalcaemia‌ ‌may‌ ‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
increased‌ ‌when‌ ‌used‌ ‌in‌ ‌combination‌ ‌with‌ ‌platinum-based‌ ‌chemotherapy.‌ ‌ 
Serum‌ ‌electrolyte‌ ‌level‌ ‌determinations‌ ‌should‌ ‌be‌ ‌performed‌ ‌prior‌ ‌to‌ ‌treatment‌ ‌and‌‌periodically‌‌
 
 
 
 
 
 
 
 
 
 
 
 
during‌ ‌treatment‌ ‌with‌ ‌cetuximab.‌ ‌Electrolyte‌ ‌replenishment‌ ‌is‌ ‌recommended‌ ‌as‌ ‌needed.‌ ‌ 
‌ 
Neutropenia‌ ‌and‌ ‌related‌ ‌infectious‌ ‌complications‌ ‌ 
‌ 
Patients‌‌receiving‌‌cetuximab‌‌in‌‌combination‌‌with‌‌platinum-based‌‌chemotherapy‌‌are‌‌at‌‌increased‌‌
 
 
 
 
 
 
 
 
 
 
 
risk‌ ‌of‌ ‌severe‌ ‌neutropenia,‌ ‌which‌ ‌can‌ ‌lead‌ ‌to‌ ‌later‌ ‌infectious‌ ‌complications‌ ‌such‌ ‌as‌ ‌febrile‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
neutropenia,‌‌pneumonia,‌‌or‌‌sepsis.‌‌Close‌‌monitoring‌‌is‌‌recommended‌‌in‌‌these‌‌patients,‌‌especially‌‌
 
 
 
 
 
   
 
 
 
 
 
in‌‌those‌‌with‌‌skin‌‌lesions,‌‌mucositis‌‌or‌‌diarrhea,‌‌which‌‌may‌‌facilitate‌‌the‌‌development‌‌of‌‌infections‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
(see‌ ‌section‌ ‌4.8‌ ‌of‌ ‌the‌ ‌product‌ ‌data‌ ‌sheet).‌ ‌ 
‌ 
Special‌ ‌populations‌ ‌ 
‌ 
To‌ ‌date,‌ ‌only‌ ‌patients‌ ‌with‌ ‌adequate‌ ‌kidney‌ ‌and‌ ‌liver‌ ‌function‌ ‌(serum‌ ‌creatinine‌ ‌≤‌ ‌1.5‌ ‌times,‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
transaminases‌ ‌≤‌ ‌5‌ ‌times‌ ‌and‌ ‌bilirubin‌ ‌≤‌ ‌1.5‌ ‌times‌ ‌the‌ ‌upper‌ ‌limit‌ ‌of‌ ‌normal)‌ ‌have‌ ‌been‌ ‌studied.‌ ‌ 
‌ 
Cetuximab‌ ‌has‌ ‌not‌ ‌been‌ ‌studied‌ ‌in‌ ‌patients‌ ‌with‌ ‌one‌ ‌or‌ ‌more‌ ‌of‌ ‌the‌ ‌following‌ ‌laboratory‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
parameters:‌ ‌ 
‌ 
•‌ ‌hemoglobin‌ ‌<9‌ ‌g‌ ‌/‌ ‌dl‌ ‌ 
•‌ ‌white‌ ‌blood‌ ‌cell‌ ‌count‌ ‌<3000‌ ‌/‌ ‌mm³‌ ‌ 
•‌ ‌absolute‌ ‌neutrophil‌ ‌count‌ ‌<1500‌ ‌/‌ ‌mm³‌ ‌ 
•‌ ‌platelet‌ ‌count‌ ‌<100,000‌ ‌/‌ ‌mm³‌ ‌ 
‌ 
7.1.6.‌ ‌Interaction‌ ‌with‌ ‌other‌ ‌medicinal‌ ‌products‌ ‌and‌ ‌other‌ ‌forms‌ ‌of‌ ‌interaction‌ ‌ 
‌ 
The‌‌frequency‌‌of‌‌severe‌‌leukopenia‌‌or‌‌severe‌‌neutropenia‌‌may‌‌be‌‌higher‌‌and‌‌therefore‌‌may‌‌lead‌‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
a‌‌higher‌‌rate‌‌of‌‌infectious‌‌complications‌‌such‌‌as‌‌febrile‌‌neutropenia,‌‌pneumonia,‌‌and‌‌sepsis‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
combination‌ ‌with‌ ‌platinum-based‌ ‌chemotherapy,‌ ‌compared‌ ‌to‌ ‌chemotherapy‌ ‌based‌ ‌on‌ ‌platinum‌‌
 
 
 
 
 
 
 
 
 
 
alone‌ ‌(see‌ ‌section‌ ‌4.4‌ ‌of‌ ‌the‌ ‌product‌ ‌data‌ ‌sheet).‌ ‌ 
The‌ ‌frequency‌ ‌of‌ ‌cardiac‌‌ischemia,‌‌including‌‌myocardial‌‌infarction‌‌and‌‌congestive‌‌heart‌‌failure,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
and‌‌the‌‌frequency‌‌of‌‌hand-foot‌‌syndrome‌‌(palmoplantar‌‌erythrodysesthesia)‌‌were‌‌higher‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
combination‌ ‌with‌ ‌5-fluorouracil‌ ‌than‌ ‌with‌ ‌the‌ ‌infusion‌ ‌of‌ ‌5-fluorouracil‌ ‌alone.‌ ‌ 
‌ 
A‌‌formal‌‌interaction‌‌study‌‌showed‌‌that‌‌the‌‌pharmacokinetics‌‌of‌‌cetuximab‌‌remain‌‌unchanged‌‌after‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
co-administration‌ ‌of‌ ‌a‌ ‌single‌ ‌dose‌ ‌of‌ ‌irinotecan‌ ‌(350‌ ‌mg‌ ‌/‌ ‌m²‌ ‌body‌ ‌surface‌ ‌area).‌ ‌Also,‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
co-administration‌ ‌of‌ ‌cetuximab‌ ‌did‌ ‌not‌ ‌alter‌ ‌the‌ ‌pharmacokinetics‌ ‌of‌ ‌irinotecan.‌ ‌ 
‌ 
No‌ ‌other‌ ‌formal‌ ‌interaction‌ ‌studies‌ ‌with‌ ‌cetuximab‌ ‌have‌ ‌been‌ ‌performed‌ ‌in‌ ‌humans.‌ ‌ 
‌ 
7.1.7.‌ ‌Pregnancy‌ ‌and‌ ‌breatfeeding‌ ‌ 
‌ 
EGFR‌ ‌is‌ ‌involved‌ ‌in‌ ‌the‌ ‌development‌ ‌of‌ ‌the‌ ‌fetus.‌ ‌Limited‌ ‌observations‌ ‌in‌ ‌animals‌ ‌indicate‌ ‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
34‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
placental‌ ‌transfer‌ ‌of‌ ‌cetuximab‌ ‌and‌ ‌other‌ ‌IgG1‌ ‌antibodies‌ ‌have‌ ‌been‌ ‌shown‌ ‌to‌ ‌cross‌ ‌the‌ ‌ 
placental‌ ‌barrier.‌ ‌Animal‌ ‌data‌ ‌did‌ ‌not‌ ‌reveal‌ ‌indicative‌ ‌evidence‌ ‌of‌ ‌teratogenicity.‌ ‌However,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
depending‌‌on‌‌the‌‌dose,‌‌a‌‌higher‌‌incidence‌‌of‌‌abortions‌‌was‌‌observed‌‌(see‌‌section‌‌5.3).‌‌There‌‌are‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
insufficient‌ ‌data‌ ‌in‌ ‌pregnant‌ ‌or‌ ‌lactating‌ ‌women.‌ 
It‌ ‌is‌ ‌strongly‌ ‌recommended‌ ‌that‌ ‌cetuximab‌ ‌be‌ ‌administered‌ ‌during‌ ‌pregnancy‌ ‌or‌‌in‌‌women‌‌not‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
using‌‌adequate‌‌contraception‌‌only‌‌if‌‌the‌‌potential‌‌benefit‌‌to‌‌the‌‌mother‌‌justifies‌‌the‌‌potential‌‌risk‌‌to‌‌
 
 
 
   
 
 
   
 
 
 
 
 
   
the‌ ‌fetus.‌ ‌ 
It‌‌is‌‌recommended‌‌that‌‌women‌‌do‌‌not‌‌breastfeed‌‌their‌‌infants‌‌during‌‌treatment‌‌with‌‌cetuximab‌‌and‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
for‌ ‌2‌ ‌months‌ ‌after‌ ‌the‌ ‌last‌ ‌dose,‌ ‌as‌ ‌it‌ ‌is‌ ‌unknown‌ ‌whether‌ ‌cetuximab‌ ‌is‌ ‌excreted‌ ‌in‌ ‌human‌ ‌milk.‌ ‌ 
‌ 
7.1.8.‌ ‌Adverse‌ ‌Reactions‌ ‌ 
‌ 
See‌ ‌SmPC‌ ‌of‌ ‌the‌ ‌product.‌ ‌ 
‌ 
7.1.9.‌ ‌Overdose‌ ‌ 
‌ 
Currently‌ ‌there‌ ‌is‌ ‌limited‌ ‌experience‌ ‌with‌ ‌single‌ ‌doses‌ ‌greater‌ ‌than‌ ‌400‌ ‌mg‌ ‌/‌ ‌m²‌ ‌of‌ ‌surface‌ ‌area.‌ ‌ 
body‌‌or‌‌weekly‌‌administrations‌‌of‌‌doses‌‌greater‌‌than‌‌250‌‌mg‌‌/‌‌m²‌‌of‌‌body‌‌surface.‌‌In‌‌clinical‌‌trials‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
with‌‌doses‌‌up‌‌to‌‌700‌‌mg‌‌/‌‌m²‌‌administered‌‌every‌‌2‌‌weeks,‌‌the‌‌safety‌‌profile‌‌was‌‌consistent‌‌with‌‌
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
that‌ ‌described‌ ‌in‌ ‌section‌ ‌4.8.‌ ‌of‌ ‌the‌ ‌product‌ ‌data‌ ‌sheet.‌ ‌ 
‌ 
‌ 
7.1.10.‌ ‌Pharmaceutical‌ ‌Data‌ ‌ 
‌ 
List‌ ‌of‌ ‌excipients‌ ‌ 
‌ 
Sodium‌ ‌chloride‌ ‌ 
Wisteria‌ ‌ 
Polysorbate‌ ‌80‌ ‌ 
Citric‌ ‌acid‌ ‌monohydrate‌ ‌ 
Sodium‌ ‌hydroxide‌ ‌ 
Water‌ ‌for‌ ‌injections‌ ‌ 
‌ 
Incompatibilities‌ ‌ 
‌ 
This‌‌medicinal‌‌product‌‌must‌‌not‌‌be‌‌mixed‌‌with‌‌others‌‌except‌‌those‌‌mentioned‌‌in‌‌section‌‌6.6‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
product's‌ ‌technical‌ ‌data‌ ‌sheet.‌ ‌A‌ ‌separate‌ ‌infusion‌ ‌line‌ ‌must‌ ‌be‌ ‌used.‌ ‌ 
‌ 
Period‌ ‌of‌ ‌validity‌ ‌ 
‌ 
2‌ ‌years.‌ ‌ 
The‌‌physical‌‌and‌‌chemical‌‌stability‌‌of‌‌cetuximab‌‌5‌‌mg‌‌/‌‌ml‌‌has‌‌been‌‌demonstrated‌‌during‌‌use‌‌for‌‌
 
 
 
 
 
 
   
   
 
 
 
 
 
 
 
48‌ ‌hours‌ ‌at‌ ‌25‌ ‌°‌ ‌C,‌ ‌if‌ ‌the‌ ‌solution‌ ‌is‌ ‌prepared‌ ‌as‌ ‌described‌ ‌in‌ ‌section‌ ‌6.6‌ ‌of‌ ‌the‌ ‌product‌ ‌data‌ ‌sheet.‌ ‌ 
Cetuximab‌ ‌does‌ ‌not‌ ‌contain‌ ‌any‌ ‌antimicrobial‌ ‌preservatives‌ ‌or‌ ‌bacteriostatic‌ ‌agents.‌ ‌From‌ ‌the‌ ‌point‌ ‌ 
From‌ ‌a‌ ‌microbiological‌ ‌point‌ ‌of‌ ‌view,‌ ‌the‌ ‌drug‌ ‌should‌ ‌be‌ ‌used‌ ‌immediately‌ ‌after‌ ‌opening.‌ ‌But‌ ‌ 
used‌ ‌immediately,‌ ‌storage‌ ‌times‌ ‌and‌ ‌conditions‌ ‌prior‌ ‌to‌ ‌use‌ ‌are‌ ‌ 
responsibility‌‌of‌‌the‌‌user‌‌and‌‌normally‌‌they‌‌should‌‌not‌‌exceed‌‌24‌‌hours‌‌at‌‌a‌‌temperature‌‌between‌‌2‌‌
 
 
 
 
 
 
 
 
 
 
 
     
 
   
and‌ ‌8ºC,‌ ‌unless‌ ‌the‌ ‌opening‌ ‌has‌ ‌taken‌ ‌place‌ ‌under‌ ‌controlled‌ ‌and‌ ‌validated‌ ‌aseptic‌ ‌conditions.‌ ‌ 
‌ 
Special‌ ‌precautions‌ ‌for‌ ‌storage‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
35‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
Store‌ ‌in‌ ‌a‌ ‌refrigerator‌ ‌(2‌ ‌°‌ ‌C‌ ‌to‌ ‌8‌ ‌°‌ ‌C).‌ ‌Do‌ ‌not‌ ‌freeze.‌ ‌ 
For‌ ‌storage‌ ‌conditions‌ ‌after‌ ‌opening,‌ ‌see‌ ‌section‌ ‌"Shelf‌ ‌life"‌ ‌ 
‌ 
‌ 
7.1.11.‌ ‌Cetuximab‌ ‌dose‌ ‌modifications‌ ‌for‌ ‌infusion-related‌ ‌reactions‌‌ ‌
  
If‌ ‌an‌ ‌infusion-related‌ ‌reaction‌ ‌occurs,‌ ‌the‌ ‌investigator‌ ‌should‌ ‌institute‌ ‌therapeutic‌ ‌measures‌‌
 
 
 
 
 
 
 
 
 
 
 
corresponding‌ ‌to‌ ‌the‌ ‌best‌ ‌available‌ ‌medical‌ ‌practice.‌ ‌Based‌ ‌on‌ ‌previous‌ ‌experience‌ ‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
infusion-related‌ ‌reactions‌ ‌ 
Re-administration‌ ‌of‌ ‌treatment‌ ‌after‌ ‌an‌ ‌infusion-related‌ ‌reaction‌ ‌ ‌
   
Once‌‌the‌‌infusion‌‌rate‌‌of‌‌cetuximab‌‌has‌‌been‌‌decreased‌‌due‌‌to‌‌the‌‌occurrence‌‌of‌‌an‌‌infusion-related‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
reaction,‌ ‌this‌ ‌decrease‌ ‌will‌‌continue‌‌during‌‌subsequent‌‌infusions.‌‌If‌‌a‌‌subject‌‌develops‌‌a‌‌second‌‌
 
 
 
 
 
 
 
     
 
   
 
infusion-related‌‌reaction‌‌at‌‌the‌‌slower‌‌infusion‌‌rate,‌‌cetuximab‌‌should‌‌be‌‌permanently‌‌discontinued.‌‌
 
   
 
 
 
 
 
 
 
 
 
If‌ ‌at‌ ‌any‌ ‌time‌ ‌a‌ ‌patient‌ ‌experiences‌ ‌a‌‌Grade‌‌3‌‌or‌‌4‌‌infusion-related‌‌reaction,‌‌cetuximab‌‌will‌‌be‌‌
 
 
 
   
 
   
   
   
 
 
 
 
 
withdrawn‌‌from‌‌treatment.‌‌If‌‌there‌‌is‌‌any‌‌doubt‌‌as‌‌to‌‌whether‌‌a‌‌subject's‌‌reaction‌‌is‌‌a‌‌grade‌‌1-4‌‌
 
 
   
   
 
 
 
 
   
 
     
 
 
infusion-related‌‌reaction,‌‌the‌‌study‌‌coordinator‌‌and‌‌/‌‌or‌‌principal‌‌investigator‌‌should‌‌be‌‌contacted‌‌
 
 
 
 
 
   
 
 
 
 
 
 
immediately‌ ‌to‌ ‌discuss‌ ‌and‌ ‌grade.‌ ‌ 
‌ 
‌ 
‌ 
Proposal‌ ‌to‌ ‌synchronize‌ ‌cetuximab‌ ‌and‌ ‌chemotherapy‌ ‌in‌ ‌case‌ ‌of‌ ‌delays‌ ‌ 
‌ 
‌ 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
‌
 
Week‌‌ 
1‌ ‌
 
Week‌‌ 
2‌ ‌
 
Week‌‌ 
3‌ ‌
 
Week‌‌ 
4‌ ‌
 
Week‌
5‌ ‌
 
Week‌‌ 
6‌ ‌
 
Week‌‌ 
7‌ ‌
 
Week‌‌ 
8‌ ‌
 
Week‌‌ 
9‌ ‌
 
Week‌
10‌ ‌
 
Week‌‌ 
11‌ ‌
 
Week‌‌ 
12‌ ‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
Cetux‌
imab‌‌ 
(mg/‌
m²)‌ 
500‌ ‌
 
--‌ ‌
 
500‌ ‌
 
--‌ ‌
 
250‌ ‌
 
250‌ ‌
 
500‌ ‌
 
--‌ ‌
 
500‌ ‌
 
250‌ ‌
 
500‌ ‌
 
--‌ ‌
 
Che‌
moth‌
erapy‌ ‌
 
dose‌ ‌
 
--‌ ‌
 
dose‌ ‌
 
--‌ ‌
 
dose‌ ‌
 
dose‌ ‌
 
dose‌ ‌
 
--‌ ‌
 
dose‌ ‌
 
--‌ ‌
 
dose‌ ‌
 
--‌ ‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
‌
 
Toxicity‌‌ 
requiring‌ ‌delay‌‌ 
in‌‌ 
chemotherapy‌‌ ‌
  
Cutaneous‌ ‌toxicity‌‌ 
requiring‌ ‌delay‌ ‌in‌‌ 
cetuximab‌ ‌
 
‌
 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
36‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Whenever‌‌chemotherapy‌‌is‌‌administered,‌‌cetuximab‌‌will‌‌be‌‌administered‌‌at‌‌a‌‌dose‌‌of‌‌500‌‌mg‌‌/‌‌m²‌‌
 
   
 
 
 
 
     
 
 
 
   
 
unless‌ ‌dermal‌ ‌toxicity‌ ‌precludes‌ ‌administration.‌ ‌ 
Whenever‌‌chemotherapy‌‌must‌‌be‌‌delayed,‌‌cetuximab‌‌will‌‌be‌‌administered‌‌at‌‌a‌‌dose‌‌of‌‌250‌‌mg‌‌/‌‌m²‌‌
 
 
 
 
 
 
 
 
     
 
 
 
   
 
in‌‌order‌‌to‌‌allow‌‌the‌‌administration‌‌of‌‌500‌‌mg‌‌/‌‌m²‌‌one‌‌week‌‌later,‌‌coinciding‌‌with‌‌the‌‌planned‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
administration‌ ‌of‌ ‌chemotherapy.‌ ‌ 
Provided‌ ‌that‌ ‌cetuximab‌ ‌has‌ ‌been‌ ‌delayed‌ ‌due‌ ‌to‌ ‌skin‌ ‌toxicity,‌ ‌but‌ ‌chemotherapy‌ ‌is‌ ‌given‌ ‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
planned,‌‌resolution‌‌of‌‌skin‌‌toxicity‌‌will‌‌be‌‌verified‌‌one‌‌week‌‌later.‌‌If‌‌appropriate,‌‌cetuximab‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
administered‌‌at‌‌a‌‌dose‌‌of‌‌250‌‌mg‌‌/‌‌m²‌‌to‌‌allow‌‌a‌‌return‌‌to‌‌synchronous‌‌administration‌‌at‌‌the‌‌time‌‌of‌‌
     
 
 
 
   
   
   
   
 
   
 
 
 
the‌ ‌next‌ ‌chemotherapy‌ ‌administration.‌ ‌It‌ ‌is‌ ‌recommended‌ ‌to‌ ‌use‌ ‌these‌ ‌same‌ ‌principles‌ ‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
anticipated‌ ‌cases‌ ‌of‌ ‌dose‌ ‌reduction‌ ‌of‌ ‌cetuximab.‌ ‌ 
‌ 
‌ 
‌ 
Cetuximab‌ ‌dose‌ ‌reduction‌ ‌in‌ ‌case‌ ‌of‌ ‌skin‌ ‌reactions:‌ ‌ 
‌ 
‌ 
Other‌ ‌reasons‌ ‌to‌ ‌discontinue‌ ‌cetuximab;‌ ‌ 
If‌ ‌a‌ ‌patient‌ ‌develops‌ ‌breakthrough‌ ‌illness‌ ‌that,‌ ‌in‌ ‌the‌ ‌opinion‌ ‌of‌ ‌the‌ ‌investigator,‌ ‌requires‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinuation‌ ‌of‌ ‌cetuximab‌ ‌treatment,‌ ‌it‌ ‌should‌ ‌be‌ ‌resolved‌ ‌within‌‌a‌‌framework‌‌that‌‌does‌‌not‌‌
 
 
 
   
 
 
 
   
 
 
 
 
require‌ ‌delaying‌ ‌more‌ ‌than‌ ‌one‌ ‌infusion.‌ ‌ 
After‌‌stopping‌‌treatment,‌‌the‌‌patient‌‌will‌‌continue‌‌with‌‌cetuximab‌‌at‌‌the‌‌dose‌‌she‌‌was‌‌receiving‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
before‌ ‌treatment.‌ ‌ 
If‌‌treatment‌‌must‌‌be‌‌delayed‌‌for‌‌a‌‌longer‌‌period,‌‌the‌‌patient‌‌will‌‌discontinue‌‌treatment.‌‌In‌‌special‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
cases‌ ‌with‌ ‌the‌ ‌approval‌ ‌of‌ ‌the‌ ‌coordinator‌ ‌the‌ ‌patient‌ ‌could‌ ‌continue‌ ‌with‌ ‌the‌ ‌treatment.‌ ‌ 
Treatment‌‌with‌‌cetuximab‌‌will‌‌not‌‌be‌‌interrupted‌‌due‌‌to‌‌delays‌‌due‌‌to‌‌chemotherapy‌‌toxicity.‌‌In‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
case‌ ‌of‌ ‌chemo‌ ‌delays,‌ ‌the‌ ‌patient‌ ‌will‌ ‌receive‌ ‌cetuximab‌ ‌treatment‌ ‌as‌ ‌planned.‌ ‌ 
‌ 
7.2.‌ ‌FOLFOX6‌ ‌(m)‌ ‌
 
Drugs‌‌in‌‌this‌‌combination‌‌are‌‌commercially‌‌available.‌‌These‌‌drugs‌‌will‌‌be‌‌formulated,‌‌packaged,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
labeled‌‌and‌‌stored‌‌according‌‌to‌‌the‌‌procedures‌‌indicated‌‌by‌‌the‌‌local‌‌manufacturer,‌‌the‌‌supplier‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌center.‌‌Consult‌‌the‌‌product‌‌data‌‌sheet‌‌for‌‌information‌‌on‌‌packaging‌‌and‌‌formulation,‌‌labeling,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
storage,‌ ‌preparation,‌ ‌supply‌ ‌/‌ ‌return,‌ ‌and‌ ‌counting‌ ‌of‌ ‌the‌ ‌combination.‌ ‌ 
‌ 
As‌‌they‌‌are‌‌commercialized‌‌drugs‌‌of‌‌habitual‌‌use‌‌in‌‌the‌‌study‌‌pathology,‌‌the‌‌supply‌‌will‌‌be‌‌carried‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
out‌‌through‌‌the‌‌usual‌‌channels‌‌of‌‌the‌‌National‌‌Health‌‌System,‌‌with‌‌the‌‌prior‌‌favorable‌‌opinion‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌CEIC‌ ‌and‌ ‌the‌ ‌approval‌ ‌of‌ ‌the‌ ‌Center's‌ ‌Directorate.‌ ‌ 
‌ 
Prior‌‌to‌‌administration‌‌of‌‌FOLFOX6‌‌(m)‌‌chemotherapy,‌‌the‌‌investigator‌‌or‌‌designee‌‌will‌‌review‌‌the‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
subject's‌‌hematology‌‌and‌‌biochemical‌‌tests,‌‌liver‌‌function‌‌tests,‌‌and‌‌the‌‌incidence‌‌of‌‌hematologic‌‌or‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
non-hematologic‌‌toxicities,‌‌and‌‌follow‌‌the‌‌parameters‌‌of‌‌sections‌‌7.2.2‌‌and‌‌7.2.3‌‌to‌‌determine‌‌if‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
   
   
 
treatment‌ ‌is‌ ‌adequate.‌ ‌ 
‌ 
7.2.1‌ ‌Premedication‌ ‌FOLFOX6‌ ‌(m)‌ ‌ 
‌ 
Prior‌‌to‌‌administration‌‌of‌‌FOLFOX6‌‌(m),‌‌all‌‌subjects‌‌should‌‌receive‌‌antiemetic‌‌products‌‌(eg,‌‌oral‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
or‌‌IV‌‌dexamethasone‌‌and‌‌5-hydroxytryptamine3‌‌[5-HT3]‌‌receptor‌‌antagonists).‌‌Antiemetics‌‌should‌‌
 
 
 
 
 
 
 
 
 
 
be‌‌administered‌‌on‌‌the‌‌day‌‌of‌‌treatment,‌‌starting‌‌at‌‌least‌‌30‌‌minutes‌‌before‌‌the‌‌administration‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFOX6‌‌(m).‌‌Alternative‌‌and‌‌additional‌‌antiemetics‌‌may‌‌be‌‌used,‌‌when‌‌clinically‌‌indicated,‌‌at‌‌
 
 
 
 
 
 
 
 
 
 
 
   
the‌ ‌discretion‌ ‌of‌ ‌the‌ ‌investigator,‌ ‌or‌ ‌in‌ ‌accordance‌ ‌with‌ ‌standard‌ ‌institutional‌ ‌practice.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
37‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
7.2.2‌ ‌FOLFOX6‌ ‌(m)‌ ‌ 
‌ 
Administration‌ ‌of‌ ‌FOLFOX6‌ ‌(m)‌ ‌chemotherapy‌ ‌will‌ ‌begin‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each‌ ‌treatment‌ ‌cycle.‌ ‌ 
‌ 
The‌ ‌FOLFOX6‌ ‌(m)‌ ‌regimen‌ ‌will‌ ‌be‌ ‌administered‌ ‌every‌ ‌2‌ ‌weeks‌ ‌(+/-‌ ‌3‌ ‌days),‌ ‌as‌ ‌follows:‌ ‌ 
‌ 
Table:‌ ‌Scheme‌ ‌FOLFOX6‌ ‌(m)‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
aExtension‌‌of‌‌the‌‌oxaliplatin‌‌infusion‌‌time‌‌from‌‌2‌‌to‌‌6‌‌hours‌‌is‌‌allowed,‌‌at‌‌the‌‌discretion‌‌of‌‌the‌‌investigator,‌‌to‌‌mitigate‌‌acute‌‌toxicities.‌‌It‌‌is‌‌not‌‌necessary‌‌to‌‌change‌‌
 
 
 
 
 
 
   
   
   
   
 
 
 
 
   
 
 
     
 
   
 
the‌ ‌duration‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌leucovorin‌ ‌infusions.‌ ‌ 
b‌ ‌At‌ ‌the‌ ‌discretion‌ ‌of‌ ‌the‌ ‌investigator,‌ ‌leucovorin‌ ‌and‌ ‌oxaliplatin‌ ‌may‌ ‌be‌ ‌administered‌ ‌sequentially‌ ‌according‌ ‌to‌ ‌standard‌ ‌treatment‌ ‌and‌ ‌local‌ ‌regulations.‌ ‌ 
cOxaliplatin‌ ‌is‌ ‌not‌ ‌compatible‌ ‌with‌ ‌normal‌ ‌saline‌ ‌or‌ ‌5-FU.‌ ‌The‌ ‌infusion‌ ‌line‌ ‌should‌ ‌be‌ ‌thoroughly‌ ‌cleaned‌ ‌with‌ ‌D5W‌ ‌before‌ ‌and‌ ‌after‌ ‌5-FU‌ ‌administration.‌.‌ ‌ 
‌ 
‌ 
Figure‌ ‌2.‌ ‌FOLFOX6‌ ‌(m)‌ ‌chemotherapy‌ ‌administration‌ ‌schedule‌ ‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Drug‌‌ ‌
  
Dose‌ ‌ 
Day‌ ‌ 
Administration‌ ‌ 
‌ 
Oxaliplatin‌ ‌ 
85‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ ‌
   
Infusion‌ ‌i.v.‌ ‌of‌ ‌85‌‌mg‌‌/‌
 
 
 
 
   
m2‌ ‌of‌ ‌oxaliplatin‌ ‌in‌
 
 
 
 
250-500‌‌ml‌‌of‌‌D5W‌‌and‌
 
 
 
 
 
infusion‌ ‌i.v.‌ ‌400‌ ‌mg‌ ‌/‌
 
 
 
   
m2‌ ‌leucovorin‌‌racemate‌
 
 
 
(or‌‌200‌‌mg‌‌/‌‌m2‌‌l-LV)‌‌in‌
 
 
   
 
   
D5W,‌‌both‌‌administered‌
 
 
 
over‌ ‌120‌ ‌minutes‌‌(±‌‌15‌
 
 
 
 
 
minutes)‌ ‌a‌ ‌at‌ ‌the‌ ‌same‌
   
 
 
 
time‌ ‌in‌ ‌separate‌ ‌bags‌
 
 
 
 
using‌ ‌a‌ ‌Yc‌ ‌line‌ ‌ 
Leucovorin‌ ‌ 
200‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ 
‌ 
Fluorouracil‌ ‌ 
400‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ 
Bolus‌ ‌IV‌ ‌ 
‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
38‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Every‌‌2‌‌weeks‌‌a‌‌new‌‌cycle‌‌of‌‌FOLFOX6‌‌(m)‌‌treatment‌‌will‌‌be‌‌repeated,‌‌although‌‌it‌‌will‌‌not‌‌be‌‌
   
   
 
 
 
 
 
 
 
 
 
   
 
 
 
administered‌‌to‌‌subjects‌‌with‌‌ANC‌‌<1.5‌‌x‌‌109‌‌cells‌‌/‌‌L,‌‌or‌‌if‌‌the‌‌platelet‌‌count‌‌is‌‌<75‌‌x‌‌109‌‌/‌‌L,‌‌if‌‌
 
 
 
 
 
   
 
   
 
   
 
 
   
   
   
   
the‌ ‌skin‌ ‌toxicity,‌ ‌stomatitis‌ ‌or‌ ‌diarrhea‌ ‌have‌ ‌not‌ ‌recovered‌ ‌to‌ ‌grade‌ ‌≤‌ ‌1,‌ ‌or‌ ‌if‌ ‌fatigue‌ ‌has‌ ‌not‌‌
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
recovered‌‌to‌‌grade‌‌≤‌‌2.‌‌A‌‌delay‌‌of‌‌up‌‌to‌‌4‌‌weeks‌‌is‌‌allowed‌‌to‌‌start‌‌a‌‌new‌‌course‌‌of‌‌treatment‌‌for‌‌
 
 
   
   
 
 
 
   
   
 
 
   
 
 
 
 
 
resolution‌ ‌of‌ ‌the‌‌toxicities.‌‌If‌‌treatment‌‌with‌‌one‌‌component‌‌of‌‌the‌‌FOLFOX6‌‌(m)‌‌regimen‌‌(for‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
example,‌‌5-FU‌‌/‌‌leucovorin‌‌or‌‌oxaliplatin)‌‌is‌‌delayed,‌‌the‌‌other‌‌component‌‌is‌‌also‌‌delayed‌‌in‌‌the‌‌
 
   
 
 
   
 
 
 
   
 
 
 
 
same‌ ‌way,‌ ‌so‌ ‌that‌ ‌both‌ ‌therapies‌ ‌can‌ ‌be‌ ‌administered‌ ‌together‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each.‌ ‌2‌ ‌week‌ ‌cycle.‌ ‌ 
‌ 
In‌ ‌the‌ ‌event‌ ‌that‌ ‌oxaliplatin‌ ‌administration‌ ‌is‌ ‌interrupted‌ ‌for‌ ‌any‌ ‌reason‌ ‌before‌ ‌6‌ ‌months‌ ‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
treatment‌‌have‌‌elapsed‌‌or‌‌there‌‌is‌‌progression‌‌of‌‌the‌‌disease,‌‌treatment‌‌with‌‌5-FU‌‌/‌‌leucovorin‌‌and‌‌
 
 
 
 
   
 
 
 
 
 
 
   
 
 
cetuximab‌ ‌can‌ ‌continue‌ ‌to‌ ‌be‌ ‌administered‌ ‌once‌ ‌every‌ ‌14‌ ‌days‌ ‌(‌ ‌+/-‌ ‌3‌ ‌days)‌ ‌until‌ ‌disease‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
progression‌ ‌or‌ ‌intolerance‌ ‌to‌ ‌study‌ ‌treatment.‌ ‌ 
In‌ ‌no‌ ‌case‌ ‌can‌ ‌a‌ ‌patient‌ ‌be‌ ‌kept‌ ‌under‌ ‌study‌ ‌with‌ ‌oxaliplatin‌ ‌alone,‌ ‌or‌ ‌in‌ ‌combination‌ ‌with‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab.‌ ‌ 
‌ 
If‌‌the‌‌discontinuation‌‌of‌‌FOLFOX6‌‌(m)‌‌chemotherapy‌‌is‌‌≤‌‌6‌‌weeks‌‌from‌‌the‌‌previous‌‌cycle,‌‌if‌‌the‌‌
 
 
 
 
 
 
       
 
 
 
 
   
 
subject‌ ‌has‌ ‌recovered‌ ‌from‌ ‌toxicities,‌ ‌as‌ ‌noted‌ ‌above,‌ ‌and‌ ‌if‌ ‌the‌ ‌disease‌ ‌has‌ ‌not‌ ‌progressed,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFOX6‌ ‌chemotherapy‌ ‌should‌ ‌be‌ ‌restarted‌ ‌(m‌ ‌)‌ ‌with‌ ‌or‌ ‌without‌ ‌cetuximab‌ ‌with‌ ‌the‌ ‌doses‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
specified‌‌in‌‌Tables‌‌2,‌‌3‌‌and‌‌4.‌‌If‌‌the‌‌interruption‌‌of‌‌FOLFOX6‌‌(m)‌‌chemotherapy‌‌is>‌‌6‌‌weeks‌‌but‌‌
 
 
 
   
 
   
 
 
 
 
 
 
   
 
 
the‌‌subject‌‌has‌‌recovered‌‌from‌‌toxicities‌‌and‌‌the‌‌disease‌‌has‌‌not‌‌progressed,‌‌staff‌‌The‌‌sponsor‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌study‌‌should‌‌review‌‌the‌‌case‌‌together‌‌with‌‌the‌‌investigator‌‌to‌‌determine‌‌if‌‌the‌‌treatment‌‌should‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
be‌ ‌resumed.‌ ‌ 
‌ 
7.2.3‌ ‌Dose‌ ‌levels‌ ‌and‌ ‌dose‌ ‌modification‌ ‌guidelines‌ ‌for‌ ‌the‌ ‌FOLFOX6‌ ‌(m)‌ ‌regimen‌ ‌ 
‌ 
The‌ ‌toxicity‌ ‌of‌ ‌FOLFOX6‌ ‌(m)‌ ‌in‌ ‌subjects‌ ‌should‌ ‌be‌ ‌closely‌ ‌monitored.‌ ‌Doses‌ ‌of‌ ‌5-FU‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
oxaliplatin‌ ‌can‌‌be‌‌adjusted‌‌according‌‌to‌‌the‌‌individual‌‌tolerance‌‌of‌‌each‌‌subject.‌‌The‌‌leucovorin‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dose‌‌will‌‌remain‌‌fixed‌‌at‌‌400‌‌mg‌‌/‌‌m2‌‌of‌‌racemate‌‌(d,‌‌l-leucovorin)‌‌or‌‌200‌‌mg‌‌/‌‌m2‌‌of‌‌l-leucovorin.‌‌
 
 
 
   
 
   
 
 
 
 
 
 
 
   
 
 
 
Table‌ ‌2‌ ‌to‌ ‌4‌ ‌shows‌ ‌recommended‌ ‌dose‌ ‌levels‌ ‌and‌ ‌guidelines.‌ ‌of‌ ‌dose‌ ‌modification,‌ ‌due‌ ‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
neurological‌ ‌and‌ ‌non-neurological‌ ‌toxicity,‌ ‌of‌ ‌both‌ ‌oxaliplatin‌ ‌and‌ ‌5-FU.‌ ‌ 
‌ 
Table‌ ‌3‌ ‌describes‌ ‌the‌ ‌recommended‌ ‌dose‌ ‌reductions‌ ‌for‌ ‌non-neurologic‌ ‌toxicity.‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Table‌ ‌3.‌ ‌Dose‌ ‌reductions‌ ‌of‌ ‌FOLFOX6‌ ‌(m):‌ ‌non-neurological‌ ‌toxicity‌ ‌
 
‌ 
‌ 
‌ 
Initial‌ ‌dose‌ ‌ 
Dose‌ ‌-‌ ‌1‌ ‌ 
Dose‌ ‌-‌ ‌2‌ ‌ 
Oxaliplatin‌ ‌ 
85‌ ‌mg/m‌2‌ ‌ 
65‌ ‌mg/m‌2‌ ‌ 
50‌ ‌mg/m‌2‌ ‌ 
5-FU‌ ‌Bolus‌ ‌ 
400‌ ‌mg/m‌2‌ ‌ 
320‌ ‌mg/m‌2‌ ‌ 
240‌ ‌mg/m‌2‌ ‌ 
5-FU‌ ‌Infusion‌ ‌ 
2.400‌ ‌mg/m‌2‌ ‌ 
1.900‌ ‌mg/m‌2‌ ‌ 
1.500‌ ‌mg/m‌2‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
39‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Table‌ ‌4‌ ‌below‌ ‌describes‌ ‌the‌ ‌recommended‌ ‌dose‌ ‌modifications‌ ‌at‌ ‌the‌ ‌start‌ ‌of‌ ‌each‌ ‌subsequent‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
therapy‌ ‌cycle.‌ ‌All‌ ‌dose‌ ‌modifications‌ ‌must‌ ‌be‌ ‌based‌ ‌on‌ ‌the‌ ‌worst‌ ‌preceding‌ ‌toxicity.‌ 
‌ 
Table‌ ‌4‌ ‌Dose‌ ‌modifications‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Table‌ ‌4‌ ‌Dose‌ ‌modifications‌ 
Toxicity‌ ‌
 
‌ 
Grade‌ ‌NCI*‌ ‌(value)‌ ‌ 
Dose‌ ‌level‌ ‌
 
‌ 
for‌ ‌subsequent‌ ‌cycles‌ ‌
 
‌ 
Based‌ ‌on‌ ‌the‌ ‌toxicity‌ ‌of‌ ‌the‌ ‌interval**‌ ‌ 
In‌ ‌the‌ ‌moment‌ ‌of‌ ‌
 
‌ 
retreatment‌ ‌ 
Absence‌ ‌of‌ ‌toxicity‌ ‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌ 
Neutropenia‌ ‌(ANC)‌ ‌
 
‌ 
Grade‌ ‌1‌ ‌(ANC < LIN‌ ‌–‌ ‌1,5 x 10‌9‌/L)‌‌ ‌
  
‌ 
Grade‌ ‌2‌ ‌(ANC‌ ‌1,5 x 10‌9‌/L‌ ‌-‌ ‌1,0 x 10‌9‌/L)‌ ‌
 
‌ 
Grade‌ ‌3‌ ‌(ANC‌ ‌1,0 x 10‌9‌/L‌ ‌–‌ ‌0,5 x 10‌9‌/L)‌ ‌
 
‌ 
Grade‌ ‌4‌ ‌(ANC < 0,5 x 10‌9‌/L)‌ ‌ 
‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌ 
‌
 
‌ 
If‌ ‌ANC‌ ‌<1.5‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌at‌ ‌the‌ ‌beginning‌‌ 
of‌ ‌the‌ ‌cycle,‌ ‌suspend‌ ‌and‌ ‌check‌ ‌weekly,‌‌ 
then‌ ‌treat‌ ‌according‌ ‌to‌ ‌the‌ ‌toxicity‌ ‌of‌ ‌the‌‌ 
interval.‌ ‌
 
‌ 
If‌ ‌ANC‌ ‌<1.5‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌after‌ ‌4‌ ‌weeks,‌‌ 
discontinue‌ ‌treatment.‌ ‌ 
Thrombocytopenia‌ ‌
 
‌ 
Grade‌ ‌1‌ ‌(PLT < LIN‌ ‌-‌ ‌75,0 x 10‌9‌/L)‌ ‌
 
‌ 
Grade‌ ‌2‌ ‌(PLT‌ ‌75,0‌ ‌x‌ ‌10‌9‌/L‌ ‌-‌ ‌50,0‌ ‌x‌‌ 
10‌9‌/L)‌ ‌ 
Grade‌ ‌3‌ ‌(PLT‌ ‌50,0‌ ‌x‌ ‌10‌9‌/L‌ ‌-‌ ‌25,0‌ ‌x‌‌ 
10‌9‌/L)‌ ‌ 
Grade‌ ‌4‌ ‌(PLT < 25,0 x 10‌9‌/L)‌ ‌ 
‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
‌
 
‌ 
If‌ ‌PLT‌ ‌<75.0‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌at‌ ‌the‌ ‌beginning‌‌ 
of‌ ‌the‌ ‌cycle,‌ ‌suspend‌ ‌and‌ ‌check‌ ‌weekly‌‌ 
and‌ ‌then‌ ‌treat‌ ‌according‌ ‌to‌ ‌the‌ ‌toxicity‌ ‌of‌‌ 
the‌ ‌interval.‌ ‌
 
‌ 
If‌ ‌PLT‌ ‌<75.0‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌after‌ ‌4‌ ‌weeks,‌‌ 
discontinue‌ ‌treatment.‌ ‌ 
Febrile‌ ‌neutropenia‌ ‌
 
‌ 
ANC‌ ‌< 1,0‌ ‌x‌ ‌10‌9‌/L‌ ‌(neutropenia‌ ‌of‌ ‌grade‌‌ 
3‌ ‌o‌ ‌4)‌ ‌y‌ ‌fever‌ ‌>‌ ‌38,5 ºC‌ ‌ 
‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
40‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
*‌ ‌Common‌ ‌toxicity‌ ‌criteria‌ ‌from‌ ‌the‌ ‌National‌ ‌Cancer‌ ‌Institute‌ ‌(CTC‌ ‌version‌ ‌3.0).‌ ‌ 
**‌ ‌Refers‌ ‌to‌ ‌the‌ ‌starting‌ ‌dose‌ ‌used‌ ‌in‌ ‌the‌ ‌previous‌ ‌cycle.‌ ‌ 
1‌ ‌In‌ ‌case‌ ‌of‌ ‌mucositis‌ ‌/‌ ‌stomatitis,‌ ‌reduce‌ ‌only‌ ‌the‌ ‌dose‌ ‌of‌ ‌5-FU,‌ ‌not‌ ‌that‌ ‌of‌ ‌oxaliplatin.‌ ‌ 
2‌ ‌Exceptions:‌ ‌alopecia,‌ ‌fatigue,‌ ‌anorexia,‌ ‌nausea‌ ‌/‌ ‌vomiting‌ ‌if‌ ‌they‌ ‌can‌ ‌be‌ ‌controlled‌ ‌with‌ ‌antiemetics,‌ ‌viral‌ ‌infections.‌ ‌ 
‌ 
Table‌ ‌5‌ ‌describes‌ ‌the‌ ‌recommended‌‌dose‌‌modifications‌‌for‌‌oxaliplatin,‌‌based‌‌on‌‌the‌‌duration‌‌of‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
neurotoxicity‌ ‌associated‌ ‌with‌ ‌oxaliplatin.‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
‌ 
Other‌ ‌hematologic‌ ‌toxicities‌ ‌
 
‌ 
‌ 
Dose‌ ‌modifications‌ ‌for‌ ‌leukopenia‌ ‌at‌ ‌the‌ ‌start‌ ‌of‌ ‌subsequent‌‌ 
cycles‌ ‌of‌ ‌therapy‌ ‌and‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌ ‌retreatment‌ ‌are‌ ‌also‌ ‌based‌‌ 
on‌ ‌the‌ ‌NCI‌ ‌toxicity‌ ‌criteria‌ ‌(CTC‌ ‌version‌ ‌3.0)‌ ‌and‌ ‌are‌ ‌the‌ ‌same‌‌ 
as‌ ‌those‌ ‌recommended‌ ‌above‌ ‌for‌ ‌neutropenia.‌ ‌ 
Diarrhea‌ ‌
 
‌ 
Grade‌ ‌1‌ ‌
 
‌ 
Grade‌ ‌2‌ ‌
 
‌ 
Grade‌ ‌3‌ ‌
 
‌ 
Grade‌ ‌4‌ ‌
 
‌ 
‌ 
‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL.‌ ‌ 
‌
 
‌ 
For‌ ‌grade‌ ‌2‌ ‌diarrhea‌ ‌at‌ ‌the‌ ‌start‌ ‌of‌ ‌the‌‌ 
cycle,‌ ‌suspend‌ ‌and‌ ‌check‌ ‌weekly,‌ ‌then‌‌ 
treat‌ ‌according‌ ‌to‌ ‌interval‌ ‌toxicity.‌ ‌
 
‌ 
‌ 
‌ 
If‌ ‌grade‌ ‌2‌ ‌diarrhea‌ ‌persists‌ ‌after‌ ‌4‌ ‌weeks,‌‌ 
discontinue‌ ‌treatment.‌ ‌ 
Other‌ ‌non-hematologic‌ ‌toxicities‌1,2‌ ‌
 
‌ 
‌ 
Dose‌ ‌modifications‌ ‌for‌ ‌other‌ ‌non-hematologic‌ ‌toxicities‌ ‌at‌ ‌the‌‌ 
beginning‌ ‌of‌ ‌subsequent‌ ‌therapy‌ ‌cycles‌ ‌and‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌‌ 
retreatment‌ ‌are‌ ‌also‌ ‌based‌ ‌on‌ ‌the‌ ‌NCI‌ ‌toxicity‌ ‌criteria‌ ‌(CTC‌‌ 
version‌ ‌3.0)‌ ‌and‌ ‌are‌ ‌the‌ ‌same‌ ‌as‌ ‌those‌ ‌recommended‌ ‌above‌ ‌for‌‌ 
diarrhea.‌ ‌ 
The‌ ‌LV‌ ‌dose‌ ‌will‌ ‌not‌ ‌be‌ ‌adjusted‌ ‌due‌ ‌to‌ ‌toxicity.‌ ‌It‌ ‌should‌ ‌remain‌ ‌at‌ ‌400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌racemate‌ ‌(or‌ ‌200‌ ‌mg‌ ‌/‌ ‌m2‌ ‌l-LV)‌ ‌in‌ ‌all‌ ‌cycles.‌ ‌LV‌ ‌should‌ ‌be‌ ‌given‌ ‌just‌ ‌before‌ ‌each‌‌ 
5-FU‌ ‌dose;‌ ‌thus,‌ ‌if‌ ‌5-FU‌ ‌is‌ ‌delayed,‌ ‌LV‌ ‌will‌ ‌also‌ ‌be‌ ‌delayed.‌ ‌ 
Table‌ ‌5.‌ ‌Dose‌ ‌modification‌ ‌rules‌ ‌due‌ ‌to‌ ‌neurotoxicity‌ ‌associated‌ ‌with‌ ‌oxaliplatin‌ ‌ 
‌ 
Toxicity‌ ‌(grade)‌ ‌ 
Toxicity‌ ‌duration‌ ‌ 
Persistente‌ ‌
 
‌ 
(not‌ ‌resolved‌ ‌between‌ ‌cycles)‌ ‌ 
‌ 
1‌ ‌-‌ ‌7‌ ‌days‌ ‌ 
> 7‌ ‌days‌ ‌ 
‌ 
Paresthesias‌ ‌/‌ ‌dysesthesias1‌‌ 
of‌ ‌short‌ ‌duration‌ ‌that‌ ‌resolve‌‌ 
and‌ ‌do‌ ‌not‌ ‌interfere‌ ‌with‌‌ 
function‌ ‌(grade‌ ‌1)‌ ‌ 
No‌ ‌change‌ ‌ 
No‌ ‌change‌ ‌ 
No‌ ‌change‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
41‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
1‌ ‌May‌ ‌be‌ ‌induced‌ ‌by‌ ‌cold.‌ ‌ 
Every‌‌2‌‌weeks‌‌a‌‌new‌‌cycle‌‌of‌‌FOLFOX6‌‌(m)‌‌treatment‌‌will‌‌be‌‌repeated,‌‌although‌‌it‌‌will‌‌not‌‌be‌‌
   
   
 
 
 
 
 
 
 
 
 
   
 
 
 
administered‌‌to‌‌subjects‌‌with‌‌ANC‌‌<1.5‌‌x‌‌109‌‌cells‌‌/‌‌L,‌‌or‌‌if‌‌the‌‌platelet‌‌count‌‌is‌‌<75‌‌x‌‌109‌‌/‌‌L,‌‌if‌‌
 
 
 
 
 
   
 
   
 
   
 
 
   
   
   
   
the‌‌skin‌‌toxicity‌‌(not‌‌related‌‌to‌‌cetuximab),‌‌stomatitis‌‌or‌‌diarrhea‌‌have‌‌not‌‌recovered‌‌to‌‌grade‌‌≤‌‌1,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
or‌‌if‌‌fatigue‌‌has‌‌not‌‌recovered‌‌to‌‌grade‌‌≤2.‌‌A‌‌delay‌‌of‌‌up‌‌to‌‌4‌‌weeks‌‌is‌‌allowed‌‌to‌‌start‌‌a‌‌new‌‌cycle‌‌
   
 
 
 
 
 
 
   
 
 
     
   
   
   
 
 
of‌‌treatment‌‌for‌‌the‌‌resolution‌‌of‌‌toxicities.‌‌If‌‌treatment‌‌with‌‌one‌‌component‌‌of‌‌the‌‌FOLFOX6‌‌(m)‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
regimen‌ ‌(for‌ ‌example,‌ ‌5-FU‌ ‌/‌ ‌leucovorin‌‌or‌‌oxaliplatin)‌‌is‌‌delayed,‌‌the‌‌other‌‌component‌‌is‌‌also‌‌
 
 
 
   
 
 
   
 
 
 
   
 
delayed‌‌in‌‌the‌‌same‌‌way,‌‌so‌‌that‌‌both‌‌therapies‌‌can‌‌be‌‌administered‌‌together‌‌on‌‌day‌‌1‌‌of‌‌each‌‌2‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
week‌ ‌cycle.‌ ‌ 
7.2.4‌ ‌Stopping‌ ‌FOLFOX6‌ ‌chemotherapy‌ ‌(m)‌ ‌ 
Subjects‌ ‌will‌ ‌be‌ ‌allowed‌ ‌to‌ ‌receive‌ ‌treatment‌ ‌with‌ ‌FOLFOX6‌ ‌(m)‌ ‌for‌ ‌up‌ ‌to‌ ‌6‌ ‌months‌ ‌or‌‌until‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
disease‌‌progression,‌‌or‌‌until‌‌unacceptable‌‌toxicities‌‌and‌‌/‌‌or‌‌consent‌‌is‌‌withdrawn.‌‌If‌‌patients‌‌do‌‌not‌‌
 
 
 
 
 
 
   
 
   
   
 
 
 
show‌ ‌progression‌ ‌after‌ ‌6‌ ‌months‌ ‌of‌ ‌treatment‌ ‌with‌ ‌FOLFIRI‌ ‌(m)‌ ‌or‌ ‌FOLFOX6‌ ‌(m),‌ ‌they‌ ‌will‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
continue‌ ‌receiving‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌monotherapy‌ ‌until‌ ‌progression.‌ ‌ 
‌ 
If‌ ‌FOLFOX6‌ ‌(m)‌ ‌chemotherapy‌ ‌is‌ ‌discontinued‌ ‌before‌ ‌6‌ ‌months‌ ‌of‌ ‌treatment‌ ‌or‌ ‌disease‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
progression‌ ‌e.g.‌ ‌due‌ ‌to‌ ‌FOLFOX-6‌ ‌(m)‌ ‌toxicity,‌ ‌the‌‌subject‌‌may‌‌continue‌‌to‌‌receive‌‌cetuximab‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
monotherapy‌‌every‌‌14‌‌days‌‌(+/-‌‌-‌‌3‌‌days)‌‌until‌‌you‌‌develop‌‌disease‌‌progression‌‌or‌‌are‌‌unable‌‌to‌‌
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
tolerate‌ ‌the‌ ‌investigational‌ ‌product.‌ ‌ 
The‌‌disease‌‌of‌‌all‌‌subjects‌‌will‌‌be‌‌reassessed‌‌after‌‌12‌‌weeks‌‌±‌‌1‌‌week‌‌for‌‌the‌‌period‌‌the‌‌patient‌‌
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
continues‌ ‌in‌ ‌the‌ ‌trial‌ ‌until‌ ‌progression.‌ ‌ 
‌ 
Tumor‌‌evaluation‌‌will‌‌be‌‌performed‌‌on‌‌subjects‌‌who‌‌have‌‌withdrawn‌‌from‌‌the‌‌study‌‌for‌‌reasons‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
other‌‌than‌‌radiographically‌‌documented‌‌disease‌‌progression.‌‌All‌‌these‌‌subjects‌‌should‌‌be‌‌monitored‌‌
 
 
 
 
 
 
 
 
 
 
 
 
for‌ ‌disease‌ ‌progression‌ ‌(revised‌ ‌RECIST‌ ‌1.1‌ ‌criteria)‌ ‌every‌ ‌12‌ ‌weeks‌ ‌+/-‌ ‌1‌ ‌week‌ ‌until‌ ‌disease‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
progression‌ ‌or‌ ‌end‌ ‌of‌ ‌study.‌ ‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Paresthesias‌ ‌/‌ ‌dysesthesias1‌‌ 
interfering‌ ‌with‌ ‌function‌ ‌but‌‌ 
not‌ ‌activities‌ ‌of‌ ‌daily‌ ‌living‌‌ 
(ADL)‌ ‌(grade‌ ‌2)‌ ‌ 
No‌ ‌change‌ ‌ 
No‌ ‌change‌ ‌ 
Dicrease‌ ‌to‌ ‌65‌ ‌
 
‌ 
mg/m‌2‌ ‌
 
‌ 
‌ 
Paresthesia‌ ‌/‌ ‌dysesthesia1‌‌ 
with‌ ‌pain‌ ‌or‌ ‌functional‌‌ 
impairment‌ ‌that‌ ‌also‌‌ 
interferes‌ ‌with‌ ‌ADL‌ ‌(grade‌ ‌3)‌ ‌ 
1st‌ ‌time:‌ ‌dicrease‌ ‌to‌ ‌65‌ ‌mg/m‌2‌ ‌
 
‌ 
‌
 
‌ 
2nd‌ ‌time:‌ ‌dicrease‌ ‌
 
‌ 
to‌ ‌40‌ ‌mg/m‌2‌ ‌ 
DISCONTINUE‌ ‌ 
DISCONTINUE‌ ‌ 
Persistent‌ ‌paraesthesia‌ ‌/‌‌ 
dysesthesia‌ ‌incapacitating‌ ‌or‌‌ 
life-threatening‌ ‌(grade‌ ‌4)‌ ‌ 
DISCONTINUE‌ ‌ 
DISCONTINUE‌ ‌ 
DISCONTINUE‌ ‌ 
Laryngopharyngeal‌‌ 
dysesthesias‌ ‌ 
No‌ ‌change‌ ‌ 
Increase‌ ‌the‌ ‌duration‌ ‌of‌ ‌the‌‌ 
infusion‌ ‌to‌ ‌6‌ ‌hours‌ ‌ 
Increase‌ ‌the‌ ‌duration‌ ‌of‌ ‌the‌‌ 
infusion‌ ‌to‌ ‌6‌ ‌hours‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
42‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
7.3‌ ‌FOLFIRI‌ ‌(m)‌ ‌
 
‌ 
Drugs‌‌in‌‌this‌‌combination‌‌are‌‌commercially‌‌available.‌‌These‌‌drugs‌‌will‌‌be‌‌formulated,‌‌packaged,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
labeled‌‌and‌‌stored‌‌according‌‌to‌‌the‌‌procedures‌‌indicated‌‌by‌‌the‌‌local‌‌manufacturer,‌‌the‌‌supplier‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌center.‌‌Consult‌‌the‌‌product‌‌data‌‌sheet‌‌for‌‌information‌‌on‌‌packaging‌‌and‌‌formulation,‌‌labeling,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
storage,‌ ‌preparation,‌ ‌supply‌ ‌/‌ ‌return,‌ ‌and‌ ‌counting‌ ‌of‌ ‌the‌ ‌combination.‌ ‌ 
‌ 
As‌‌they‌‌are‌‌commercialized‌‌drugs‌‌of‌‌habitual‌‌use‌‌in‌‌the‌‌study‌‌pathology,‌‌the‌‌supply‌‌will‌‌be‌‌carried‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
out‌‌through‌‌the‌‌usual‌‌channels‌‌of‌‌the‌‌National‌‌Health‌‌System,‌‌with‌‌the‌‌prior‌‌favorable‌‌opinion‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌CEIC‌ ‌and‌ ‌the‌ ‌approval‌ ‌of‌ ‌the‌ ‌Center's‌ ‌Directorate.‌ ‌ 
‌ 
Prior‌‌to‌‌the‌‌administration‌‌of‌‌FOLFIRI‌‌(m)‌‌chemotherapy,‌‌the‌‌investigator‌‌or‌‌his‌‌/‌‌her‌‌designee‌‌will‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
analyze‌‌the‌‌subject's‌‌hematology‌‌and‌‌biochemical‌‌tests,‌‌liver‌‌function‌‌tests,‌‌and‌‌the‌‌incidence‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hematologic‌‌or‌‌non-hematologic‌‌toxicities,‌‌and‌‌follow‌‌the‌‌parameters‌‌of‌‌sections‌‌7.3.2‌‌and‌‌7.3.3‌‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
determine‌ ‌if‌ ‌the‌ ‌treatment‌ ‌is‌ ‌adequate.‌ ‌ 
‌ 
7.3.1‌ ‌Premedication‌ ‌FOLFIRI‌ ‌(m)‌ ‌ 
‌ 
Prior‌‌to‌‌administration‌‌of‌‌FOLFIRI‌‌(m),‌‌all‌‌subjects‌‌should‌‌receive‌‌antiemetic‌‌products‌‌(eg,‌‌oral‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IV‌‌dexamethasone‌‌and‌‌5-hydroxytryptamine3‌‌[5-HT3]‌‌receptor‌‌antagonists).‌‌Antiemetics‌‌should‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
administered‌ ‌on‌ ‌the‌ ‌day‌ ‌of‌ ‌treatment,‌ ‌beginning‌ ‌at‌ ‌least‌ ‌30‌ ‌minutes‌ ‌before‌ ‌FOLFIRI‌ ‌(m)‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
administration.‌‌Alternative‌‌and‌‌additional‌‌antiemetics‌‌may‌‌be‌‌used,‌‌when‌‌clinically‌‌indicated,‌‌at‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
   
 
discretion‌ ‌of‌ ‌the‌ ‌investigator,‌ ‌or‌ ‌in‌ ‌accordance‌ ‌with‌ ‌standard‌ ‌institutional‌ ‌practice.‌ ‌ 
‌ 
‌ 
7.3.2‌ ‌Dose‌ ‌schedule‌ ‌FOLFIRI‌ ‌(m)‌ ‌ 
‌ 
Administration‌ ‌of‌ ‌FOLFIRI‌ ‌(m)‌ ‌chemotherapy‌ ‌will‌ ‌begin‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each‌ ‌treatment‌ ‌cycle.‌ ‌ 
‌ 
The‌ ‌FOLFIRI‌ ‌(m)‌ ‌regimen‌ ‌will‌ ‌be‌ ‌administered‌ ‌every‌ ‌2‌ ‌weeks‌ ‌(+/-‌ ‌3‌ ‌days),‌ ‌as‌ ‌follows:‌ ‌ 
‌ 
Table‌ ‌5:‌ ‌FOLFIRI‌ ‌regimen‌ ‌(m)‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Drug‌‌ ‌
  
Dose‌ ‌ 
Days‌ ‌ 
Administration‌ ‌ 
Irinotecan‌ ‌ 
180‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ 
IV‌ ‌diluted‌ ‌in‌ ‌30‌ ‌-‌ ‌90‌‌
 
 
 
   
 
minute‌ ‌infusion‌ ‌ 
Leucovorin‌ ‌ 
200‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ 
IV‌ ‌diluted‌ ‌in‌ ‌120‌ ‌IV‌‌
 
 
 
 
 
bolus‌ ‌infusion‌ ‌ 
Fluorouracil‌ ‌ 
400‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ 
IV‌ ‌Bolus‌ ‌ 
Fluorouracil‌ ‌ 
2400‌ ‌mg/m‌2‌ ‌ 
1‌ ‌ 
using‌
‌an‌ ‌ambulatory‌‌
 
 
 
pump‌ ‌for‌ ‌a‌ ‌period‌ ‌of‌‌
 
 
 
 
 
46-48‌ ‌hours‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
43‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
FOLFIRI‌ ‌chemotherapy‌ ‌administration‌ ‌schedule‌ ‌(m)‌ ‌ 
‌ 
Administration‌ ‌order:‌ ‌ 
1)‌ ‌Irinotecan‌ ‌and‌ ‌folinic‌ ‌acid‌ ‌in‌ ‌Y‌ ‌administration‌ ‌ 
2)‌ ‌Fluorouracil‌ ‌using‌ ‌an‌ ‌ambulatory‌ ‌pump‌ ‌for‌ ‌a‌ ‌period‌ ‌of‌ ‌46-48‌ ‌hours‌ ‌ 
‌ 
A‌ ‌new‌ ‌cycle‌ ‌of‌ ‌FOLFIRI‌‌(m)‌‌treatment‌‌will‌‌be‌‌repeated‌‌every‌‌2‌‌weeks,‌‌although‌‌it‌‌will‌‌not‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
administered‌‌to‌‌subjects‌‌with‌‌ANC‌‌<1.5‌‌x‌‌109‌‌cells‌‌/‌‌L,‌‌or‌‌if‌‌the‌‌platelet‌‌count‌‌is‌‌<75‌‌x‌‌109‌‌/‌‌L,‌‌if‌‌
 
 
 
 
 
   
 
   
 
   
 
 
   
   
   
   
the‌ ‌skin‌ ‌toxicity,‌ ‌stomatitis‌ ‌or‌ ‌diarrhea‌ ‌have‌ ‌not‌ ‌recovered‌ ‌to‌ ‌grade‌ ‌≤‌ ‌1,‌ ‌or‌ ‌if‌ ‌fatigue‌ ‌has‌ ‌not‌‌
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
recovered‌‌to‌‌grade‌‌≤‌‌2.‌‌A‌‌delay‌‌of‌‌up‌‌to‌‌4‌‌weeks‌‌is‌‌allowed‌‌to‌‌start‌‌a‌‌new‌‌course‌‌of‌‌treatment‌‌for‌‌
 
 
   
   
 
 
 
   
   
 
 
   
 
 
 
 
 
resolution‌ ‌of‌ ‌the‌ ‌toxicities.‌ ‌If‌ ‌treatment‌ ‌with‌ ‌one‌ ‌component‌ ‌of‌ ‌the‌ ‌FOLFIRI‌ ‌(m)‌‌regimen‌‌(for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
example,‌‌5-FU‌‌/‌‌leucovorin‌‌or‌‌irinotecan)‌‌is‌‌delayed,‌‌the‌‌other‌‌component‌‌is‌‌also‌‌delayed‌‌in‌‌the‌‌
 
   
 
 
   
 
 
 
   
 
 
 
 
same‌ ‌way,‌ ‌so‌ ‌that‌ ‌both‌ ‌therapies‌ ‌can‌ ‌be‌ ‌administered‌ ‌together‌ ‌on‌ ‌day‌ ‌1‌ ‌of‌ ‌each‌ ‌2‌ ‌week‌ ‌cycle.‌ ‌ 
‌ 
If‌‌irinotecan‌‌is‌‌discontinued‌‌for‌‌any‌‌reason‌‌before‌‌6‌‌months‌‌of‌‌treatment‌‌or‌‌disease‌‌progression,‌‌
 
   
 
 
 
 
   
 
 
 
 
 
 
treatment‌‌with‌‌5-FU‌‌/‌‌leucovorin‌‌and‌‌cetuximab‌‌can‌‌be‌‌continued‌‌once‌‌every‌‌14‌‌days‌‌(‌‌+/-‌‌3‌‌days)‌‌
 
 
   
 
 
 
 
 
 
 
 
 
   
   
 
until‌ ‌disease‌ ‌progression‌ ‌or‌ ‌intolerance‌ ‌to‌ ‌study‌ ‌treatment.‌ ‌ 
In‌ ‌no‌ ‌case‌ ‌can‌ ‌a‌ ‌patient‌ ‌be‌ ‌kept‌ ‌under‌ ‌study‌ ‌with‌ ‌irinotecan‌ ‌alone,‌ ‌or‌ ‌in‌ ‌combination‌ ‌with‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab.‌ ‌ 
‌ 
If‌‌the‌‌discontinuation‌‌of‌‌FOLFIRI‌‌chemotherapy‌‌(m)‌‌is‌‌≤‌‌6‌‌weeks‌‌from‌‌the‌‌previous‌‌cycle,‌‌if‌‌the‌‌
 
 
 
 
 
 
       
 
 
 
 
   
 
subject‌ ‌has‌ ‌recovered‌ ‌from‌ ‌toxicities,‌ ‌as‌ ‌indicated‌ ‌above,‌‌and‌‌if‌‌the‌‌disease‌‌has‌‌not‌‌progressed,‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
FOLFIRI‌‌chemotherapy‌‌should‌‌be‌‌restarted‌‌(m‌‌)‌‌with‌‌or‌‌without‌‌cetuximab‌‌with‌‌the‌‌doses‌‌specified‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
in‌‌Tables‌‌5,‌‌6‌‌and‌‌7.‌‌If‌‌the‌‌interruption‌‌of‌‌FOLFIRI‌‌chemotherapy‌‌(m)‌‌is>‌‌6‌‌weeks‌‌but‌‌the‌‌subject‌‌
 
 
   
 
   
 
 
 
 
 
 
   
 
 
 
 
has‌‌recovered‌‌from‌‌toxicities‌‌and‌‌the‌‌disease‌‌has‌‌not‌‌progressed,‌‌staff‌‌The‌‌promoter‌‌of‌‌the‌‌study‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should‌ ‌review‌ ‌the‌ ‌case‌ ‌together‌ ‌with‌ ‌the‌ ‌investigator‌ ‌to‌ ‌determine‌ ‌if‌ ‌the‌ ‌treatment‌ ‌should‌ ‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
resumed.‌ ‌ 
‌ 
‌ 
7.3.3‌ ‌Dose‌ ‌levels‌ ‌and‌ ‌dose‌ ‌modification‌ ‌guidelines‌ ‌for‌ ‌the‌ ‌FOLFIRI‌ ‌regimen‌ ‌(m)‌ ‌ 
‌ 
The‌ ‌toxicity‌ ‌of‌ ‌FOLFIRI‌ ‌(m)‌ ‌in‌ ‌subjects‌ ‌should‌ ‌be‌ ‌closely‌ ‌monitored.‌ ‌The‌ ‌doses‌ ‌of‌ ‌5-FU‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
irinotecan‌ ‌can‌ ‌be‌ ‌adjusted‌ ‌according‌ ‌to‌ ‌the‌‌individual‌‌tolerance‌‌of‌‌each‌‌subject.‌‌The‌‌leucovorin‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dose‌‌will‌‌remain‌‌fixed‌‌at‌‌400‌‌mg‌‌/‌‌m2‌‌of‌‌racemate‌‌(d,‌‌l-leucovorin)‌‌or‌‌200‌‌mg‌‌/‌‌m2‌‌of‌‌l-leucovorin.‌‌
 
 
 
   
 
   
 
 
 
 
 
 
 
   
 
 
 
Tables‌‌5,‌‌6‌‌and‌‌7‌‌show‌‌the‌‌recommended‌‌dose‌‌levels‌‌and‌‌the‌‌guidelines‌‌for‌‌dose‌‌modification,‌‌due‌‌
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
to‌ ‌neurological‌ ‌and‌ ‌non-neurological‌ ‌toxicity,‌ ‌for‌ ‌both‌ ‌irinotecan‌ ‌and‌ ‌5-FU.‌ ‌ 
‌ 
Table‌ ‌6‌ ‌describes‌ ‌the‌ ‌recommended‌ ‌dose‌ ‌reductions‌ ‌for‌ ‌non-neurologic‌ ‌toxicity.‌ ‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Table‌ ‌6.‌ ‌FOLFIRI‌ ‌dose‌ ‌reductions‌ ‌(m):‌ ‌non-neurological‌ ‌toxicity‌ ‌
 
‌ 
‌ 
‌ 
Initial‌ ‌dose‌ ‌ 
Dose‌ ‌-‌ ‌1‌ ‌ 
Dose‌ ‌-‌ ‌2‌ ‌ 
Irinotecan‌ ‌ 
180‌ ‌mg/m‌2‌ ‌ 
145‌ ‌mg/m‌2‌ ‌ 
116‌ ‌mg/m‌2‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
44‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
‌ 
Table‌ ‌7‌ ‌below‌ ‌describes‌ ‌the‌ ‌recommended‌ ‌dose‌ ‌modifications‌ ‌at‌ ‌the‌ ‌start‌ ‌of‌ ‌each‌ ‌subsequent‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
therapy‌ ‌cycle.‌ ‌All‌ ‌dose‌ ‌modifications‌ ‌must‌ ‌be‌ ‌based‌ ‌on‌ ‌the‌ ‌worst‌ ‌preceding‌ ‌toxicity.‌ 
‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
5-FU‌ ‌Bolus‌ ‌ 
400‌ ‌mg/m‌2‌ ‌ 
320‌ ‌mg/m‌2‌ ‌ 
240‌ ‌mg/m‌2‌ ‌ 
5-FU‌ ‌infusion‌ 
2.400‌ ‌mg/m‌2‌ ‌ 
1.900‌ ‌mg/m‌2‌ ‌ 
1.500‌ ‌mg/m‌2‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
45‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Table‌ ‌7‌ ‌FOLFIRI‌ ‌dose‌ ‌modifications‌ ‌(m)‌ ‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
Table‌ ‌7‌ ‌FOLFIRI‌ ‌dose‌ ‌modifications‌ ‌(m)‌ 
Toxicidad‌ ‌
 
‌ 
Grado‌ ‌NCI*‌ ‌(valor)‌ ‌ 
Nivel‌ ‌de‌ ‌dosis‌ ‌
 
‌ 
para‌ ‌los‌ ‌ciclos‌ ‌posteriores‌ ‌
 
‌ 
Basado‌ ‌en‌ ‌la‌ ‌toxicidad‌ ‌del‌ ‌intervalo**‌ ‌ 
En‌ ‌el‌ ‌momento‌ ‌del‌ ‌
 
‌ 
retratamiento‌ ‌ 
Toxicity‌ ‌
 
‌ 
Grade‌ ‌NCI*‌ ‌(value)‌ ‌ 
Dose‌ ‌level‌ ‌
 
‌ 
for‌ ‌subsequent‌ ‌cycles‌ ‌
 
‌ 
Based‌ ‌on‌ ‌the‌ ‌toxicity‌ ‌of‌ ‌the‌ ‌interval**‌ ‌ 
In‌ ‌the‌ ‌moment‌ ‌of‌ ‌
 
‌ 
retreatment‌ ‌ 
Absence‌ ‌of‌ ‌toxicity‌ ‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌ 
Neutropenia‌ ‌(ANC)‌ ‌
 
‌ 
Grade‌ ‌1‌ ‌(ANC < LIN‌ ‌–‌ ‌1,5 x 10‌9‌/L)‌‌ ‌
  
‌ 
Grade‌ ‌2‌ ‌(ANC‌ ‌1,5 x 10‌9‌/L‌ ‌-‌ ‌1,0 x 10‌9‌/L)‌ ‌
 
‌ 
Grade‌ ‌3‌ ‌(ANC‌ ‌1,0 x 10‌9‌/L‌ ‌–‌ ‌0,5 x 10‌9‌/L)‌ ‌
 
‌ 
Grade‌ ‌4‌ ‌(ANC < 0,5 x 10‌9‌/L)‌ ‌ 
‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌ 
‌
 
‌ 
If‌ ‌ANC‌ ‌<1.5‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌at‌ ‌the‌ ‌beginning‌‌ 
of‌ ‌the‌ ‌cycle,‌ ‌suspend‌ ‌and‌ ‌check‌ ‌weekly,‌‌ 
then‌ ‌treat‌ ‌according‌ ‌to‌ ‌the‌ ‌toxicity‌ ‌of‌ ‌the‌‌ 
interval.‌ ‌
 
‌ 
If‌ ‌ANC‌ ‌<1.5‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌after‌ ‌4‌ ‌weeks,‌‌ 
discontinue‌ ‌treatment.‌ ‌ 
Thrombocytopenia‌ ‌
 
‌ 
Grade‌ ‌1‌ ‌(PLT < LIN‌ ‌-‌ ‌75,0 x 10‌9‌/L)‌ ‌
 
‌ 
Grade‌ ‌2‌ ‌(PLT‌ ‌75,0‌ ‌x‌ ‌10‌9‌/L‌ ‌-‌ ‌50,0‌ ‌x‌‌ 
10‌9‌/L)‌ ‌ 
Grade‌ ‌3‌ ‌(PLT‌ ‌50,0‌ ‌x‌ ‌10‌9‌/L‌ ‌-‌ ‌25,0‌ ‌x‌‌ 
10‌9‌/L)‌ ‌ 
Grade‌ ‌4‌ ‌(PLT < 25,0 x 10‌9‌/L)‌ ‌ 
‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
‌
 
‌ 
If‌ ‌PLT‌ ‌<75.0‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌at‌ ‌the‌ ‌beginning‌‌ 
of‌ ‌the‌ ‌cycle,‌ ‌suspend‌ ‌and‌ ‌check‌ ‌weekly‌‌ 
and‌ ‌then‌ ‌treat‌ ‌according‌ ‌to‌ ‌the‌ ‌toxicity‌ ‌of‌‌ 
the‌ ‌interval.‌ ‌
 
‌ 
If‌ ‌PLT‌ ‌<75.0‌ ‌x‌ ‌109‌ ‌/‌ ‌L‌ ‌after‌ ‌4‌ ‌weeks,‌‌ 
discontinue‌ ‌treatment.‌ ‌ 
Febrile‌ ‌neutropenia‌ ‌
 
‌ 
ANC‌ ‌< 1,0‌ ‌x‌ ‌10‌9‌/L‌ ‌(neutropenia‌ ‌of‌ ‌grade‌‌ 
‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
46‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
‌ 
*‌ ‌Common‌ ‌toxicity‌ ‌criteria‌ ‌from‌ ‌the‌ ‌National‌ ‌Cancer‌ ‌Institute‌ ‌(CTC‌ ‌version‌ ‌3.0).‌ ‌ 
**‌ ‌Refers‌ ‌to‌ ‌the‌ ‌starting‌ ‌dose‌ ‌used‌ ‌in‌ ‌the‌ ‌previous‌ ‌cycle.‌ ‌ 
1‌ ‌In‌ ‌case‌ ‌of‌ ‌mucositis‌ ‌/‌ ‌stomatitis,‌ ‌reduce‌ ‌only‌ ‌the‌ ‌dose‌ ‌of‌ ‌5-FU,‌ ‌not‌ ‌that‌ ‌of‌ ‌oxaliplatin.‌ ‌ 
2‌ ‌Exceptions:‌ ‌alopecia,‌ ‌fatigue,‌ ‌anorexia,‌ ‌nausea‌ ‌/‌ ‌vomiting‌ ‌if‌ ‌they‌ ‌can‌ ‌be‌ ‌controlled‌ ‌with‌ ‌antiemetics,‌ ‌viral‌ ‌infections.‌ ‌ 
‌ 
7.3.4‌ ‌Interruption‌ ‌of‌ ‌FOLFIRI‌ ‌(m)‌ ‌ 
Subjects‌‌will‌‌be‌‌allowed‌‌to‌‌receive‌‌treatment‌‌with‌‌FOLFIRI‌‌(m)‌‌for‌‌up‌‌to‌‌6‌‌months‌‌of‌‌treatment,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
until‌‌disease‌‌progression‌‌or‌‌unacceptable‌‌toxicities‌‌and‌‌/‌‌or‌‌withdrawal‌‌of‌‌consent.‌‌If‌‌patients‌‌do‌‌not‌‌
 
 
 
 
 
 
   
 
 
 
   
 
 
 
show‌ ‌progression‌ ‌after‌ ‌6‌ ‌months‌ ‌of‌ ‌treatment‌ ‌with‌ ‌FOLFIRI‌ ‌(m)‌ ‌or‌ ‌FOLFOX6‌ ‌(m),‌ ‌they‌ ‌will‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
continue‌ ‌to‌ ‌receive‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌monotherapy‌ ‌until‌ ‌progression.‌ ‌ 
‌ 
If‌‌FOLFIRI‌‌(m)‌‌chemotherapy‌‌is‌‌discontinued‌‌before‌‌6‌‌months‌‌of‌‌treatment‌‌or‌‌disease‌‌progression,‌‌
 
 
 
   
 
   
 
 
 
 
 
 
e.g.‌ ‌due‌ ‌to‌ ‌FOLFIRI‌ ‌(m)‌ ‌toxicity,‌ ‌the‌ ‌subject‌ ‌may‌ ‌continue‌ ‌to‌ ‌receive‌ ‌cetuximab‌ ‌monotherapy‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
every‌ ‌14‌ ‌days‌ ‌(+/-‌ ‌3‌ ‌days)‌ ‌until‌ ‌you‌ ‌develop‌ ‌disease‌ ‌progression‌ ‌or‌ ‌are‌ ‌unable‌ ‌to‌ ‌tolerate‌ ‌the‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
investigational‌ ‌product.‌ ‌ 
The‌‌disease‌‌of‌‌all‌‌subjects‌‌will‌‌be‌‌reassessed‌‌after‌‌12‌‌weeks‌‌±‌‌1‌‌week‌‌for‌‌the‌‌period‌‌the‌‌patient‌‌
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
continues‌ ‌in‌ ‌the‌ ‌trial‌ ‌until‌ ‌progression.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 
3‌ ‌o‌ ‌4)‌ ‌y‌ ‌fever‌ ‌>‌ ‌38,5 ºC‌ ‌ 
‌ 
‌ 
Other‌ ‌hematologic‌ ‌toxicities‌ ‌
 
‌ 
‌ 
Dose‌ ‌modifications‌ ‌for‌ ‌leukopenia‌ ‌at‌ ‌the‌ ‌start‌ ‌of‌ ‌subsequent‌‌ 
cycles‌ ‌of‌ ‌therapy‌ ‌and‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌ ‌retreatment‌ ‌are‌ ‌also‌ ‌based‌‌ 
on‌ ‌the‌ ‌NCI‌ ‌toxicity‌ ‌criteria‌ ‌(CTC‌ ‌version‌ ‌3.0)‌ ‌and‌ ‌are‌ ‌the‌ ‌same‌‌ 
as‌ ‌those‌ ‌recommended‌ ‌above‌ ‌for‌ ‌neutropenia.‌ ‌ 
Diarrhea‌ ‌
 
‌ 
Grade‌ ‌1‌ ‌
 
‌ 
Grade‌ ‌2‌ ‌
 
‌ 
Grade‌ ‌3‌ ‌
 
‌ 
Grade‌ ‌4‌ ‌
 
‌ 
‌ 
‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Maintain‌ ‌the‌ ‌dose‌ ‌level‌ ‌
 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL‌ ‌
 
‌ 
‌ 
Reduce‌ ‌1‌ ‌dose‌ ‌level‌ ‌of‌ ‌5-FU‌ ‌and‌ ‌OXAL.‌ ‌ 
‌
 
‌ 
For‌ ‌grade‌ ‌2‌ ‌diarrhea‌ ‌at‌ ‌the‌ ‌start‌ ‌of‌ ‌the‌‌ 
cycle,‌ ‌suspend‌ ‌and‌ ‌check‌ ‌weekly,‌ ‌then‌‌ 
treat‌ ‌according‌ ‌to‌ ‌interval‌ ‌toxicity.‌ ‌
 
‌ 
‌ 
‌ 
If‌ ‌grade‌ ‌2‌ ‌diarrhea‌ ‌persists‌ ‌after‌ ‌4‌ ‌weeks,‌‌ 
discontinue‌ ‌treatment.‌ ‌ 
Other‌ ‌non-hematologic‌ ‌toxicities‌1,2‌ ‌
 
‌ 
‌ 
Dose‌ ‌modifications‌ ‌for‌ ‌other‌ ‌non-hematologic‌ ‌toxicities‌ ‌at‌ ‌the‌‌ 
beginning‌ ‌of‌ ‌subsequent‌ ‌therapy‌ ‌cycles‌ ‌and‌ ‌at‌ ‌the‌ ‌time‌ ‌of‌‌ 
retreatment‌ ‌are‌ ‌also‌ ‌based‌ ‌on‌ ‌the‌ ‌NCI‌ ‌toxicity‌ ‌criteria‌ ‌(CTC‌‌ 
version‌ ‌3.0)‌ ‌and‌ ‌are‌ ‌the‌ ‌same‌ ‌as‌ ‌those‌ ‌recommended‌ ‌above‌ ‌for‌‌ 
diarrhea.‌ ‌ 
The‌ ‌LV‌ ‌dose‌ ‌will‌ ‌not‌ ‌be‌ ‌adjusted‌ ‌due‌ ‌to‌ ‌toxicity.‌ ‌It‌ ‌should‌ ‌remain‌ ‌at‌ ‌400‌ ‌mg‌ ‌/‌ ‌m2‌ ‌racemate‌ ‌(or‌ ‌200‌ ‌mg‌ ‌/‌ ‌m2‌ ‌l-LV)‌ ‌in‌ ‌all‌ ‌cycles.‌ ‌LV‌ ‌should‌ ‌be‌ ‌given‌ ‌just‌ ‌before‌ ‌each‌‌ 
5-FU‌ ‌dose;‌ ‌thus,‌ ‌if‌ ‌5-FU‌ ‌is‌ ‌delayed,‌ ‌LV‌ ‌will‌ ‌also‌ ‌be‌ ‌delayed.‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
47‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Tumor‌‌evaluation‌‌will‌‌be‌‌performed‌‌on‌‌subjects‌‌who‌‌have‌‌withdrawn‌‌from‌‌the‌‌study‌‌for‌‌reasons‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
other‌‌than‌‌radiographically‌‌documented‌‌disease‌‌progression.‌‌All‌‌these‌‌subjects‌‌should‌‌be‌‌monitored‌‌
 
 
 
 
 
 
 
 
 
 
 
 
for‌ ‌disease‌ ‌progression‌ ‌(revised‌ ‌RECIST‌ ‌1.1‌ ‌criteria)‌ ‌every‌ ‌12‌ ‌weeks‌ ‌+/-‌ ‌1‌ ‌week‌ ‌until‌ ‌disease‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
progression‌ ‌or‌ ‌end‌ ‌of‌ ‌study..‌ ‌ 
7.4‌ ‌Concomitant‌ ‌treatment‌ ‌
 
Throughout‌ ‌the‌ ‌study,‌ ‌researchers‌ ‌may‌ ‌prescribe‌‌medications‌‌or‌‌concomitant‌‌treatments‌‌deemed‌‌
 
 
 
 
 
 
 
 
 
 
 
necessary‌ ‌to‌ ‌provide‌ ‌adequate‌ ‌supportive‌ ‌care,‌ ‌with‌ ‌the‌ ‌exception‌ ‌of‌ ‌those‌ ‌listed‌ ‌in‌ ‌section‌ ‌7.5.‌ ‌ 
‌ 
Concomitant‌‌medications‌‌will‌‌be‌‌noted‌‌at‌‌baseline‌‌in‌‌the‌‌corresponding‌‌CRDs‌‌and‌‌will‌‌include‌‌all‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
drugs‌‌used‌‌one‌‌month‌‌before‌‌the‌‌start‌‌of‌‌treatment.‌‌For‌‌ALL‌‌other‌‌visits,‌‌concomitant‌‌medications‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will‌ ‌be‌ ‌listed‌ ‌ONLY‌ ‌if‌ ‌they‌ ‌are‌ ‌associated‌ ‌with‌ ‌adverse‌ ‌events.‌ ‌ 
‌ 
Concomitant‌‌medication‌‌should‌‌be‌‌recorded‌‌up‌‌to‌‌30‌‌days‌‌after‌‌the‌‌last‌‌dose‌‌of‌‌study‌‌treatment‌‌has‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ended.‌‌Concomitant‌‌medication‌‌used‌‌for‌‌medically‌‌significant‌‌adverse‌‌events‌‌that‌‌are‌‌ongoing‌‌at‌‌
 
 
 
 
 
 
 
 
 
 
 
   
the‌‌end‌‌of‌‌study‌‌treatment‌‌should‌‌be‌‌followed‌‌until‌‌the‌‌adverse‌‌events‌‌resolve‌‌or‌‌are‌‌considered‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
stable.‌ ‌ 
‌ 
The‌‌use‌‌of‌‌topical,‌‌oral‌‌or‌‌IV‌‌antibiotics‌‌is‌‌allowed.‌‌to‌‌treat‌‌toxicities‌‌related‌‌to‌‌the‌‌skin‌‌or‌‌nails,‌‌at‌‌
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
   
the‌ ‌discretion‌ ‌of‌ ‌the‌ ‌investigator;‌ ‌its‌ ‌use‌ ‌will‌ ‌be‌ ‌recorded‌ ‌in‌ ‌the‌ ‌corresponding‌ ‌CRD.‌ ‌ 
For‌ ‌patients‌ ‌on‌ ‌anticoagulant‌ ‌therapy,‌ ‌close‌ ‌control‌ ‌of‌ ‌coagulation‌ ‌parameters‌ ‌is‌ ‌recommended‌‌
 
 
 
 
 
 
 
 
 
 
 
 
during‌ ‌the‌ ‌study‌ ‌treatment‌ ‌period.‌ ‌ 
‌ 
‌ 
‌ 
7.4.1‌ ‌Growing‌ ‌factors‌ ‌ 
‌ 
For‌ ‌low‌‌white‌‌blood‌‌cell‌‌counts,‌‌granulocyte‌‌colony‌‌stimulating‌‌factor‌‌(G-CSF)‌‌should‌‌be‌‌used;‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
however,‌ ‌the‌ ‌routine‌ ‌prophylactic‌ ‌use‌ ‌of‌ ‌G-CSF‌ ‌is‌ ‌not‌ ‌recommended‌ ‌in‌ ‌this‌ ‌study.‌ ‌G-CSF‌ ‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapeutic‌ ‌purposes‌ ‌in‌ ‌patients‌ ‌with‌ ‌severe‌‌neutropenic‌‌complications‌‌such‌‌as‌‌tissue‌‌infections,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
septic‌‌syndrome,‌‌fungal‌‌infections,‌‌etc.,‌‌can‌‌be‌‌administered‌‌at‌‌the‌‌discretion‌‌of‌‌the‌‌investigator‌‌or‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
according‌ ‌to‌ ‌the‌ ‌guideline‌ ‌of‌ ‌the‌ ‌institution.‌ ‌Epoetins‌ ‌may‌ ‌be‌ ‌used‌ ‌at‌ ‌the‌ ‌discretion‌ ‌of‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator‌ ‌to‌ ‌treat‌ ‌chemotherapy-induced‌ ‌anemia.‌ ‌ 
7.5‌ ‌Prohibited‌ ‌treatments‌ ‌during‌ ‌the‌ ‌study‌ ‌period‌ 
Subjects‌ ‌should‌ ‌withdraw‌ ‌from‌ ‌the‌ ‌study‌ ‌if‌ ‌they‌ ‌receive‌ ‌during‌ ‌the‌ ‌treatment‌ ‌phase‌ ‌other‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigational‌ ‌products,‌ ‌products‌ ‌that‌ ‌act‌ ‌as‌ ‌anti-EGFr‌ ‌other‌ ‌than‌ ‌cetuximab,‌ ‌experimental‌ ‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
approved‌‌antitumor‌‌treatments‌‌(eg‌‌bevacizumab),‌‌chemotherapy,‌‌radiation‌‌therapy‌‌(except‌‌for‌‌use‌‌
 
 
 
 
 
 
 
 
 
 
 
for‌‌pain‌‌control)‌‌or‌‌systemic‌‌steroids‌‌(except‌‌for‌‌use‌‌for‌‌symptomatic‌‌toxicities‌‌of‌‌the‌‌skin‌‌or‌‌nails‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
that‌‌require‌‌discontinuation‌‌of‌‌the‌‌dose‌‌of‌‌cetuximab‌‌[see‌‌section‌‌7.1.4],‌‌use‌‌as‌‌a‌‌premedication‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
chemotherapy‌‌or‌‌after‌‌chemotherapy‌‌to‌‌delay‌‌chemotherapy-related‌‌toxicities‌‌or‌‌use‌‌for‌‌an‌‌infusion‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
reaction)‌ ‌during‌ ‌the‌ ‌treatment‌ ‌phase.‌ ‌ 
‌ 
Rifampizin,‌ ‌phenobarbital,‌ ‌ketoconazole,‌ ‌clarithromycin,‌ ‌erythromycin,‌ ‌HIV‌ ‌protease‌ ‌inhibitors,‌‌
 
 
 
 
 
 
 
 
cyclosporine‌ ‌/‌ ‌tacrolimus,‌ ‌nefazodone,‌ ‌or‌ ‌St.‌ ‌John's‌ ‌wort‌ ‌cannot‌ ‌be‌ ‌co-administered‌ ‌in‌ ‌this‌ ‌study.‌ ‌ 
‌ 
Subjects‌ ‌should‌ ‌not‌ ‌be‌ ‌scheduled‌ ‌for‌ ‌any‌ ‌elective‌ ‌surgery‌ ‌(excluding‌ ‌central‌ ‌venous‌ ‌catheter‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
placement)‌‌during‌‌study‌‌participation‌‌or‌‌up‌‌to‌‌7‌‌days‌‌after‌‌the‌‌last‌‌study‌‌treatment‌‌administration‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
(after‌ ‌chemotherapy‌ ‌and‌ ‌/‌ ‌or‌ ‌cetuximab,‌ ‌depending‌ ‌on‌ ‌which‌ ‌is‌ ‌administered‌ ‌last).‌‌If‌‌a‌‌subject‌
 
 
   
 
 
 
 
 
 
 
     
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
48‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
undergoes‌‌unplanned‌‌surgery‌‌during‌‌the‌‌course‌‌of‌‌the‌‌study,‌‌all‌‌study‌‌treatment‌‌should‌‌be‌‌stopped‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
immediately‌‌and‌‌the‌‌sponsor‌‌should‌‌be‌‌notified‌‌as‌‌soon‌‌as‌‌possible.‌‌A‌‌subject‌‌may‌‌be‌‌allowed‌‌to‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
restart‌ ‌study‌ ‌treatment‌ ‌after‌ ‌the‌ ‌sponsor's‌ ‌study‌ ‌team‌ ‌discusses‌ ‌each‌ ‌surgical‌ ‌case‌ ‌with‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator‌ ‌to‌ ‌determine‌ ‌whether‌ ‌it‌ ‌is‌ ‌appropriate‌ ‌to‌ ‌restart‌ ‌treatment.‌ ‌ 
‌ 
‌
 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
49‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
8.‌ ‌STUDY‌ ‌PROCEDURES‌ ‌
 
Please‌ ‌refer‌ ‌to‌‌the‌‌Assessment‌‌Schedule‌‌(Appendix‌‌A)‌‌for‌‌a‌‌description‌‌of‌‌the‌‌procedures‌‌to‌‌be‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
performed‌ ‌at‌ ‌each‌ ‌visit.‌ ‌ 
Serious‌ ‌adverse‌ ‌events‌ ‌will‌ ‌be‌ ‌collected‌ ‌as‌ ‌described‌ ‌in‌ ‌section‌ ‌9.‌ ‌ 
8.1‌ ‌Selection‌ ‌
 
‌ 
Before‌‌carrying‌‌out‌‌any‌‌specific‌‌study‌‌procedure,‌‌informed‌‌consent‌‌must‌‌be‌‌obtained,‌‌approved‌‌by‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌CEIC,‌ ‌dated‌ ‌and‌ ‌signed.‌ ‌All‌ ‌hematological‌ ‌and‌ ‌biochemical‌ ‌tests,‌ ‌pregnancy‌ ‌tests‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
carcinoembryonic‌‌antigen‌‌(CEA)‌‌will‌‌be‌‌analyzed‌‌in‌‌a‌‌local‌‌laboratory.‌‌Procedures‌‌that‌‌are‌‌part‌‌of‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
routine‌‌treatment‌‌are‌‌not‌‌considered‌‌study‌‌specific‌‌procedures.‌‌Procedures‌‌that‌‌are‌‌part‌‌of‌‌regular‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
attendance‌ ‌can‌ ‌be‌ ‌used‌ ‌as‌ ‌screening‌ ‌procedures‌ ‌to‌ ‌determine‌ ‌eligibility.‌ ‌Before‌ ‌starting‌ ‌study‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment,‌ ‌all‌ ‌subjects‌ ‌will‌ ‌be‌ ‌evaluated‌ ‌for‌ ‌eligibility.‌‌The‌‌selection‌‌process‌‌begins‌‌the‌‌day‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subject‌‌signs‌‌the‌‌informed‌‌consent‌‌approved‌‌by‌‌the‌‌CEIC‌‌and‌‌continues‌‌until‌‌the‌‌inclusion‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patient‌ ‌in‌ ‌the‌ ‌trial‌ ‌and‌ ‌subsequent‌ ‌initiation‌ ‌of‌ ‌the‌ ‌study‌ ‌treatment.‌ ‌In‌ ‌this‌ ‌study,‌ ‌only‌ ‌eligible‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subjects‌ ‌will‌ ‌receive‌ ‌the‌ ‌study‌ ‌treatment.‌ ‌ 
‌ 
Before‌‌carrying‌‌out‌‌the‌‌study‌‌procedures‌‌listed‌‌below,‌‌the‌‌KRAS‌‌status‌‌must‌‌be‌‌determined‌‌by‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central‌ ‌Laboratory‌ ‌of‌ ‌the‌ ‌Navarra‌ ‌University‌ ‌Clinic‌ ‌(CUN)‌ ‌(If‌ ‌the‌ ‌patient‌ ‌already‌ ‌has‌ ‌a‌ ‌prior‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
determination‌‌of‌‌the‌‌status‌‌of‌‌the‌‌KRAS‌‌gene,‌‌it‌‌may‌‌be‌‌included‌‌in‌‌the‌‌test‌‌without‌‌the‌‌need‌‌to‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
re-determine‌ ‌K-RAS).‌ ‌ 
‌ 
All‌ ‌subjects‌ ‌must‌ ‌have‌ ‌completed‌ ‌the‌ ‌following‌ ‌procedures‌ ‌in‌ ‌≤‌ ‌28‌ ‌days‌ ‌(unless‌ ‌otherwise‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specified)‌ ‌prior‌ ‌to‌ ‌the‌ ‌start‌ ‌of‌ ‌study‌ ‌treatment:‌ ‌ 
Review‌ ‌of‌ ‌the‌ ‌inclusion‌ ‌and‌ ‌exclusion‌ ‌criteria.‌ ‌ 
Clinical‌ ‌and‌ ‌medication‌ ‌history‌ ‌ 
The‌‌paraffin-embedded‌‌tumor‌‌block‌‌from‌‌both‌‌the‌‌primary‌‌site‌‌and‌‌the‌‌liver‌‌metastases‌‌must‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
extracted,‌‌prepared‌‌and‌‌sent‌‌to‌‌the‌‌central‌‌laboratory‌‌(Clínica‌‌Universitaria‌‌de‌‌Navarra,‌‌Pathological‌‌
 
 
 
   
 
 
 
 
 
 
 
 
Anatomy‌ ‌Service)‌ ‌and‌ ‌the‌ ‌blood‌ ‌samples‌ ‌must‌ ‌be‌ ‌extracted,‌ ‌prepared‌ ‌and‌ ‌sent‌ ‌to‌ ‌the‌ ‌central‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
laboratory‌ ‌(‌ ‌Hospital‌ ‌Clinic‌ ‌de‌ ‌Barcelona,‌ ‌​Pathological‌ ‌Anatomy‌ ‌Service).‌ ‌ 
These‌‌samples‌‌will‌‌be‌‌used‌‌to‌‌assess‌‌KRAS‌‌and‌‌BRAF‌‌mutational‌‌status‌‌and‌‌expression‌‌of‌‌PTEN,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PIK3,‌ ‌MMP-7,‌ ‌IGFRp,‌ ‌IGF-1,‌ ‌IGFBP-3/5,‌ ‌in‌ ‌addition‌ ‌to‌ ‌other‌ ‌possible‌ ‌biomarkers.‌ ‌KRAS‌
 
 
 
 
 
 
 
 
 
 
 
 
mutation‌‌status‌‌should‌‌be‌‌performed‌‌by‌‌an‌‌experienced‌‌laboratory‌‌using‌‌a‌‌validated‌‌method‌‌prior‌‌to‌‌
 
 
 
 
 
 
 
 
 
   
 
 
   
patient‌ ‌enrollment.‌ ‌ 
Measurements‌ ‌of‌ ‌resting‌ ‌pulse,‌ ‌blood‌ ‌pressure,‌ ‌respiratory‌ ‌rate‌ ‌and‌ ‌temperature.‌ ‌ 
Weight‌ ‌and‌ ‌height.‌ ‌ 
Informed‌ ‌consent.‌ ‌ 
ECOG‌‌(Eastern‌‌Cooperative‌‌Oncology‌‌Group)‌‌performance‌‌status‌‌(≤‌‌7‌‌days‌‌before‌‌starting‌‌study‌‌
 
 
 
 
 
 
 
   
 
 
 
 
treatment).‌ ‌ 
Physical‌‌examination,‌‌laboratory‌‌tests‌‌(≤‌‌7‌‌days‌‌before‌‌the‌‌start‌‌of‌‌study‌‌treatment‌‌unless‌‌otherwise‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
indicated):‌ ‌ 
Hematological‌ ‌tests:‌ ‌hemoglobin,‌ ‌hematocrit,‌ ‌red‌ ‌cell‌ ‌count‌ ‌(RBC),‌ ‌mean‌ ‌corpuscular‌ ‌volume,‌‌
 
 
 
 
 
 
 
 
 
 
 
platelets,‌ ‌white‌ ‌blood‌ ‌cell‌ ‌count‌ ‌(WBC)‌ ‌and‌ ‌differential‌ ‌WBC‌ ‌(neutrophils,‌ ‌lymphocytes,‌‌
 
 
 
 
 
 
 
 
 
 
 
monocytes,‌ ‌eosinophils,‌ ‌basophils).‌ ‌ 
Biochemical‌ ‌tests:‌ ‌sodium,‌ ‌potassium,‌ ‌chloride,‌ ‌bicarbonate,‌‌blood‌‌urea‌‌nitrogen‌‌(BUN)‌‌or‌‌urea‌‌
 
 
 
 
 
 
 
 
 
 
 
 
(depending‌ ‌on‌ ‌the‌ ‌local‌ ‌practice‌ ‌of‌ ‌the‌ ‌center),‌ ‌lactate‌ ‌dehydrogenase‌ ‌(LDH),‌ ‌magnesium,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
creatinine,‌‌albumin,‌‌total‌‌proteins,‌‌total‌‌bilirubin,‌‌alkaline‌‌phosphatase‌‌,‌‌alanine‌‌aminotransferase‌‌
 
 
 
 
 
 
 
   
 
 
(ALT),‌ ‌aspartate‌ ‌aminotransferase‌ ‌(AST),‌ ‌calcium,‌ ‌phosphorus‌ ‌and‌ ‌uric‌ ‌acid.‌ ‌ 
Serum‌ ‌biomarker‌ ‌measurements‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
50‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Serum‌ ‌CEA.‌ ‌ 
Serum‌‌or‌‌urine‌‌pregnancy‌‌test‌‌for‌‌women‌‌of‌‌childbearing‌‌age‌‌(≤72‌‌hours‌‌before‌‌the‌‌start‌‌of‌‌study‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment).‌ ‌ 
ECG‌ ‌(all‌ ‌reports‌ ‌will‌ ‌be‌ ‌clinically‌ ‌evaluated‌ ‌by‌ ‌the‌ ‌investigator)‌ ‌ 
Radiological‌‌images‌‌of‌‌the‌‌thorax,‌‌abdomen,‌‌pelvis,‌‌and‌‌other‌‌locations‌‌of‌‌the‌‌disease‌‌by‌‌CT‌‌(or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI‌ ‌if‌ ‌clinically‌ ‌indicated);‌ ‌more‌ ‌details‌ ‌in‌ ‌section‌ ‌8.6.‌ ‌ 
8.2‌ ‌Inclusion‌‌ ‌
  
‌ 
Upon‌ ‌confirmation‌ ‌of‌ ‌eligibility,‌ ‌subjects‌ ‌will‌ ‌be‌ ‌enrolled‌ ‌in‌ ‌the‌ ‌study‌ ‌and‌ ‌trial‌ ‌treatment‌ ‌will‌ ‌begin.‌ ‌ 
8.3‌ ‌Treatment‌ ‌phase‌ ‌
 
‌ 
When‌‌all‌‌eligibility‌‌criteria‌‌are‌‌met,‌‌study‌‌treatment‌‌should‌‌be‌‌started‌‌as‌‌soon‌‌as‌‌possible.‌‌Study‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
day‌‌1‌‌is‌‌defined‌‌as‌‌the‌‌day‌‌the‌‌first‌‌dose‌‌of‌‌treatment‌‌is‌‌received.‌‌One‌‌cycle‌‌is‌‌considered‌‌every‌‌14‌‌
     
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
(±‌ ‌3)‌ ‌day‌ ‌period‌ ‌plus‌ ‌the‌ ‌time‌ ‌it‌ ‌takes‌ ‌for‌ ‌chemotherapy-related‌ ‌toxicities‌ ‌to‌ ‌resolve.‌ ‌ 
‌ 
Cetuximab‌‌will‌‌be‌‌administered‌‌at‌‌a‌‌dose‌‌of‌‌500‌‌mg‌‌/‌‌m2‌‌every‌‌2‌‌weeks‌‌on‌‌day‌‌1‌‌of‌‌each‌‌cycle.‌‌
 
 
 
 
   
 
 
 
   
 
   
 
 
   
 
 
 
The‌‌concomitant‌‌chemotherapeutic‌‌agents‌‌used‌‌should‌‌not‌‌be‌‌administered‌‌until‌‌one‌‌hour‌‌after‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
completion‌ ‌of‌ ‌the‌ ‌cetuximab‌ ‌infusion.‌ ‌ 
‌ 
Subjects‌ ‌with‌ ‌unacceptable‌ ‌FOLFOX6‌ ‌(m)‌ ‌/‌ ‌FOLFIRI‌ ‌(m)‌ ‌-related‌ ‌toxicities‌ ‌may‌ ‌discontinue‌‌
 
 
 
 
   
 
 
 
 
 
 
FOLFOX6‌ ‌(m)‌ ‌/‌ ‌FOLFIRI‌ ‌(m)‌ ‌treatment‌ ‌and‌ ‌receive‌ ‌biweekly‌‌cetuximab‌‌as‌‌monotherapy.‌‌The‌‌
 
   
 
 
 
 
 
 
 
 
 
 
combined‌‌treatment‌‌phase‌‌runs‌‌from‌‌enrollment‌‌to‌‌the‌‌decision‌‌to‌‌discontinue‌‌the‌‌administration‌‌of‌‌
 
 
 
 
 
   
 
   
 
 
 
 
FOLFOX6‌‌(m)‌‌/‌‌FOLFIRI‌‌(m).‌‌The‌‌overall‌‌treatment‌‌period‌‌ends‌‌when‌‌it‌‌is‌‌decided‌‌to‌‌discontinue‌‌
 
   
 
 
 
 
 
 
 
     
   
 
biweekly‌‌cetuximab.‌‌Evaluations‌‌of‌‌subjects‌‌receiving‌‌biweekly‌‌cetuximab‌‌as‌‌monotherapy‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌same‌ ‌as‌ ‌those‌ ‌expected‌ ‌for‌ ‌combination‌ ‌therapy.‌ ‌ 
‌ 
During‌ ‌the‌ ‌time‌ ‌of‌ ‌chemotherapy‌ ‌treatment,‌ ‌the‌ ‌following‌ ‌procedures‌ ‌will‌ ‌be‌ ‌performed:‌ ‌ 
Record‌ ‌of‌ ‌concomitant‌ ‌medication‌ ‌(day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle).‌ ‌ 
Adverse‌ ‌event‌ ‌log:‌ ‌including‌ ‌toxicities‌ ‌related‌ ‌to‌ ‌skin‌ ‌or‌ ‌nails‌ ‌(day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle).‌ ‌ 
ECOG‌ ‌(Eastern‌ ‌Cooperative‌ ‌Oncology‌ ‌Group)‌ ‌performance‌ ‌status‌ ‌(day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle).‌ ‌ 
Physical‌ ‌examination‌ ‌(day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle).‌ ‌ 
Measurements‌ ‌of‌ ‌resting‌ ‌pulse,‌ ‌respiratory‌ ‌rate,‌ ‌temperature‌ ‌and‌ ‌blood‌ ‌pressure‌ ‌(day‌‌1‌‌of‌‌each‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
cycle).‌ ‌ 
Weight‌ ‌(day‌ ‌1‌ ‌of‌ ‌each‌ ‌cycle).‌ ‌ 
Body‌‌Surface‌‌Area‌‌(SC):‌‌will‌‌be‌‌calculated‌‌on‌‌Day‌‌1‌‌of‌‌Cycle‌‌1‌‌and‌‌at‌‌the‌‌beginning‌‌of‌‌any‌‌cycle‌‌
 
 
 
 
 
 
 
 
   
 
   
   
 
 
 
 
 
during‌ ‌which‌ ‌the‌ ‌subject's‌ ‌weight‌ ‌has‌ ‌changed‌ ‌by‌ ‌10%‌ ‌from‌ ‌baseline‌ ‌(ie‌ ‌Cycle‌ ‌1).‌ ‌ 
Laboratory‌ ‌tests‌ ‌(≤‌ ‌48‌ ‌hours‌ ‌before‌ ‌the‌ ‌start‌ ‌of‌ ‌each‌ ‌cycle).‌ ‌When‌ ‌possible,‌ ‌the‌ ‌same‌ ‌local‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
laboratory‌ ‌should‌ ‌be‌ ‌used‌ ‌throughout‌ ‌the‌ ‌study:‌ ‌ 
Hematological‌‌tests:‌‌hemoglobin,‌‌hematocrit,‌‌red‌‌cell‌‌count,‌‌mean‌‌corpuscular‌‌volume,‌‌platelets,‌‌
 
 
 
 
 
 
 
 
 
 
 
leukocyte‌ ‌count‌ ‌and‌ ‌differential‌ ‌(neutrophils,‌ ‌lymphocytes,‌ ‌monocytes,‌ ‌eosinophils,‌ ‌basophils).‌ ‌ 
Biochemical‌ ‌tests:‌ ‌sodium,‌ ‌potassium,‌ ‌chloride,‌ ‌bicarbonate,‌ ‌BUN‌ ‌or‌ ‌urea‌ ‌(depending‌ ‌on‌ ‌local‌‌
 
 
 
 
 
 
 
 
 
 
 
 
institution‌ ‌practice),‌ ‌LDH,‌ ‌magnesium,‌‌creatinine,‌‌albumin,‌‌total‌‌protein,‌‌total‌‌bilirubin,‌‌alkaline‌‌
 
 
 
 
 
 
 
 
 
 
 
phosphatase,‌ ‌ALT,‌ ‌AST,‌ ‌calcium,‌ ‌phosphorus‌ ‌and‌ ‌uric‌ ‌acid.‌ ‌ 
Serum‌ ‌CEA‌ ‌(every‌ ‌8‌ ‌weeks‌ ‌+/-‌ ‌1‌ ‌week).‌ ‌ 
Radiological‌‌images‌‌of‌‌the‌‌chest,‌‌abdomen,‌‌pelvis‌‌and‌‌the‌‌rest‌‌of‌‌the‌‌disease‌‌sites,‌‌either‌‌by‌‌CT‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI.‌ ‌Disease‌ ‌assessment‌ ‌should‌‌be‌‌performed‌‌every‌‌12‌‌weeks,‌‌throughout‌‌the‌‌trial‌‌period‌‌until‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
documentation‌ ‌of‌ ‌disease‌ ‌progression.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
51‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Serum‌ ‌biomarker‌ ‌measurements:‌ ‌until‌ ‌disease‌‌progression‌‌is‌‌documented‌‌(every‌‌12‌‌weeks‌‌+/-‌‌1‌‌
 
 
 
 
 
   
 
 
 
 
   
week).‌ ‌ 
‌ 
Treatment‌ ‌will‌ ‌be‌ ‌stopped‌ ‌in‌ ‌the‌ ‌following‌ ‌cases:‌ ‌ 
Withdrawal‌ ‌of‌ ‌consent‌ ‌from‌ ‌the‌ ‌patient‌ ‌ 
Progressive‌ ‌disease‌ ‌ 
Intolerable‌ ‌toxicity‌ ‌ 
Investigator's‌ ‌decision‌ ‌based‌ ‌on‌ ‌what‌ ‌he‌ ‌considers‌ ‌best‌ ‌for‌ ‌the‌ ‌patient.‌ ‌ 
8.4‌ ‌Safety‌ ‌follow-up‌ ‌visit‌ ‌
 
When‌ ‌a‌ ‌subject‌ ‌definitively‌ ‌discontinues‌ ‌trial‌ ‌treatment,‌ ‌they‌ ‌will‌ ‌undergo‌ ‌a‌ ‌follow-up‌ ‌safety‌‌
   
 
 
 
 
 
 
 
   
 
 
assessment‌ ‌no‌ ‌earlier‌ ‌than‌ ‌30‌ ‌±‌ ‌3‌ ‌days‌ ‌after‌ ‌the‌ ‌last‌ ‌dose‌ ‌of‌ ‌study‌ ‌treatment.‌ ‌ 
‌ 
The‌ ‌following‌ ‌evaluations‌ ‌will‌ ‌be‌ ‌carried‌ ‌out:‌ ‌ 
Registration‌ ‌of‌ ‌concomitant‌ ‌drugs.‌ ‌ 
Adverse‌ ‌event‌ ‌log:‌ ‌including‌ ‌toxicities‌ ‌that‌ ‌are‌ ‌related‌ ‌to‌ ‌the‌ ‌skin‌ ‌or‌ ‌nails.‌ ‌ 
ECOG‌ ‌performance‌ ‌status.‌ ‌ 
Physical‌ ‌exploration‌ ‌ 
Resting‌ ‌pulse,‌ ‌respiratory‌ ‌rate,‌ ‌temperature,‌ ‌and‌ ‌blood‌ ‌pressure.‌ ‌ 
Weight.‌ ‌ 
Laboratory‌ ‌tests‌ ‌(where‌ ‌possible‌ ‌the‌ ‌same‌ ‌local‌ ‌laboratory‌ ‌should‌ ‌be‌ ‌used‌ ‌throughout‌ ‌the‌ ‌study):‌ ‌ 
Hematological‌‌tests:‌‌hemoglobin,‌‌hematocrit,‌‌red‌‌cell‌‌count,‌‌mean‌‌corpuscular‌‌volume,‌‌platelets,‌‌
 
 
 
 
 
 
 
 
 
 
 
leukocyte‌ ‌count‌ ‌and‌ ‌differential‌ ‌(neutrophils,‌ ‌lymphocytes,‌ ‌monocytes,‌ ‌eosinophils,‌ ‌basophils).‌ ‌ 
Biochemical‌ ‌tests:‌ ‌sodium,‌ ‌potassium,‌ ‌chloride,‌ ‌bicarbonate,‌ ‌BUN‌ ‌or‌ ‌urea‌ ‌(depending‌ ‌on‌ ‌local‌‌
 
 
 
 
 
 
 
 
 
 
 
 
institution‌ ‌practice),‌ ‌LDH,‌ ‌magnesium,‌‌creatinine,‌‌albumin,‌‌total‌‌protein,‌‌total‌‌bilirubin,‌‌alkaline‌‌
 
 
 
 
 
 
 
 
 
 
 
phosphatase,‌ ‌ALT,‌ ‌AST,‌ ‌calcium,‌ ‌phosphorus‌ ‌and‌ ‌uric‌ ‌acid.‌ ‌ 
Serum‌‌CEA‌‌[Note:‌‌Serum‌‌CEA‌‌will‌‌only‌‌be‌‌tested‌‌in‌‌subjects‌‌who‌‌have‌‌withdrawn‌‌from‌‌the‌‌study‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
for‌‌reasons‌‌other‌‌than‌‌disease‌‌progression‌‌and‌‌have‌‌not‌‌undergone‌‌a‌‌serum‌‌CEA‌‌test‌‌within‌‌8‌‌weeks‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
+/-‌ ‌1‌ ‌week‌ ‌previous].‌ ‌ 
Radiographic‌‌images‌‌of‌‌the‌‌chest,‌‌abdomen,‌‌pelvis,‌‌and‌‌other‌‌disease‌‌sites‌‌if‌‌the‌‌subject‌‌withdrew‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
from‌ ‌treatment‌ ‌for‌ ‌reasons‌ ‌other‌ ‌than‌ ‌PE‌ ‌(according‌ ‌to‌ ‌the‌ ‌revised‌ ‌RECIST‌ ‌1.1‌ ‌criteria).‌ ‌ 
Serum‌ ‌biomarker‌ ‌measurements:‌ ‌until‌ ‌disease‌‌progression‌‌is‌‌documented‌‌(every‌‌12‌‌weeks‌‌+/-‌‌1‌‌
 
 
 
 
 
   
 
 
 
 
   
week).‌ ‌ 
‌ 
All‌‌subjects‌‌with‌‌serious‌‌adverse‌‌events‌‌at‌‌the‌‌time‌‌of‌‌the‌‌safety‌‌follow-up‌‌visit‌‌will‌‌continue‌‌with‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
follow-up‌ ‌until‌ ‌resolution‌ ‌of‌ ‌those‌ ‌events..‌ ‌ 
8.5.‌ ‌Follow-up‌ ‌visits‌ ‌from‌ ‌end‌ ‌of‌ ‌treatment‌ ‌without‌ ‌progression‌ ‌to‌ ‌disease‌ ‌progression‌ ‌
 
Once‌‌the‌‌treatment‌‌for‌‌any‌‌cause‌‌other‌‌than‌‌disease‌‌progression‌‌has‌‌been‌‌completed,‌‌the‌‌following‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
procedures‌ ‌will‌ ‌be‌ ‌performed‌ ‌every‌ ‌12‌ ‌weeks‌ ‌until‌ ‌disease‌ ‌progression:‌ ‌ 
ECOG‌ ‌(Eastern‌ ‌Cooperative‌ ‌Oncology‌ ‌Group)‌ ‌performance‌ ‌status.‌ ‌ 
Physical‌ ‌exploration‌ ‌.‌ ‌ 
Lab‌ ‌tests.‌ ‌When‌ ‌possible,‌ ‌the‌ ‌same‌ ‌local‌ ‌laboratory‌ ‌should‌ ‌be‌ ‌used‌ ‌throughout‌ ‌the‌ ‌study:‌ ‌ 
Hematological‌‌tests:‌‌hemoglobin,‌‌hematocrit,‌‌red‌‌cell‌‌count,‌‌mean‌‌corpuscular‌‌volume,‌‌platelets,‌‌
 
 
 
 
 
 
 
 
 
 
 
leukocyte‌ ‌count‌ ‌and‌ ‌differential‌ ‌(neutrophils,‌ ‌lymphocytes,‌ ‌monocytes,‌ ‌eosinophils,‌ ‌basophils).‌ ‌ 
Biochemical‌ ‌tests:‌ ‌sodium,‌ ‌potassium,‌ ‌chloride,‌ ‌bicarbonate,‌ ‌BUN‌ ‌or‌ ‌urea‌ ‌(depending‌ ‌on‌ ‌local‌‌
 
 
 
 
 
 
 
 
 
 
 
 
institution‌ ‌practice),‌ ‌LDH,‌ ‌magnesium,‌‌creatinine,‌‌albumin,‌‌total‌‌protein,‌‌total‌‌bilirubin,‌‌alkaline‌‌
 
 
 
 
 
 
 
 
 
 
 
phosphatase,‌ ‌ALT,‌ ‌AST,‌ ‌calcium,‌ ‌phosphorus‌ ‌and‌ ‌uric‌ ‌acid.‌ ‌ 
Serum‌ ‌CEA‌ ‌(every‌ ‌8‌ ‌weeks‌ ‌+/-‌ ‌1‌ ‌week).‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
52‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Radiological‌‌images‌‌of‌‌the‌‌chest,‌‌abdomen,‌‌pelvis‌‌and‌‌the‌‌rest‌‌of‌‌the‌‌disease‌‌sites,‌‌either‌‌by‌‌CT‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI.‌ ‌Disease‌ ‌assessment‌ ‌should‌‌be‌‌performed‌‌every‌‌12‌‌weeks,‌‌throughout‌‌the‌‌trial‌‌period‌‌until‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
documentation‌ ‌of‌ ‌disease‌ ‌progression.‌ ‌ 
Serum‌ ‌biomarker‌ ‌measurements:‌ ‌until‌ ‌disease‌‌progression‌‌is‌‌documented‌‌(every‌‌12‌‌weeks‌‌+/-‌‌1‌‌
 
 
 
 
 
   
 
 
 
 
   
week)‌.‌ ‌ 
‌ 
8.6‌ ‌Long-term‌ ‌follow-up‌ ‌visits‌ ‌
 
After‌ ‌disease‌ ‌progression,‌‌all‌‌subjects‌‌will‌‌be‌‌contacted‌‌through‌‌a‌‌clinic‌‌visit‌‌or‌‌by‌‌phone‌‌(by‌‌a‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
member‌‌of‌‌the‌‌center's‌‌staff)‌‌to‌‌assess‌‌disease‌‌status,‌‌subsequent‌‌anticancer‌‌therapy,‌‌and‌‌survival‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
after‌‌the‌‌last‌‌drug‌‌administration.‌‌in‌‌study.‌‌They‌‌will‌‌be‌‌contacted‌‌every‌‌12‌‌weeks‌‌±‌‌4‌‌weeks‌‌from‌
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
the‌‌visit‌‌(follow-up‌‌or‌‌security)‌‌until‌‌24‌‌months‌‌after‌‌the‌‌last‌‌inclusion‌‌or‌‌death‌‌of‌‌the‌‌last‌‌subject,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
whichever‌ ‌occurs‌ ‌first.‌‌  
8.6‌ ‌Tumor‌ ‌response‌ ‌evaluation‌ ‌
 
During‌‌the‌‌selection,‌‌baseline‌‌measurements‌‌of‌‌the‌‌tumor‌‌will‌‌be‌‌performed.‌‌Assessments‌‌of‌‌tumor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
response‌ ‌will‌ ‌be‌ ‌performed‌ ‌using‌ ‌a‌ ‌revised‌ ‌version‌ ‌of‌ ‌the‌ ‌RECIST‌ ‌1.1‌ ‌criteria‌ ‌(Appendix‌ ‌E).‌ ‌ 
‌ 
Subjects‌ ‌will‌ ‌be‌ ‌assessed‌ ‌for‌ ‌tumor‌ ‌response‌ ‌every‌ ‌12‌ ‌weeks‌ ‌throughout‌ ‌the‌ ‌trial‌ ‌period‌ ‌until‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
disease‌‌progression‌‌is‌‌documented‌‌(per‌‌the‌‌revised‌‌RECIST‌‌1.1‌‌criteria).‌‌In‌‌patients‌‌with‌‌symptoms‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
suggestive‌‌of‌‌disease‌‌progression,‌‌tumor‌‌progression‌‌should‌‌be‌‌assessed‌‌at‌‌the‌‌time‌‌of‌‌symptoms.‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
For‌‌subjects‌‌in‌‌whom‌‌disease‌‌progression‌‌has‌‌been‌‌determined,‌‌the‌‌treatment‌‌phase‌‌of‌‌the‌‌study‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will‌‌be‌‌discontinued‌‌and‌‌will‌‌undergo‌‌follow-up‌‌safety‌‌evaluations‌‌30‌‌days‌‌±‌‌3‌‌days‌‌after‌‌the‌‌last‌‌
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
study‌ ‌treatment.‌ ‌ 
‌ 
Tumor‌‌evaluation‌‌will‌‌be‌‌performed‌‌on‌‌subjects‌‌who‌‌have‌‌withdrawn‌‌from‌‌the‌‌study‌‌for‌‌reasons‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
other‌‌than‌‌radiographically‌‌documented‌‌disease‌‌progression.‌‌All‌‌these‌‌subjects‌‌should‌‌be‌‌followed‌‌
 
 
 
 
 
 
 
 
 
 
 
 
up‌‌for‌‌disease‌‌progression‌‌(revised‌‌RECIST‌‌1.1‌‌criteria)‌‌every‌‌12‌‌weeks‌‌+/-‌‌1‌‌week‌‌until‌‌disease‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
progression‌ ‌or‌ ‌the‌ ‌end‌ ‌of‌ ‌the‌ ‌study.‌ ‌ 
‌ 
At‌‌baseline,‌‌CT‌‌(helical‌‌or‌‌conventional)‌‌with‌‌5-mm‌‌slices‌‌of‌‌the‌‌chest,‌‌abdomen,‌‌and‌‌pelvis‌‌are‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
required,‌‌along‌‌with‌‌relevant‌‌images‌‌of‌‌all‌‌other‌‌disease‌‌sites.‌‌Magnetic‌‌resonance‌‌imaging‌‌(MRI)‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
is‌ ‌not‌ ‌acceptable‌ ‌to‌ ‌evaluate‌ ‌the‌ ‌disease‌ ‌as‌ ‌a‌ ‌single‌ ‌test‌ ‌but‌ ‌can‌ ‌be‌ ‌performed‌ ‌additionally‌ ‌if‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
clinically‌‌indicated.‌‌If‌‌chest‌‌CT‌‌is‌‌normal‌‌at‌‌baseline,‌‌a‌‌chest‌‌radiograph‌‌(CXR)‌‌will‌‌be‌‌performed‌‌
 
   
 
   
   
   
 
 
 
 
 
 
at‌‌each‌‌subsequent‌‌tumor‌‌imaging‌‌during‌‌the‌‌treatment‌‌phase.‌‌In‌‌the‌‌event‌‌that‌‌the‌‌chest‌‌radiograph‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
is‌‌found‌‌to‌‌be‌‌abnormal‌‌during‌‌the‌‌treatment‌‌phase,‌‌a‌‌chest‌‌CT‌‌will‌‌be‌‌obtained‌‌and‌‌this‌‌modality‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
should‌‌be‌‌used‌‌to‌‌obtain‌‌subsequent‌‌images‌‌of‌‌the‌‌tumor.‌‌If‌‌the‌‌baseline‌‌chest‌‌CT‌‌is‌‌found‌‌to‌‌be‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
abnormal,‌‌a‌‌chest‌‌CT‌‌will‌‌be‌‌performed‌‌during‌‌the‌‌treatment‌‌phase,‌‌even‌‌if‌‌no‌‌target‌‌lesions‌‌have‌‌
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
been‌ ‌located‌ ‌on‌ ‌that‌ ‌scan.‌ ‌The‌ ‌same‌ ‌evaluation‌ ‌method‌ ‌and‌ ‌technique‌ ‌should‌ ‌be‌ ‌used‌ ‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
characterize‌‌each‌‌lesion‌‌identified‌‌and‌‌described‌‌at‌‌baseline‌‌and‌‌during‌‌follow-up.‌‌All‌‌radiological‌‌
 
 
 
 
 
   
 
 
 
 
 
 
evaluations‌‌should‌‌obtain‌‌images‌‌of‌‌all‌‌disease‌‌sites‌‌identified‌‌at‌‌baseline,‌‌even‌‌if‌‌they‌‌have‌‌been‌‌
 
 
 
 
 
 
 
 
   
 
   
 
 
 
chosen‌ ‌by‌ ‌the‌ ‌investigator‌ ‌as‌ ‌non-target‌ ‌lesions.‌ ‌ 
‌ 
A‌‌change‌‌from‌‌CT‌‌to‌‌MRI‌‌(or‌‌vice‌‌versa)‌‌of‌‌the‌‌liver‌‌is‌‌considered‌‌the‌‌only‌‌acceptable‌‌modality‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
change‌‌and‌‌should‌‌not‌‌preclude‌‌assessment‌‌of‌‌response‌‌if,‌‌in‌‌the‌‌judgment‌‌of‌‌the‌‌center‌‌radiologist,‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
there‌ ‌are‌ ‌no‌‌significant‌‌differences‌‌in‌‌assessment‌‌when‌‌changing‌‌modalities.‌‌This‌‌can‌‌occur‌‌if‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
     
subject‌ ‌is‌ ‌medically‌ ‌contraindicated‌ ‌for‌ ‌IV‌ ‌contrast.‌‌for‌‌CT‌‌during‌‌the‌‌trial.‌‌This‌‌change‌‌would‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
require‌ ‌the‌ ‌prior‌ ‌approval‌ ‌of‌ ‌the‌ ‌developer.‌ ‌CT‌ ‌and‌ ‌MRI‌ ‌are‌ ‌the‌ ‌best‌ ‌and‌ ‌most‌ ‌reproducible‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
methods‌ ‌currently‌ ‌available‌ ‌to‌ ‌measure‌ ‌selected‌ ‌index‌ ‌lesions‌ ‌for‌ ‌response‌ ‌assessment.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
53‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
Ultrasound‌ ‌should‌ ‌not‌ ‌be‌ ‌used‌ ‌for‌ ‌the‌ ‌evaluation‌ ‌of‌ ‌visceral‌ ‌injuries.‌ ‌However,‌ ‌it‌‌is‌‌a‌‌possible‌‌
 
 
 
 
 
 
 
 
 
 
 
       
 
alternative‌‌to‌‌clinical‌‌measurements‌‌of‌‌palpable‌‌superficial‌‌lymph‌‌nodes,‌‌subcutaneous‌‌lesions,‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
thyroid‌‌nodules‌‌or‌‌to‌‌confirm‌‌the‌‌complete‌‌disappearance‌‌of‌‌superficial‌‌lesions‌‌normally‌‌evaluated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
by‌ ‌clinical‌ ‌examination.‌ ‌ 
‌ 
Study‌ ‌treatment‌ ‌(FOLFOX6‌ ‌(m)‌ ‌/‌ ‌FOLFIRI‌ ‌(m)‌ ‌chemotherapy‌ ‌+‌ ‌biweekly‌ ‌cetuximab)‌ ‌will‌ ‌be‌‌
 
 
 
   
 
 
   
 
 
 
 
discontinued‌‌in‌‌subjects‌‌with‌‌PE‌‌confirmed‌‌by‌‌RECIST‌‌criteria‌‌v.1.1‌‌and‌‌will‌‌be‌‌followed‌‌up‌‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
safety‌ ‌(after‌ ‌at‌ ‌least‌ ‌30‌ ‌days‌ ‌since‌ ‌the‌ ‌last‌ ‌study‌ ‌drug‌ ‌administration).‌ ‌ 
‌ 
8.7‌ ‌Withdrawal‌ ‌and‌ ‌replacement‌ ‌of‌ ‌subjects‌ ‌
 
‌ 
8.7.1‌  ‌Withdrawal‌ ‌of‌ ‌patients‌ ‌ 
‌ 
Subjects‌‌have‌‌the‌‌right‌‌to‌‌withdraw‌‌completely‌‌or‌‌partially‌‌from‌‌the‌‌study‌‌at‌‌any‌‌time‌‌and‌‌for‌‌any‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
reason‌ ‌without‌ ‌prejudice‌ ‌to‌ ‌their‌ ‌future‌ ‌medical‌ ‌assistance‌ ‌by‌ ‌the‌ ‌doctor‌ ‌or‌ ‌the‌ ‌center.‌ ‌ 
‌ 
Withdrawal‌ ‌of‌ ‌full‌‌consent‌‌from‌‌a‌‌study‌‌means‌‌that‌‌the‌‌subject‌‌does‌‌not‌‌wish‌‌to‌‌receive‌‌further‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
investigational‌‌treatment,‌‌nor‌‌does‌‌it‌‌wish‌‌or‌‌is‌‌unable‌‌to‌‌continue‌‌participating‌‌in‌‌the‌‌study.‌‌Any‌‌
 
 
 
   
 
   
 
 
 
 
 
 
 
 
subject‌‌can‌‌completely‌‌withdraw‌‌her‌‌consent‌‌to‌‌participate‌‌in‌‌the‌‌study‌‌at‌‌any‌‌time‌‌during‌‌the‌‌study.‌‌
 
 
 
 
 
   
   
 
   
 
 
 
 
 
The‌‌investigator‌‌will‌‌discuss‌‌with‌‌the‌‌subject‌‌the‌‌most‌‌appropriate‌‌way‌‌to‌‌withdraw‌‌to‌‌ensure‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
subject's‌‌health.‌‌Any‌‌subject‌‌who‌‌completely‌‌withdraws‌‌their‌‌consent‌‌to‌‌participate‌‌in‌‌the‌‌study‌‌will‌‌
 
 
 
 
 
 
 
 
   
   
 
 
 
not‌‌receive‌‌further‌‌investigational‌‌treatment‌‌and‌‌/‌‌or‌‌study‌‌observations‌‌immediately‌‌after‌‌the‌‌date‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
they‌ ‌request‌ ‌it.‌ ‌ 
‌ 
Partial‌‌withdrawal‌‌of‌‌consent‌‌means‌‌that‌‌the‌‌subject‌‌does‌‌not‌‌want‌‌to‌‌continue‌‌being‌‌treated‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌investigational‌ ‌product‌ ‌but‌ ‌still‌ ‌wishes‌ ‌to‌ ‌collaborate‌ ‌by‌ ‌remaining‌ ‌in‌ ‌the‌ ‌study‌ ‌to‌ ‌provide‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
additional‌‌data‌‌(eg,‌‌participating‌‌in‌‌all‌‌subsequent‌‌study‌‌visits‌‌or‌‌procedures).‌‌Subjects‌‌may‌‌waive‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
continuing‌‌to‌‌receive‌‌the‌‌investigational‌‌product‌‌at‌‌any‌‌time‌‌during‌‌the‌‌study.‌‌These‌‌subjects,‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
addition‌ ‌to‌ ‌those‌ ‌who‌ ‌have‌ ‌stopped‌ ‌receiving‌ ‌the‌ ‌investigational‌ ‌product‌ ‌for‌ ‌other‌ ‌reasons‌‌(eg,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
decision‌ ‌of‌ ‌the‌ ‌investigator‌ ‌or‌ ‌sponsor)‌ ‌should‌ ‌continue‌ ‌with‌ ‌the‌ ‌study‌ ‌observation‌ ‌program.‌ ‌ 
‌ 
Reasons‌ ‌for‌ ‌withdrawal‌ ‌of‌ ‌the‌ ‌investigational‌ ‌product‌ ‌or‌ ‌observation‌ ‌may‌ ‌include:‌ ‌ 
Withdrawal‌ ‌of‌ ‌consent‌ ‌from‌ ‌the‌ ‌patient‌ ‌ 
Progressive‌ ‌disease‌ ‌ 
Intolerable‌ ‌toxicity‌ ‌ 
Investigator's‌ ‌decision‌ ‌based‌ ‌on‌ ‌what‌ ‌he‌ ‌considers‌ ‌best‌ ‌for‌ ‌the‌ ‌patient‌ ‌ 
‌ 
If‌ ‌a‌ ‌subject‌ ‌(or‌ ‌her‌ ‌legally‌ ‌authorized‌ ‌representative)‌ ‌requests‌ ‌or‌ ‌decides‌ ‌to‌ ‌withdraw‌‌from‌‌the‌‌
   
 
 
 
 
 
 
 
 
 
 
 
 
 
study,‌‌every‌‌effort‌‌should‌‌be‌‌made‌‌to‌‌complete‌‌and‌‌report‌‌the‌‌observations‌‌as‌‌widely‌‌as‌‌possible‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
until‌ ‌the‌ ‌withdrawal‌‌date.‌‌All‌‌information‌‌must‌‌be‌‌included‌‌in‌‌the‌‌corresponding‌‌data‌‌collection‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
notebooks.‌ ‌ 
‌ 
8.7.2‌ ‌Replacement‌ ‌of‌ ‌subjects‌ ‌ 
‌ 
Subjects‌ ‌who‌ ‌withdraw‌ ‌from‌ ‌the‌ ‌study‌ ‌after‌ ‌inclusion‌ ‌will‌ ‌not‌ ‌be‌ ‌substituted.‌ ‌This‌ ‌study‌ ‌will‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
include‌ ‌approximately‌ ‌170‌ ‌subjects.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
54‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
9.‌ ‌Collection,‌ ‌registration‌ ‌and‌ ‌notification‌ ‌of‌ ‌security‌ ‌data‌ ‌
 
9.1‌ ‌Definitions‌ ‌
 
9.1.1‌ ‌Adverse‌ ‌events‌ ‌ 
‌ 
In‌ ‌the‌ ‌International‌ ‌Conference‌ ‌on‌ ‌Harmonization‌ ‌(ICH)‌ ‌for‌ ‌Good‌ ‌Clinical‌ ‌Practice,‌ ‌an‌ ‌AE‌ ‌is‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
defined‌‌as‌‌"any‌‌undesirable‌‌medical‌‌experience‌‌in‌‌a‌‌patient‌‌or‌‌clinical‌‌research‌‌subject‌‌treated‌‌with‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
a‌ ‌pharmaceutical‌ ‌product‌ ‌and‌ ‌that‌ ‌does‌ ‌not‌ ‌necessarily‌ ‌have‌ ‌a‌ ‌causal‌ ‌relationship‌ ‌with‌ ‌it.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment".‌ ‌(ICH‌ ‌E6:‌ ‌1.2).‌ ‌ 
‌ 
The‌ ‌progression‌ ‌of‌ ‌the‌ ‌disease‌ ‌itself‌ ‌is‌ ‌not‌ ‌considered‌ ‌an‌ ‌adverse‌ ‌event.‌ ‌However,‌ ‌signs‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
symptoms‌ ‌of‌ ‌disease‌ ‌progression‌ ‌can‌ ‌be‌ ‌recorded‌ ‌as‌ ‌adverse‌ ‌events‌ ‌or‌ ‌serious‌ ‌adverse‌ ‌events.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Death‌‌due‌‌to‌‌disease‌‌progression‌‌during‌‌the‌‌study‌‌should‌‌be‌‌reported‌‌on‌‌the‌‌death‌‌reports‌‌page‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌data‌ ‌collection‌ ‌notebook,‌ ‌indicating‌ ‌the‌ ‌type‌ ‌of‌ ‌primary‌ ‌tumor‌ ‌as‌ ‌the‌ ‌reason‌ ‌for‌ ‌death.‌ ‌ 
‌ 
Worsening‌ ‌of‌ ‌a‌ ‌pre-existing‌ ‌condition‌ ‌(eg,‌ ‌diabetes,‌ ‌migraine‌ ‌headaches,‌ ‌gout)‌ ‌should‌ ‌also‌ ‌be‌‌
 
   
 
 
 
 
 
 
 
 
 
 
considered‌‌an‌‌AE‌‌if‌‌there‌‌is‌‌an‌‌increase‌‌in‌‌disease‌‌severity,‌‌frequency,‌‌or‌‌duration‌‌or‌‌an‌‌association‌‌
 
 
   
   
 
   
 
 
 
 
 
 
 
 
with‌ ‌significantly‌ ‌worse‌ ‌outcomes.‌ ‌ 
‌ 
Interventions‌ ‌for‌ ‌pretreatment‌ ‌disorders‌ ‌(eg,‌ ‌elective‌ ‌cosmetic‌ ‌surgery)‌ ‌or‌ ‌medical‌ ‌procedures‌‌
 
 
 
 
 
 
 
 
 
 
 
planned‌ ‌prior‌ ‌to‌ ‌study‌ ‌inclusion‌ ‌are‌ ‌not‌ ‌considered‌ ‌AE.‌ ‌ 
‌ 
The‌ ‌investigator‌ ‌is‌ ‌responsible‌ ‌for‌ ‌analyzing‌ ‌laboratory‌ ‌test‌ ‌results‌‌and‌‌determining‌‌whether‌‌an‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
abnormal‌‌value‌‌in‌‌a‌‌particular‌‌study‌‌subject‌‌represents‌‌a‌‌change‌‌from‌‌pre-study‌‌values.‌‌In‌‌general,‌‌
 
 
   
 
 
 
   
 
 
 
 
 
 
abnormal‌‌laboratory‌‌results‌‌of‌‌no‌‌clinical‌‌significance‌‌(at‌‌the‌‌discretion‌‌of‌‌the‌‌investigator)‌‌should‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
not‌‌be‌‌recorded‌‌as‌‌EA;‌‌however,‌‌changes‌‌in‌‌laboratory‌‌values‌‌​that‌‌require‌‌treatment‌‌or‌‌adjustment‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from‌ ‌previous‌ ‌treatment‌ ‌will‌ ‌be‌ ‌considered‌ ‌AE.‌ ‌ 
‌ 
9.1.2‌ ‌Serious‌ ‌adverse‌ ‌events‌ ‌ 
‌ 
A‌ ‌serious‌ ‌adverse‌ ‌event‌ ‌(SAE)‌ ‌is‌ ‌defined‌ ‌as‌ ‌an‌ ‌AE‌ ‌that‌ ‌ 
It‌ ‌is‌ ‌mortal.‌ ‌ 
It‌ ‌is‌ ‌life-threatening‌ ‌(implies‌ ‌an‌ ‌immediate‌ ‌risk‌ ‌of‌ ‌death‌ ‌for‌ ‌the‌ ‌subject).‌ ‌ 
It‌ ‌requires‌ ‌the‌ ‌hospitalization‌ ‌of‌ ‌the‌ ‌patient‌ ‌or‌ ‌the‌ ‌prolongation‌ ‌of‌ ‌the‌ ‌existing‌ ‌hospitalization.‌ ‌ 
It‌ ‌results‌ ‌in‌ ‌a‌ ‌persistent‌ ‌or‌ ‌significant‌ ‌disability‌ ‌/‌ ‌incapacity.‌ ‌ 
It‌ ‌is‌ ‌a‌ ‌congenital‌ ‌anomaly‌ ‌/‌ ‌birth‌ ‌defect.‌ ‌ 
Another‌ ‌significant‌ ‌medical‌ ‌risk.‌ ‌ 
‌ 
A‌‌hospitalization‌‌that‌‌meets‌‌the‌‌regulatory‌‌definition‌‌of‌‌"severe"‌‌is‌‌any‌‌admission‌‌of‌‌a‌‌patient‌‌to‌‌the‌‌
 
 
 
 
 
 
 
 
   
 
 
   
   
 
hospital‌‌that‌‌includes‌‌a‌‌minimum‌‌stay‌‌of‌‌one‌‌night‌‌in‌‌a‌‌healthcare‌‌facility.‌‌Any‌‌AE‌‌that‌‌does‌‌not‌‌
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
meet‌‌the‌‌definitions‌‌of‌‌severe‌‌(eg,‌‌accident‌‌and‌‌emergency‌‌department‌‌visit,‌‌outpatient‌‌surgery,‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
need‌‌for‌‌urgent‌‌study)‌‌may‌‌be‌‌classified‌‌as‌‌SAE‌‌if‌‌the‌‌investigator‌‌considers‌‌that‌‌it‌‌qualifies‌‌for‌‌
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
"other‌‌risk".‌‌significant‌‌physician‌‌".‌‌Examples‌‌include‌‌allergic‌‌bronchospasm,‌‌seizures,‌‌and‌‌blood‌‌
 
 
 
   
 
 
 
 
 
 
 
dyscrasias.‌ ‌ 
‌ 
Hospitalization‌‌to‌‌perform‌‌the‌‌procedures‌‌required‌‌by‌‌the‌‌protocol‌‌(or‌‌for‌‌elective‌‌procedures‌‌that‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
have‌‌been‌‌scheduled‌‌before‌‌inclusion‌‌and‌‌that‌‌are‌‌not‌‌an‌‌exclusion‌‌criterion)‌‌or‌‌the‌‌administration‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of‌ ‌the‌ ‌study‌ ‌treatment‌ ‌is‌ ‌not‌ ‌classified‌ ‌as‌ ‌SAE.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
55‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
9.1.3‌ ‌Unexpected‌ ‌adverse‌ ‌event‌ ‌(not‌ ‌listed)‌ ‌ 
‌ 
An‌ ‌unexpected‌ ‌AA,‌ ‌the‌ ‌nature‌ ‌or‌ ‌severity‌ ‌of‌ ‌which‌ ‌does‌ ‌not‌ ‌correspond‌ ‌to‌ ‌the‌ ‌information‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
regarding‌ ‌the‌ ‌product.‌ ‌ 
‌ 
As‌ ‌all‌ ‌the‌ ‌products‌ ‌administered‌ ‌in‌ ‌this‌ ‌trial‌ ‌are‌ ‌marketed‌ ‌in‌ ‌Spain‌ ‌and‌ ‌are‌ ‌used‌ ‌within‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
authorized‌‌conditions‌‌of‌‌use,‌‌the‌‌reference‌‌documents‌‌to‌‌establish‌‌the‌‌expectancy‌‌of‌‌adverse‌‌events‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
will‌ ‌be‌ ‌the‌ ‌updated‌ ‌technical‌ ‌sheets‌ ‌available‌ ‌at:‌ ‌ 
‌ 
https://sinaem4.agemed.es/consaem/fichasTecnicas.do?metodo=detalleForm&version=new‌ ‌ 
‌ 
In‌ ‌the‌ ‌case‌ ‌of‌ ‌Cetuximab,‌ ‌the‌ ‌information‌ ‌from‌ ‌the‌ ‌latest‌ ‌version‌ ‌of‌ ‌the‌ ‌Investigator's‌ ‌Manual‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should‌ ‌also‌ ‌be‌ ‌taken‌ ‌into‌ ‌account..‌ ‌ 
‌ 
9.1.4‌ ‌Adverse‌ ‌Drug‌ ‌Reaction‌ ‌(AR)‌ ‌and‌ ‌Serious‌ ‌Adverse‌ ‌Reaction‌ ‌(RAG)‌ ‌ 
‌ 
Any‌‌harmful‌‌and‌‌accidental‌‌response‌‌to‌‌a‌‌medical‌‌product‌‌related‌‌to‌‌any‌‌administered‌‌dose.‌‌The‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
term‌‌"response‌‌to‌‌a‌‌drug"‌‌means‌‌that,‌‌at‌‌a‌‌minimum,‌‌a‌‌causal‌‌relationship‌‌between‌‌the‌‌drug‌‌and‌‌the‌‌
 
 
   
 
 
     
   
 
 
 
 
 
 
 
adverse‌ ‌event‌ ‌would‌ ‌be‌ ‌a‌ ‌reasonable‌ ‌possibility,‌ ‌that‌ ‌is,‌ ‌the‌ ‌relationship‌ ‌cannot‌ ‌be‌ ‌ruled‌ ‌out.‌ ‌ 
A‌ ‌severe‌ ‌RA‌ ‌(RAG)‌ ‌is‌ ‌an‌ ‌RA‌ ‌that‌ ‌meets‌ ‌the‌ ‌definition‌ ‌of‌ ‌severe‌ ‌(provided‌ ‌in‌ ‌point‌ ‌9.1.2).‌ ‌ 
9.2‌ ‌Reporting‌ ‌procedures‌ ‌for‌ ‌all‌ ‌adverse‌ ‌events‌ ‌
 
The‌‌investigator‌‌is‌‌responsible‌‌for‌‌ensuring‌‌that‌‌all‌‌AE‌‌(as‌‌defined‌‌in‌‌section‌‌9.1)‌‌observed‌‌by‌‌the‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator‌‌or‌‌reported‌‌by‌‌the‌‌subjects‌‌are‌‌correctly‌‌recorded‌‌in‌‌the‌‌subjects'‌‌medical‌‌records,‌‌with‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
one‌ ‌exception:‌ ‌those‌ ‌that‌ ‌occur‌ ‌before‌ ‌inclusion‌ ‌and‌ ‌that,‌ ‌furthermore,‌ ‌the‌ ‌researcher‌ ‌does‌ ‌not‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consider‌ ‌related‌ ‌to‌ ‌the‌ ‌study‌ ‌selection‌ ‌process.‌ ‌ 
‌ 
In‌‌addition,‌‌the‌‌investigator‌‌is‌‌responsible‌‌for‌‌ensuring‌‌that,‌‌for‌‌subjects‌‌included‌‌in‌‌the‌‌study‌‌and‌‌
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
receiving‌‌study‌‌treatment,‌‌all‌‌adverse‌‌events‌‌recorded‌‌in‌‌the‌‌subjects'‌‌medical‌‌records‌‌(as‌‌specified‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
above)‌ ‌are‌ ‌reported‌ ‌in‌ ‌the‌ ‌CRD.‌ ‌ 
‌ 
The‌‌investigator‌‌should‌‌record‌‌the‌‌following‌‌attributes‌‌of‌‌the‌‌AE:‌‌diagnosis‌‌or‌‌syndrome‌‌(s)‌‌of‌‌AE‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(if‌ ‌known;‌ ‌otherwise‌ ‌signs‌ ‌or‌ ‌symptoms),‌ ‌description‌ ‌of‌ ‌the‌‌event‌‌(with‌‌adequate‌‌detail‌‌for‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
event),‌‌onset‌‌dates,‌‌and‌‌resolution,‌‌severity,‌‌evaluation‌‌of‌‌the‌‌relationship‌‌with‌‌the‌‌treatment‌‌under‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌ ‌and‌ ‌measures‌ ‌taken.‌ ‌The‌ ‌investigator‌ ‌may‌ ‌be‌ ‌required‌ ‌to‌ ‌provide‌ ‌follow-up‌ ‌information,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
discharge‌ ‌reports,‌ ‌and‌ ‌extracts‌ ‌from‌ ‌medical‌ ‌or‌ ‌CRD‌ ‌records.‌ ‌ 
‌ 
If‌‌applicable,‌‌the‌‌relationship‌‌of‌‌AE‌‌to‌‌the‌‌study‌‌treatment‌‌will‌‌be‌‌determined‌‌with‌‌the‌‌following‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
question:‌ ‌"Is‌ ‌there‌ ‌a‌ ‌reasonable‌ ‌possibility‌ ‌that‌ ‌the‌ ‌event‌ ‌may‌ ‌have‌ ‌been‌ ‌caused‌ ‌by‌ ‌the‌ ‌study‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
treatment?"‌ ‌The‌ ‌investigator‌ ‌should‌ ‌answer‌ ‌this‌ ‌question‌ ‌with‌ ‌"Yes"‌ ‌or‌ ‌"No".‌ ‌ 
If‌‌AE‌‌has‌‌occurred‌‌after‌‌informed‌‌consent‌‌but‌‌before‌‌the‌‌start‌‌of‌‌study‌‌treatment,‌‌the‌‌relationship‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE‌‌with‌‌the‌‌study‌‌selection‌‌process‌‌should‌‌be‌‌assessed‌‌by‌‌asking:‌‌"Is‌‌there‌‌a‌‌reasonable‌‌possibility‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
that‌ ‌the‌ ‌event‌ ‌may‌ ‌have‌ ‌occurred‌ ‌due‌ ‌to‌ ‌the‌ ‌study‌ ‌selection‌ ‌process?‌ ‌"‌ ‌The‌ ‌researcher‌ ‌should‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
answer‌‌this‌‌question‌‌with‌‌"yes"‌‌or‌‌"no".‌‌If‌‌the‌‌answer‌‌is‌‌yes,‌‌it‌‌should‌‌be‌‌recorded‌‌which‌‌part‌‌of‌‌the‌‌
 
 
 
 
 
 
   
 
   
   
 
 
 
 
 
 
 
study‌ ‌selection‌ ‌is‌ ‌suspected.‌ ‌ 
‌ 
The‌ ‌severity‌ ‌rating‌ ‌scale‌ ‌used‌ ‌in‌ ‌this‌ ‌study‌ ‌is‌ ‌described‌ ‌in‌ ‌Appendix‌ ‌C.‌ ‌ 
Medically‌ ‌significant‌ ‌AE‌ ‌that‌ ‌the‌‌investigator‌‌or‌‌sponsor‌‌considers‌‌related‌‌to‌‌the‌‌investigational‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
product‌ ‌will‌ ‌be‌ ‌monitored‌ ‌until‌ ‌resolution‌ ‌or‌ ‌until‌ ‌they‌ ‌are‌ ‌considered‌ ‌stabilized.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
56‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
It‌‌will‌‌be‌‌up‌‌to‌‌the‌‌investigator's‌‌clinical‌‌judgment‌‌to‌‌determine‌‌whether‌‌an‌‌AE‌‌is‌‌related‌‌and‌‌severe‌‌
 
 
 
   
 
 
 
   
 
 
 
   
 
 
 
enough‌‌to‌‌require‌‌removal‌‌of‌‌the‌‌subject‌‌from‌‌treatment‌‌or‌‌study.‌‌A‌‌subject‌‌may‌‌also‌‌voluntarily‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
abandon‌ ‌treatment‌ ‌for‌ ‌what‌ ‌he‌ ‌personally‌ ‌perceives‌ ‌to‌‌be‌‌intolerable‌‌AE.‌‌If‌‌either‌‌of‌‌these‌‌two‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
situations‌‌occurs,‌‌the‌‌subject‌‌should‌‌be‌‌strongly‌‌encouraged‌‌to‌‌undergo‌‌an‌‌end-of-study‌‌evaluation‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌remain‌ ‌under‌ ‌medical‌ ‌supervision‌ ‌until‌ ‌symptoms‌ ‌cease‌ ‌or‌ ‌disorder‌ ‌stabilizes.‌ ‌ 
‌ 
9.3‌ ‌Reporting‌ ‌procedures‌ ‌for‌ ‌serious‌ ‌adverse‌ ‌events‌ ‌
 
‌ 
The‌‌SAEs‌‌will‌‌be‌‌collected‌‌and‌‌recorded‌‌throughout‌‌the‌‌study‌‌period,‌‌starting‌‌from‌‌the‌‌signing‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌informed‌‌consent‌‌until‌‌30‌‌days‌‌after‌‌the‌‌last‌‌dose‌‌of‌‌the‌‌investigational‌‌product‌‌or‌‌the‌‌end‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌‌(including‌‌the‌‌follow-up‌‌period)‌‌if‌‌this‌‌is‌‌produced‌‌later.‌‌All‌‌SAEs‌‌recorded‌‌in‌‌the‌‌subjects'‌‌
 
 
 
 
   
   
 
 
 
 
 
 
 
 
medical‌‌records‌‌(as‌‌specified‌‌above)‌‌must‌‌be‌‌reported‌‌to‌‌the‌‌study‌‌sponsor‌‌within‌‌1‌‌business‌‌day‌‌of‌‌
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
discovery‌ ‌or‌ ‌notification‌ ‌of‌ ‌the‌ ‌event.‌ ‌The‌ ‌initial‌ ‌SAE‌ ‌information‌ ‌and‌ ‌all‌ ‌modifications‌ ‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
additions‌ ‌should‌ ‌be‌ ‌recorded‌ ‌in‌ ‌a‌ ‌Serious‌ ‌Adverse‌ ‌Event‌‌Data‌‌Collection‌‌Log‌‌and‌‌faxed‌‌to‌‌the‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
sponsor.‌ ‌ 
‌ 
SAEs‌‌will‌‌also‌‌be‌‌collected‌‌and‌‌reported‌‌within‌‌1‌‌business‌‌day‌‌of‌‌discovery‌‌or‌‌notification‌‌of‌‌the‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
event‌‌if‌‌it‌‌appears>‌‌30‌‌days‌‌after‌‌the‌‌last‌‌dose‌‌of‌‌the‌‌investigational‌‌product‌‌or‌‌after‌‌the‌‌end‌‌of‌‌the‌‌
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌‌and‌‌if‌‌it‌‌is‌‌believed‌‌to‌‌be‌‌possibly‌‌related.‌‌with‌‌the‌‌investigational‌‌product.‌‌In‌‌all‌‌cases‌‌of‌‌
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
death,‌‌available‌‌autopsy‌‌reports‌‌and‌‌relevant‌‌medical‌‌reports‌‌should‌‌be‌‌faxed‌‌to‌‌the‌‌sponsor.‌‌For‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
this‌‌reporting‌‌process,‌‌subject‌‌assessments‌‌must‌‌be‌‌made‌‌30‌‌days‌‌or‌‌more‌‌after‌‌the‌‌last‌‌dose‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigational‌ ‌product‌‌has‌‌been‌‌administered.‌‌The‌‌determination‌‌of‌‌whether‌‌an‌‌adverse‌‌event‌‌is‌‌
 
 
 
 
 
 
 
 
 
 
 
   
expected‌‌will‌‌be‌‌based‌‌on‌‌the‌‌contents‌‌of‌‌the‌‌investigator's‌‌manual‌‌and‌‌the‌‌technical‌‌data‌‌sheet‌‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌products‌‌marketed.‌‌If‌‌a‌‌subject‌‌is‌‌permanently‌‌withdrawn‌‌from‌‌the‌‌study‌‌due‌‌to‌‌an‌‌SAE,‌‌this‌‌
 
 
     
   
 
 
 
 
 
 
 
 
 
 
information‌ ‌should‌ ‌be‌ ‌recorded‌ ‌on‌ ‌the‌ ‌initial‌ ‌or‌ ‌follow-up‌ ‌SAE‌ ‌notification‌ ‌form‌ ‌and‌ ‌on‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
end-of-study‌ ‌CRD.‌ ‌ 
‌ 
The‌ ‌researcher‌ ‌must‌ ‌notify:‌ ‌GEMCAD‌ ‌Technical‌ ‌Secretariat.‌ ‌ 
‌ 
The‌ ‌telephone‌ ‌and‌ ‌fax‌ ‌number‌ ‌of‌ ‌the‌ ‌contact‌ ‌person:‌ ‌ 
‌ 
GEMCAD‌ ‌Technical‌ ‌Secretariat‌ ‌ 
Secretari‌ ‌Coloma,‌ ‌64-68,‌ ‌esc.‌ ‌B,‌ ‌entlo.‌ ‌5ª‌ ‌ 
08024‌ ‌Barcelona‌ ‌ 
Tel:‌  ‌+‌ ‌34‌ ‌93‌ ‌434‌ ‌44‌ ‌12.‌ ‌ 
Fax:‌ ‌+‌ ‌34‌ ‌93‌ ‌253‌ ‌11‌ ‌68.‌
‌ 
Correo‌ ‌electrónico:‌ ‌secretaria@gemcad.org‌ ‌ 
‌ 
9.4‌ ‌Notification‌ ‌of‌ ‌adverse‌ ‌events‌ ‌to‌ ‌the‌ ‌regulatory‌ ‌agencies‌ ‌and‌ ‌the‌ ‌CEICs‌ ‌involved.‌ ‌
 
‌ 
The‌ ‌sponsor‌ ‌will‌ ‌assume‌ ‌the‌ ‌responsibility‌ ‌of‌ ‌the‌ ‌adequate‌ ‌communication‌ ‌of‌ ‌the‌ ‌AA‌ ‌to‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
regulatory‌ ‌authorities.‌ ‌ 
‌ 
The‌‌sponsor‌‌will‌‌expeditiously‌‌communicate‌‌all‌‌AAGs‌‌that‌‌are‌‌unexpected‌‌and‌‌associated‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
use‌‌of‌‌the‌‌study‌‌treatment‌‌(SUSAR)‌‌to‌‌the‌‌researchers,‌‌to‌‌the‌‌clinical‌‌research‌‌ethics‌‌committees‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(CEIC)‌‌in‌‌accordance‌‌with‌‌the‌‌regulations‌‌in‌‌force‌‌(unless‌‌the‌‌CEICs‌‌require‌‌and‌‌document‌‌other‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
measures),‌ ‌to‌ ‌the‌ ‌corresponding‌ ‌AEMPS‌ ‌and‌ ‌CCAA.‌ ‌ 
‌ 
The‌‌sponsor‌‌will‌‌be‌‌responsible‌‌for‌‌making‌‌and‌‌submitting‌‌to‌‌the‌‌regulatory‌‌authorities‌‌and‌‌CEIC‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
57‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
the‌ ‌quarterly‌ ‌lists‌ ‌of‌ ‌serious‌ ‌adverse‌ ‌reactions‌ ‌as‌ ‌provided‌ ‌by‌ ‌the‌ ‌R.D.‌ ‌223/2004‌ ‌and‌ ‌the‌ ‌GCP.‌ ‌ 
‌ 
The‌‌sponsor‌‌will‌‌be‌‌responsible‌‌for‌‌preparing‌‌and‌‌submitting‌‌to‌‌the‌‌regulatory‌‌authorities‌‌and‌‌CEIC‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
the‌‌annual‌‌safety‌‌reports‌‌of‌‌the‌‌trial,‌‌complying‌‌with‌‌what‌‌is‌‌specified‌‌in‌‌R.D.‌‌223/2004‌‌and‌‌the‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
GCP.‌‌In‌‌addition,‌‌the‌‌sponsor‌‌will‌‌provide‌‌the‌‌Cetuximab‌‌producing‌‌Laboratory‌‌with‌‌a‌‌copy‌‌of‌‌the‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
annual‌‌safety‌‌report‌‌when‌‌it‌‌is‌‌sent‌‌to‌‌the‌‌competent‌‌Health‌‌Authorities,‌‌as‌‌well‌‌as‌‌to‌‌the‌‌Clinical‌‌
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
Research‌ ‌Ethics‌ ‌Committees.‌ ‌ 
‌ 
The‌ ‌sponsor‌ ‌will‌ ‌notify‌ ‌the‌ ‌Clinical‌ ‌Research‌ ‌Ethics‌ ‌Committee‌ ‌and‌ ‌the‌ ‌competent‌ ‌health‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
authorities‌ ‌of‌ ‌any‌ ‌new‌ ‌significant‌ ‌risk‌ ‌to‌ ‌patients‌ ‌as‌ ‌necessary.‌ ‌ 
‌ 
The‌‌study‌‌sponsor‌‌is‌‌responsible‌‌for‌‌reporting‌‌all‌‌suspected‌‌serious‌‌adverse‌‌drug‌‌reactions‌‌(SARs)‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
that‌‌occur‌‌in‌‌subjects‌‌exposed‌‌to‌‌the‌‌cetuximab‌‌product‌‌to‌‌the‌‌Merck‌‌safety‌‌representative‌‌in‌‌Spain‌‌
 
 
 
 
 
 
 
 
   
 
 
 
   
 
on‌‌a‌‌regular‌‌basis‌‌(at‌‌least‌‌6‌‌months‌‌apart).‌‌).‌‌Merck‌‌may‌‌request‌‌tracking‌‌information‌‌from‌‌the‌
   
 
 
 
   
 
   
 
 
 
 
 
 
 
developer.‌ ‌ 
‌ 
All‌‌serious‌‌adverse‌‌reactions‌‌associated‌‌or‌‌possibly‌‌associated‌‌with‌‌cetuximab‌‌and‌‌their‌‌follow-up‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
reports‌‌should‌‌be‌‌sent‌‌to‌‌the‌‌Merck‌‌safety‌‌representative‌‌in‌‌Spain‌‌at‌‌the‌‌same‌‌time‌‌as‌‌they‌‌are‌‌sent‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
to‌‌the‌‌regulatory‌‌body,‌‌the‌‌IRC‌‌or‌‌the‌‌CEIC.‌‌Within‌‌24‌‌hours‌‌of‌‌such‌‌shipment,‌‌a‌‌copy‌‌of‌‌any‌‌safety‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
notification‌‌concerning‌‌the‌‌drug‌‌cetuximab‌‌must‌‌be‌‌faxed‌‌to‌‌the‌‌regulatory‌‌body,‌‌CRI‌‌or‌‌CEIC.‌‌The‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
sponsor‌‌will‌‌be‌‌responsible‌‌for‌‌ensuring‌‌that‌‌the‌‌latest‌‌investigator's‌‌manual‌‌and‌‌technical‌‌sheet‌‌are‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
used‌ ‌as‌ ‌the‌ ‌source‌ ‌document‌ ‌to‌ ‌determine‌ ‌the‌ ‌expected‌ ‌results‌ ‌of‌ ‌an‌ ‌SAE.‌ ‌ 
‌ 
‌
 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
58‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
10.‌ ‌STATISTICAL‌ ‌CONSIDERATIONS‌ ‌
 
10.1‌ ‌Study‌ ‌design‌
‌
 
Prospective,‌ ‌multicenter,‌ ‌phase‌ ‌II‌ ‌clinical‌ ‌trial‌ ‌designed‌ ‌for‌ ‌the‌ ‌evaluation‌ ‌of‌ ‌predictive‌ ‌tumor‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarkers‌‌in‌‌patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌and‌‌non-mutated‌‌KRAS‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
tumor‌ ‌treated‌ ‌with‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌treatment.‌ ‌ 
‌ 
The‌‌main‌‌objective‌‌of‌‌this‌‌study‌‌is‌‌the‌‌validation‌‌of‌‌the‌‌biomarkers‌‌BRAF,‌‌IGF1P‌‌/‌‌MMp7‌‌(DP)‌‌
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
and‌‌PI3K-PTEN‌‌to‌‌predict‌‌PFS‌‌in‌‌patients‌‌with‌‌advanced‌‌and‌‌/‌‌or‌‌metastatic‌‌colorectal‌‌cancer‌‌with‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
non-mutated‌ ‌KRAS‌ ‌treated‌ ‌with‌ ‌standard‌ ‌chemotherapy‌ ‌plus‌ ‌biweekly‌ ‌cetuximab‌ ‌as‌ ‌first‌ ‌line‌‌
 
 
 
 
 
 
 
 
 
 
 
 
therapy.‌ ‌ 
‌ 
The‌ ‌primary‌ ‌endpoint‌ ‌and‌ ‌secondary‌ ‌efficacy‌ ‌endpoint‌ ‌analysis‌ ‌will‌ ‌be‌ ‌based‌ ‌on‌ ‌the‌ ‌revised‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RECIST‌ ‌1.1‌ ‌criteria‌ ‌(Appendix‌ ‌E)‌ ‌for‌ ‌the‌ ‌intention-to-treat‌ ‌analysis‌ ‌group.‌ ‌ 
‌ 
10.2.‌ ‌Study‌ ‌variables,‌ ‌subgroups‌ ‌and‌ ‌covariates‌ ‌
 
‌ 
10.2.1‌ ‌Principal‌ ‌endpoint‌ ‌ 
‌ 
The‌ ‌primary‌‌endpoint‌‌is‌‌progression-free‌‌survival‌‌comparing‌‌two‌‌cohorts,‌‌which‌‌will‌‌be‌‌defined‌‌
 
 
   
 
 
 
 
 
 
 
 
 
according‌ ‌to‌ ‌the‌ ‌classification‌ ‌based‌ ‌on‌ ‌the‌ ‌predictive‌ ‌ability‌ ‌of‌ ‌biomarkers‌ ‌to‌ ‌respond.‌ ‌ 
‌ 
Progression-free‌ ‌survival‌ ‌time‌ ‌(PFS):‌ ‌time‌‌from‌‌the‌‌date‌‌of‌‌inclusion‌‌to‌‌the‌‌date‌‌of‌‌radiological‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression‌‌or‌‌death‌‌(whichever‌‌occurs‌‌first).‌‌Subjects‌‌who‌‌have‌‌not‌‌exhibited‌‌progression‌‌while‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
the‌‌study‌‌and‌‌have‌‌not‌‌died‌‌while‌‌in‌‌the‌‌study‌‌will‌‌be‌‌censored‌‌on‌‌the‌‌last‌‌radiological‌‌evaluation‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
date‌ ‌with‌ ‌no‌ ‌evidence‌ ‌of‌ ‌progression.‌ ‌Subjects‌ ‌who‌ ‌have‌ ‌completed‌ ‌study‌ ‌treatment‌ ‌before‌ ‌48‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
weeks‌‌for‌‌any‌‌reason‌‌should‌‌be‌‌followed‌‌up‌‌every‌‌12‌‌weeks‌‌as‌‌described‌‌in‌‌this‌‌protocol.‌‌Subjects‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
who‌‌have‌‌undergone‌‌surgery‌‌for‌‌metastases‌‌will‌‌not‌‌be‌‌censored‌‌on‌‌the‌‌date‌‌of‌‌surgery,‌‌but‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
followed‌ ‌as‌ ‌described‌ ‌in‌ ‌the‌ ‌study‌ ‌every‌ ‌12‌ ‌weeks‌ ‌until‌ ‌progression‌ ‌is‌ ‌documented.‌ ‌Subjects‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
receiving‌ ‌second-line‌ ‌treatment‌‌without‌‌documented‌‌disease‌‌progression‌‌will‌‌be‌‌censored‌‌on‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
date‌‌of‌‌the‌‌last‌‌radiological‌‌evaluation‌‌without‌‌progression‌‌prior‌‌to‌‌the‌‌change‌‌in‌‌treatment.‌‌If‌‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
any‌‌reason‌‌only‌‌the‌‌baseline‌‌CT‌‌was‌‌performed‌‌(resignation‌‌of‌‌the‌‌subject‌‌to‌‌continue‌‌in‌‌the‌‌study‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
or‌ ‌loss‌ ‌of‌ ‌follow-up),‌ ‌the‌ ‌case‌ ‌will‌ ‌be‌ ‌censored‌ ‌on‌ ‌day‌ ‌+1‌ ‌of‌ ‌the‌ ‌inclusion‌ ‌date.‌‌ ‌
  
‌ 
10.2.2‌ ‌Secondary‌ ‌endpoints‌ ‌ 
‌ 
Objective‌ ‌response‌ ‌rate‌ ‌(ORR):‌ ‌incidence‌ ‌of‌ ‌a‌ ‌CR‌ ‌or‌ ‌PR‌‌according‌‌to‌‌the‌‌revised‌‌RECIST‌‌1.1‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
criteria.‌ ‌ 
‌ 
Duration‌‌of‌‌response‌‌(RD):‌‌(calculated‌‌only‌‌for‌‌subjects‌‌having‌‌an‌‌objective‌‌response)‌‌time‌‌from‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
first‌‌objective‌‌response‌‌to‌‌progression‌‌of‌‌radiological‌‌disease‌‌according‌‌to‌‌the‌‌revised‌‌RECIST‌‌1.1‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
criteria.‌ ‌For‌ ‌subjects‌ ‌who‌ ‌present‌ ‌a‌ ‌response‌ ‌and‌ ‌have‌ ‌not‌ ‌had‌ ‌progression,‌‌the‌‌duration‌‌of‌‌the‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
response‌ ‌will‌ ‌be‌ ‌censored‌ ‌on‌ ‌the‌ ‌last‌ ‌assessment‌ ‌date‌ ‌of‌ ‌the‌ ‌evaluable‌ ‌disease.‌ ‌ 
‌ 
Overall‌‌survival‌‌(OS):‌‌Time‌‌elapsed‌‌from‌‌the‌‌date‌‌of‌‌inclusion‌‌to‌‌the‌‌date‌‌of‌‌death.‌‌For‌‌subjects‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
who‌‌have‌‌not‌‌died‌‌or‌‌who‌‌have‌‌been‌‌lost‌‌to‌‌follow-up‌‌by‌‌the‌‌data‌‌analysis‌‌cut-off‌‌date,‌‌the‌‌SG‌‌will‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
be‌ ‌censored‌ ‌on‌ ‌the‌ ‌date‌ ‌of‌ ‌the‌ ‌last‌ ‌contact.‌ ‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
59‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Safety:‌ ‌Type,‌ ‌frequency,‌ ‌intensity‌ ‌of‌ ‌adverse‌ ‌events‌ ‌related‌ ‌to‌ ‌the‌ ‌combination‌ ‌treatment.‌ ‌ 
‌ 
10.2.3‌ ‌Subgroup‌ ‌analysis‌ ‌ 
‌ 
The‌ ‌intention-to-treat‌ ‌(ITT)‌ ‌analysis‌ ‌group‌ ‌is‌ ‌defined‌ ‌as‌ ‌all‌ ‌subjects‌ ‌who‌ ‌signed‌ ‌the‌ ‌informed‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
consent‌‌and‌‌who‌‌have‌‌received‌‌the‌‌trial‌‌treatment,‌‌regardless‌‌of‌‌whether‌‌they‌‌actually‌‌receive‌‌any‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
dose‌ ‌of‌ ‌the‌ ‌study‌ ‌treatment.‌ ‌Efficacy‌ ‌presentations‌ ‌will‌ ‌be‌ ‌made‌ ‌to‌ ‌the‌ ‌ITT‌ ‌review‌ ‌group.‌ ‌ 
A‌ ‌secondary‌ ‌analysis‌ ‌group‌ ‌(analysis‌ ‌group‌ ‌per‌ ‌protocol)‌ ‌will‌ ‌be‌ ‌used‌ ‌to‌ ‌evaluate‌ ‌the‌ ‌efficacy‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
variables‌‌in‌‌all‌‌subjects‌‌who‌‌signed‌‌the‌‌informed‌‌consent‌‌and‌‌were‌‌included‌‌in‌‌the‌‌study‌‌and‌‌who‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
did‌ ‌not‌ ‌present‌ ‌significant‌ ‌deviations‌ ‌from‌ ‌the‌ ‌protocol.‌ ‌ 
‌ 
10.2.4‌ ‌Covariates‌ ‌ 
‌ 
Efficacy‌ ‌variables‌ ‌can‌ ‌be‌ ‌explored‌ ‌within‌ ‌the‌ ‌following‌ ‌subgroups:‌ ‌ 
Sex‌ ‌ 
Age‌ ‌ 
ECOG‌ ‌performance‌ ‌status‌ ‌ 
Location‌ ‌of‌ ‌the‌ ‌primary‌ ‌tumor‌ ‌(colon‌ ‌versus‌ ‌rectum)‌ ‌ 
Number‌ ‌of‌ ‌sites‌ ‌of‌ ‌metastatic‌ ‌disease‌ ‌(1‌ ‌vs>‌ ‌1‌ ‌affected‌ ‌organ)‌ ‌ 
Baseline‌ ‌LDH‌ ‌concentration‌ ‌ 
Previous‌ ‌adjuvant‌ ‌chemotherapy‌ ‌(yes‌ ‌or‌ ‌no)‌ ‌ 
The‌‌rest‌‌of‌‌the‌‌subgroup‌‌analyzes‌‌that‌‌are‌‌carried‌‌out‌‌later,‌‌if‌‌they‌‌are‌‌carried‌‌out,‌‌must‌‌be‌‌notified‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
as‌ ‌such,‌ ‌and‌ ‌the‌ ‌clinical‌ ‌report‌ ‌of‌ ‌the‌ ‌study‌ ‌must‌ ‌state‌ ‌the‌ ‌reason‌ ‌for‌ ‌said‌ ‌analyzes.‌ ‌ 
‌ 
10.2.5‌ ‌Considerations‌ ‌about‌ ‌the‌ ‌sample‌ ‌size‌ ‌ 
‌ 
Two‌‌groups‌‌will‌‌be‌‌defined‌‌based‌‌on‌‌the‌‌classification‌‌constructed‌‌from‌‌the‌‌clinical‌‌variables‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌proposed‌ ‌biomarkers.‌ ‌ 
‌ 
The‌ ‌Log-rank‌ ‌method‌‌has‌‌been‌‌used‌‌instead‌‌of‌‌a‌‌binomial‌‌method‌‌for‌‌the‌‌sample‌‌calculation‌‌in‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
order‌ ‌to‌ ‌include‌ ‌all‌ ‌the‌ ‌events‌ ‌that‌ ‌occur‌ ‌during‌ ‌follow-up.‌ ‌ 
‌ 
A‌‌minimum‌‌difference‌‌of‌‌20%‌‌(60‌‌vs.‌‌40%)‌‌in‌‌PFS‌‌is‌‌expected‌‌at‌‌12‌‌months‌‌between‌‌groups‌‌and‌
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
with‌ ‌the‌ ‌following‌ ‌assumptions:‌ ‌ 
‌ 
Alpha‌ ‌error‌ ‌(bilateral):‌ ‌5%‌ ‌ 
Beta‌ ‌error:‌ ‌20%‌ ‌ 
Monthly‌ ‌recruitment:‌ ‌8‌ ‌patients‌ ‌ 
Percentage‌ ‌of‌ ‌patients‌ ‌with‌ ‌classification‌ ‌=‌ ‌0‌ ‌is‌ ‌40%‌ 
‌ 
The‌‌number‌‌of‌‌patients‌‌required‌‌is‌‌155‌‌patients‌‌to‌‌be‌‌recruited‌‌in‌‌24‌‌months‌‌and‌‌a‌‌total‌‌duration‌‌of‌‌
 
 
 
 
   
 
 
 
 
   
 
 
   
 
 
 
the‌ ‌trial‌ ‌(recruitment‌ ‌+‌ ‌follow-up)‌ ‌of‌ ‌28‌ ‌months‌ ‌for‌ ‌115‌ ‌events‌ ‌to‌ ‌occur.‌ ‌ 
‌ 
Assuming‌ ‌10%‌ ‌non-evaluable‌ ‌pts‌ ‌we‌ ‌should‌ ‌include‌ ‌a‌ ‌total‌ ‌of‌ ‌170‌ ‌pts.‌ ‌ 
‌ 
10.3‌ ‌General‌ ‌considerations‌ ‌
 
‌ 
The‌ ‌primary‌ ‌endpoint‌ ‌and‌ ‌secondary‌‌efficacy‌‌endpoints‌‌will‌‌be‌‌analyzed‌‌using‌‌the‌‌ITT‌‌analysis‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
group‌ ‌and‌ ‌the‌ ‌per-protocol‌ ‌analysis‌ ‌group.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
60‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
‌ 
Efficacy‌‌analyzes‌‌will‌‌be‌‌based‌‌on‌‌radiographic‌‌images‌‌collected‌‌during‌‌the‌‌study‌‌and‌‌analyzed‌‌by‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌investigator.‌‌Any‌‌examination‌‌that‌‌the‌‌investigator‌‌classifies‌‌as‌‌not‌‌evaluable‌‌will‌‌be‌‌omitted‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
from‌ ‌the‌ ‌analysis‌ ‌(it‌ ‌will‌ ‌be‌ ‌considered‌ ‌as‌ ‌no‌ ‌examination).‌ ‌ 
‌ 
For‌‌continuous‌‌variables,‌‌the‌‌mean,‌‌standard‌‌error‌‌(for‌‌efficacy‌‌variables)‌‌or‌‌standard‌‌deviation‌‌(for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
other‌ ‌measurements),‌ ‌median,‌ ‌25th‌ ‌percentile,‌ ‌75th‌ ‌percentile,‌‌minimum,‌‌and‌‌maximum‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
provided.‌‌For‌‌discontinuous‌‌data,‌‌the‌‌frequency‌‌and‌‌percentage‌‌distributions‌‌will‌‌be‌‌provided.‌‌The‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
two-sided‌ ‌95%‌ ‌confidence‌ ‌intervals‌ ‌of‌ ‌the‌ ‌Kaplan-Meier‌ ‌quartiles‌ ‌will‌ ‌be‌ ‌calculated‌ ‌using‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
methods‌‌described‌‌by‌‌Brookmeyer‌‌and‌‌Crowley‌‌(Brookmeyer,‌‌1982).‌‌Two-sided‌‌95%‌‌confidence‌‌
 
 
 
 
 
 
 
 
 
 
 
intervals‌ ‌for‌ ‌the‌ ‌Kaplan-Meier‌‌rates‌‌at‌‌specific‌‌time‌‌points‌‌will‌‌be‌‌calculated‌‌using‌‌the‌‌methods‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
described‌ ‌by‌ ‌Collett‌ ‌(Collett,‌ ‌1992).‌ ‌ 
Safety‌ ‌data‌ ‌will‌ ‌be‌ ‌analyzed‌ ‌throughout‌ ‌the‌ ‌study.‌ ‌ 
‌ 
10.4‌ ‌Analysis‌ ‌of‌ ‌the‌ ‌main‌ ‌variables‌ ‌of‌ ‌the‌ ‌study‌ ‌
 
The‌‌Cox‌‌regression‌‌analysis‌‌will‌‌be‌‌performed‌‌with‌‌the‌‌experimental‌‌biomarkers‌‌and‌‌the‌‌following‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prognostic‌ ‌variables‌ ‌(LDH,‌ ‌functional‌ ‌status,‌ ‌age,‌ ‌limited‌ ‌resectable‌ ‌disease‌ ‌(<3‌ ‌nodules‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
<5cm).‌ ‌A‌ ‌classification‌ ‌will‌ ‌be‌ ‌performed‌ ‌using‌ ‌the‌ ‌most‌ ‌discriminatory‌ ‌variables.‌ ‌The‌‌
 
 
 
 
 
 
 
 
 
 
 
 
classification‌‌It‌‌will‌‌be‌‌carried‌‌out‌‌with‌‌all‌‌the‌‌clinical‌‌variables‌‌of‌‌impact‌‌in‌‌the‌‌univariate‌‌analysis,‌‌
   
 
 
 
 
 
 
 
 
 
 
   
 
 
 
including‌ ‌the‌ ‌4‌ ‌clinical‌ ‌variables‌ ‌(LDH,‌ ‌functional‌ ‌status,‌ ‌age,‌ ‌limited‌ ‌resectable‌ ‌disease‌ ‌(<3‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
nodules‌‌and‌‌<5‌‌cm)‌‌and‌‌the‌‌3‌‌pathways‌‌previously‌‌described‌‌(BRAF,‌‌DP‌‌and‌‌PTEN).‌‌-PI3K)‌‌The‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
classification‌ ‌will‌ ‌be‌ ‌carried‌ ‌out‌ ‌with‌ ‌the‌ ‌variables‌ ‌with‌ ‌the‌ ‌greatest‌ ‌impact‌ ‌in‌‌the‌‌multivariate‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
analysis.‌ ‌ 
The‌ ‌proposed‌ ‌sample‌ ‌size‌ ‌ensures‌ ‌the‌ ‌construction‌ ‌of‌ ‌a‌ ‌consistent‌ ‌multivariate‌ ‌analysis.‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
61‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
11.‌ ‌ETHICAL‌ ‌AND‌ ‌LEGAL‌ ‌CONSIDERATIONS‌ ‌
 
11.1‌ ‌Ethics‌ ‌Committee‌ ‌
 
The‌ ‌study‌ ‌will‌ ‌be‌ ‌carried‌ ‌out‌ ‌in‌ ‌accordance‌ ‌with‌ ‌the‌ ‌principles‌ ‌of‌ ‌the‌ ‌Declaration‌ ‌of‌ ‌Helsinki‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adopted‌ ‌by‌ ‌the‌ ‌18th‌ ‌World‌ ‌Medical‌ ‌Assembly,‌ ‌Helsinki,‌ ‌Finland,‌ ‌June‌ ‌1964‌ ‌and‌ ‌amended‌ ‌by‌ ‌the‌ ‌ 
29th‌ ‌World‌ ‌Medical‌ ‌Assembly,‌ ‌Tokyo,‌ ‌Japan,‌ ‌October‌ ‌1975,‌ ‌35th‌ ‌World‌ ‌Medical‌ ‌Assembly,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
Venice,‌ ‌Italy,‌ ‌October‌ ‌1983,‌ ‌41st‌ ‌World‌ ‌Medical‌ ‌Assembly,‌ ‌Hong‌ ‌Kong,‌‌September‌‌1989,‌‌48th‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
General‌‌Assembly‌‌Somerset‌‌West,‌‌South‌‌Africa,‌‌October‌‌1996,‌‌52nd‌‌General‌‌Assembly,‌‌Edinburgh‌‌
 
 
 
 
 
 
 
 
 
 
 
 
,‌ ‌Scotland,‌ ‌October‌ ‌2000,‌ ‌Paragraph‌ ‌29‌ ‌Clarification‌ ‌Note,‌ ‌added‌ ‌by‌‌WMA‌‌General‌‌Assembly,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Washington‌ ‌2002,‌ ‌Paragraph‌ ‌30‌ ‌Clarification‌ ‌Note,‌ ‌added‌ ‌by‌ ‌WMA‌ ‌General‌ ‌Assembly,‌ ‌Tokyo‌‌
 
 
 
 
 
 
 
 
 
 
 
 
2004,‌‌59th‌‌General‌‌Assembly,‌‌Seoul,‌‌Korea,‌‌October‌‌2008‌‌(Annex‌‌XIII)‌‌and‌‌with‌‌the‌‌standards‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Good‌‌Clinical‌‌Practice‌‌(GCP)‌‌issued‌‌by‌‌the‌‌working‌‌group‌‌on‌‌Efficacy‌‌of‌‌Medicinal‌‌Substances‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌European‌‌Economic‌‌Community‌‌(1990)‌‌(CPMP‌‌/‌‌ICH‌‌/‌‌135/95)‌‌and‌‌the‌‌Laws‌‌and‌‌Regulations‌‌
 
 
 
 
 
   
   
 
 
 
 
 
 
in‌ ‌force‌ ‌in‌ ‌Spain.‌ ‌ 
The‌‌Oviedo‌‌Convention‌‌of‌‌April‌‌4,‌‌1997‌‌on‌‌human‌‌rights‌‌and‌‌biomedicine,‌‌ratified‌‌in‌‌the‌‌BOE‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
October‌ ‌1999.‌ ‌ 
In‌ ‌the‌ ‌regulations‌ ‌for‌ ‌the‌ ‌adequate‌ ‌protection‌ ‌of‌ ‌personal‌ ‌data,‌ ‌according‌ ‌to‌ ‌the‌ ‌provisions‌ ‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Organic‌ ‌Law‌ ‌15/1999‌ ‌on‌ ‌the‌ ‌protection‌ ‌of‌ ‌Personal‌ ‌Data.‌ 
The‌‌rights‌‌and‌‌obligations‌‌regarding‌‌information‌‌and‌‌clinical‌‌documentation,‌‌in‌‌accordance‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
   
 
 
 
provisions‌ ‌of‌ ‌Law‌ ‌41/2002,‌ ‌of‌ ‌November‌ ‌14,‌ ‌basic‌ ‌regulating‌ ‌the‌ ‌autonomy‌ ‌of‌ ‌the‌ ‌patient.‌ ‌ 
The‌ ‌General‌ ‌Assembly‌ ‌Somerset‌ ‌West,‌ ‌South‌ ‌Africa,‌ ‌October‌ ‌1996‌ ‌and‌ ‌the‌ ‌General‌ ‌Assembly‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Edinburgh,‌ ‌Scotland,‌ ‌October‌ ‌2000.‌ ‌ 
Law‌ ‌14/2007,‌ ‌of‌ ‌July‌ ‌3,‌ ‌on‌ ‌Biomedical‌ ‌Research.‌ ‌ 
The‌‌researcher‌‌will‌‌be‌‌responsible‌‌for‌‌preparing‌‌the‌‌documents‌‌to‌‌send‌‌them‌‌to‌‌the‌‌corresponding‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethics‌‌Committee‌‌(CEIC)‌‌and‌‌obtain‌‌written‌‌approval‌‌for‌‌the‌‌study.‌‌Approval‌‌will‌‌be‌‌obtained‌‌prior‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to‌ ‌the‌ ‌start‌ ‌of‌ ‌the‌ ‌study.‌ ‌ 
Approval‌‌for‌‌both‌‌the‌‌protocol‌‌and‌‌informed‌‌consent‌‌must‌‌specify‌‌the‌‌approval‌‌date,‌‌the‌‌protocol‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌version‌ ‌number,‌ ‌or‌ ‌the‌ ‌amendment‌ ‌number.‌ ‌ 
Any‌‌amendment‌‌to‌‌the‌‌protocol‌‌after‌‌receiving‌‌approval‌‌from‌‌the‌‌Ethics‌‌Committee‌‌must‌‌be‌‌sent‌‌by‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌researcher‌ ‌to‌ ‌the‌ ‌Ethics‌ ‌Committee‌ ‌for‌ ‌approval.‌ ‌The‌ ‌investigator‌ ‌is‌ ‌also‌ ‌responsible‌ ‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
notifying‌‌the‌‌ethics‌‌committee‌‌of‌‌any‌‌serious‌‌deviation‌‌from‌‌the‌‌protocol,‌‌or‌‌any‌‌other‌‌matter‌‌that‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
implies‌ ‌an‌ ‌added‌ ‌risk‌ ‌for‌ ‌patients.‌ ‌ 
Any‌ ‌advertisement‌ ‌used‌ ‌to‌ ‌recruit‌ ‌patients‌‌for‌‌the‌‌study‌‌must‌‌be‌‌reviewed‌‌and‌‌approved‌‌by‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor‌ ‌and‌ ‌the‌ ‌ethics‌ ‌committee‌ ‌before‌ ‌use.‌ ‌
 
11.2‌ ‌Authorities‌ ‌
 
The‌‌study‌‌protocol‌‌and‌‌/‌‌or‌‌documents‌‌inherent‌‌to‌‌it‌‌will‌‌be‌‌sent‌‌to‌‌you‌‌before‌‌starting‌‌the‌‌trial,‌‌as‌‌
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
established‌ ‌by‌ ‌the‌ ‌national‌ ‌authorities.‌‌ ‌
  
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
62‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
11.3‌ ‌Protocol‌ ‌Modifications/Deviations‌ ‌
 
  ‌11.3.1‌ ‌Protocol‌ ‌Modifications‌ ‌ 
Protocol‌‌amendments,‌‌unless‌‌necessary‌‌to‌‌eliminate‌‌an‌‌immediate‌‌hazard‌‌to‌‌subjects,‌‌should‌‌only‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
be‌ ‌made‌ ‌with‌ ‌the‌ ‌prior‌‌approval‌‌of‌‌the‌‌sponsor.‌‌Investigator‌‌consensus‌‌must‌‌be‌‌obtained‌‌for‌‌all‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
amendments‌‌made‌‌to‌‌the‌‌protocol‌‌and‌‌informed‌‌consent‌‌document.‌‌The‌‌CEIC‌‌and,‌‌if‌‌applicable,‌‌the‌‌
 
   
 
 
 
 
 
 
 
 
   
 
 
AEMPS,‌ ‌must‌ ‌be‌ ‌informed‌ ‌of‌‌all‌‌the‌‌amendments‌‌and‌‌give‌‌their‌‌approval.‌‌The‌‌researcher‌‌must‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
send‌ ‌a‌ ‌copy‌ ‌of‌ ‌the‌ ‌CEIC‌ ‌approval‌ ‌letter‌ ‌to‌ ‌the‌ ‌sponsor.‌ ‌ 
Both‌‌the‌‌sponsor‌‌and‌‌the‌‌researcher‌‌reserve‌‌the‌‌right‌‌to‌‌interrupt‌‌the‌‌study,‌‌as‌‌established‌‌in‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌ ‌contract.‌ ‌The‌ ‌investigator‌ ‌must‌ ‌notify‌‌the‌‌CEIC‌‌of‌‌the‌‌completion‌‌of‌‌the‌‌study‌‌in‌‌writing‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
when‌ ‌the‌ ‌study‌ ‌has‌ ‌been‌ ‌completed‌ ‌or‌ ‌prematurely‌ ‌interrupted,‌ ‌and‌ ‌must‌ ‌send‌ ‌a‌ ‌copy‌ ‌of‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
notification‌ ‌to‌ ‌the‌ ‌sponsor.‌ ‌ 
‌ 
Subjects‌‌may‌‌be‌‌eligible‌‌to‌‌continue‌‌treatment‌‌with‌‌the‌‌investigational‌‌product‌‌by‌‌extension‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
protocol‌ ‌or‌ ‌as‌ ‌provided‌ ‌by‌ ‌the‌ ‌national‌ ‌regulatory‌ ‌mechanism.‌ ‌ 
Any‌‌modification‌‌to‌‌this‌‌protocol‌‌must‌‌be‌‌agreed‌‌by‌‌the‌‌principal‌‌investigator‌‌and‌‌reviewed‌‌by‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor.‌‌The‌‌written‌‌approval‌‌of‌‌the‌‌Ethics‌‌Committee‌‌and,‌‌if‌‌applicable,‌‌of‌‌the‌‌AEMPS‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
obtained‌ ‌before‌ ‌any‌ ‌modification‌ ‌is‌ ‌implemented.‌ ‌ 
 ‌11.3.2‌ ‌Protocol‌ ‌deviations‌ ‌ 
When‌‌an‌‌emergency‌‌occurs‌‌that‌‌requires‌‌a‌‌protocol‌‌deviation‌‌for‌‌a‌‌patient,‌‌the‌‌deviation‌‌will‌‌be‌‌
 
 
 
 
 
   
 
 
   
 
 
 
 
 
performed‌‌for‌‌that‌‌patient‌‌only.‌‌A‌‌decision‌‌will‌‌be‌‌made‌‌as‌‌soon‌‌as‌‌it‌‌is‌‌determined‌‌whether‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
patient‌‌(for‌‌whom‌‌the‌‌protocol‌‌deviation‌‌has‌‌been‌‌made)‌‌is‌‌to‌‌continue‌‌in‌‌the‌‌study.‌‌The‌‌patient's‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
medical‌‌records‌‌will‌‌fully‌‌describe‌‌the‌‌deviation‌‌from‌‌the‌‌protocol‌‌and‌‌will‌‌state‌‌the‌‌reasons‌‌for‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
deviation.‌‌In‌‌addition,‌‌the‌‌researcher‌‌will‌‌notify‌‌the‌‌Sponsor‌‌in‌‌writing‌‌of‌‌said‌‌deviation‌‌from‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
protocol.‌ ‌ 
Once‌‌the‌‌deviation‌‌has‌‌been‌‌evaluated,‌‌if‌‌it‌‌complies‌‌with‌‌the‌‌stipulations‌‌of‌‌the‌‌local‌‌regulations‌‌to‌‌
 
 
 
 
 
     
 
 
 
 
 
 
 
   
be‌ ‌communicated,‌ ‌the‌ ‌sponsor‌ ‌will‌ ‌notify‌ ‌CEICs‌ ‌and‌ ‌AEMPS.‌ ‌ 
Minor‌‌deviations‌‌from‌‌the‌‌protocol‌‌that‌‌are‌‌not‌‌derived‌‌from‌‌an‌‌emergency‌‌will‌‌be‌‌allowed‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sponsor's‌ ‌approval‌ ‌and‌ ‌should‌ ‌not‌ ‌be‌ ‌communicated‌ ‌to‌ ‌CEICs‌ ‌and‌ ‌AEMPS.‌ ‌ 
‌
 
11.4‌ ‌Informed‌ ‌consent‌ ‌
 
The‌‌investigator‌‌must‌‌obtain‌‌the‌‌informed‌‌consent‌‌of‌‌a‌‌patient,‌‌or‌‌their‌‌legal‌‌representative,‌‌before‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
any‌‌procedure‌‌related‌‌to‌‌the‌‌study‌‌in‌‌accordance‌‌with‌‌Good‌‌Clinical‌‌Practice‌‌(GCP)‌‌as‌‌established‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in‌ ‌the‌ ‌CFR‌ ‌and‌ ‌ICH‌ ‌guidelines.‌ ‌ 
Documentation‌ ‌that‌ ‌informed‌ ‌consent‌ ‌was‌ ‌obtained‌ ‌prior‌ ‌to‌ ‌patient‌ ‌entry‌ ‌into‌ ‌the‌ ‌study‌ ‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
informed‌ ‌consent‌ ‌process‌ ‌should‌ ‌be‌ ‌recorded‌ ‌in‌ ‌the‌ ‌original‌ ‌patient‌ ‌documents.‌ ‌The‌ ‌original‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
consent‌ ‌form,‌‌signed‌‌and‌‌dated‌‌by‌‌the‌‌patient‌‌and‌‌by‌‌the‌‌person‌‌conducting‌‌the‌‌consent‌‌process‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prior‌ ‌to‌ ‌the‌ ‌patient's‌ ‌entry‌ ‌into‌ ‌the‌ ‌study‌ ‌must‌ ‌be‌ ‌kept‌ ‌in‌ ‌the‌ ‌investigator's‌ ‌study‌ ‌files.‌ ‌ 
In‌‌order‌‌to‌‌mobilize‌‌any‌‌biological‌‌sample,‌‌the‌‌signing‌‌of‌‌the‌‌previously‌‌informed‌‌consent‌‌will‌‌be‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mandatory.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
63‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
11.5‌ ‌Confidentiality‌ ‌
 
In‌‌order‌‌to‌‌guarantee‌‌the‌‌confidentiality‌‌of‌‌the‌‌test‌‌data‌‌according‌‌to‌‌the‌‌provisions‌‌of‌‌Organic‌‌Law‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
15/1999‌‌on‌‌the‌‌protection‌‌of‌‌Personal‌‌Data,‌‌only‌‌the‌‌Test‌‌sponsor‌‌or‌‌personnel‌‌designated‌‌by‌‌him‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will‌‌have‌‌access‌‌to‌‌them‌‌for‌‌monitoring‌‌tasks.‌‌/‌‌audit,‌‌the‌‌researcher‌‌and‌‌his‌‌team‌‌of‌‌collaborators,‌‌
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
the‌‌Clinical‌‌Research‌‌Ethics‌‌Committee‌‌of‌‌the‌‌corresponding‌‌center‌‌or‌‌the‌‌one‌‌supervising‌‌the‌‌trial‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and‌ ‌the‌ ‌relevant‌ ‌health‌ ‌authorities.‌ ‌ 
In‌‌the‌‌aforementioned‌‌case‌‌of‌‌Monitoring‌‌/‌‌Audits,‌‌the‌‌researcher‌‌must‌‌provide‌‌direct‌‌access‌‌to‌‌the‌‌
 
 
 
 
 
   
 
 
 
 
 
 
   
 
source‌ ‌documents‌ ‌and‌ ‌data.‌ ‌ 
The‌‌content‌‌of‌‌the‌‌data‌‌collection‌‌notebooks‌‌(CRD)‌‌as‌‌well‌‌as‌‌the‌‌documents‌‌generated‌‌during‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌‌will‌‌be‌‌protected‌‌from‌‌unauthorized‌‌uses‌‌by‌‌people‌‌outside‌‌the‌‌investigation‌‌and,‌‌therefore,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will‌ ‌be‌ ‌considered‌ ‌strictly‌ ‌confidential‌ ‌and‌ ‌will‌ ‌not‌ ‌be‌ ‌disclosed‌ ‌to‌ ‌third‌ ‌parties‌ ‌except‌ ‌to‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specified‌ ‌in‌ ‌the‌ ‌previous‌ ‌section.‌ 
11.6‌ ‌Insurance‌ ‌
 
All‌‌patients‌‌in‌‌this‌‌clinical‌‌study‌‌are‌‌insured‌‌through‌‌the‌‌HDI‌‌Insurance‌‌Company‌,‌‌which‌‌meets‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
conditions‌ ‌stipulated‌ ‌by‌ ‌R.D.‌ ‌223/2004.‌ ‌ 
‌
 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
64‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
12.‌ ‌PRACTICAL‌ ‌CONSIDERATIONS‌‌ ‌
  
12.1‌ ‌Investigational‌ ‌medicinal‌ ‌product‌ ‌
 
TAll‌ ‌drugs‌ ‌indicated‌ ‌by‌ ‌the‌ ‌protocol‌ ‌of‌ ‌this‌ ‌study,‌ ‌combination‌ ‌FOLFOX-6‌ ‌(m),‌ ‌combination‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFIRI‌ ‌(m)‌ ‌and‌ ‌cetuximab‌ ‌are‌ ‌commercially‌ ‌available.‌ ‌These‌ ‌drugs‌ ‌will‌ ‌be‌ ‌formulated,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
packaged,‌‌labeled‌‌and‌‌stored‌‌according‌‌to‌‌the‌‌procedures‌‌indicated‌‌by‌‌the‌‌local‌‌manufacturer,‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
supplier‌ ‌and‌ ‌the‌ ‌center.‌ ‌ 
‌ 
The‌ ‌supply‌ ‌of‌ ‌all‌ ‌the‌ ‌medication‌‌in‌‌the‌‌trial,‌‌being‌‌commercialized‌‌drugs‌‌of‌‌habitual‌‌use‌‌in‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study‌‌pathology,‌‌will‌‌be‌‌carried‌‌out‌‌through‌‌the‌‌usual‌‌channels‌‌of‌‌the‌‌National‌‌Health‌‌System,‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌prior‌ ‌favorable‌ ‌opinion‌ ‌of‌ ‌the‌ ‌CEIC‌ ‌and‌ ‌the‌ ‌approval‌ ‌of‌ ‌the‌ ‌Center's‌ ‌Directorate.‌ ‌ 
‌ 
Compliance‌ ‌with‌ ‌the‌ ‌administration‌ ‌of‌ ‌the‌ ‌treatment‌ ‌under‌ ‌study‌ ‌ 
‌ 
When‌‌an‌‌investigational‌‌product‌‌is‌‌dispensed‌‌for‌‌administration‌‌to‌‌the‌‌subject‌‌during‌‌a‌‌study,‌‌the‌‌
 
 
 
   
 
 
 
 
 
 
   
 
 
investigator‌‌or‌‌responsible‌‌person‌‌will‌‌determine‌‌the‌‌level‌‌of‌‌compliance‌‌with‌‌the‌‌administration‌‌of‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌‌investigational‌‌product.‌‌This‌‌subject‌‌compliance‌‌with‌‌the‌‌investigational‌‌product‌‌(e.g.‌‌amount‌‌
 
 
 
 
 
 
 
 
 
 
 
 
used)‌ ‌will‌ ‌be‌ ‌recorded‌ ‌in‌ ‌the‌ ‌investigational‌ ‌drug‌ ‌administration‌ ‌data‌ ‌collection‌ ‌log.‌ ‌ 
12.2‌ ‌Associated‌ ‌diseases‌ ‌
 
The‌ ‌associated‌ ‌diseases,‌ ‌the‌ ‌corresponding‌ ‌medication‌ ‌and‌ ‌the‌ ‌changes‌ ‌that‌ ‌occurred‌ ‌in‌ ‌these‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
diseases‌ ‌and‌ ‌medications,‌ ‌will‌ ‌be‌ ‌duly‌ ‌noted‌ ‌in‌ ‌the‌ ‌CRD.‌ ‌ 
Illnesses‌ ‌that‌ ‌occur‌ ‌or‌ ‌worsen‌ ‌during‌ ‌this‌ ‌period,‌ ‌intercurrent‌ ‌illnesses,‌ ‌will‌ ‌be‌ ‌considered‌ ‌as‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
adverse‌ ‌events‌ ‌and‌ ‌documented‌ ‌on‌ ‌the‌ ‌page‌ ‌for‌ ‌this‌ ‌purpose‌ ‌in‌ ‌the‌ ‌CRD.‌ ‌ 
12.3.‌ ‌Responsibilities‌ ‌according‌ ‌to‌ ‌Good‌ ‌Clinical‌ ‌Practices‌ ‌
 
12.3.1‌ ‌Investigator‌ ‌responsabilities‌ ‌ 
The‌ ‌responsibilities‌ ‌of‌ ‌the‌ ‌principal‌ ‌investigator‌ ‌in‌ ‌each‌ ‌participating‌ ‌Center‌ ‌will‌ ‌be:‌ ‌ 
1.‌ ‌Sign‌ ‌the‌ ‌essay‌ ‌project.‌ ‌ 
2.‌ ‌Know‌ ‌in‌ ‌depth‌ ‌the‌ ‌properties‌ ‌of‌ ‌drugs.‌ ‌ 
3.‌ ‌Obtain‌ ‌the‌ ‌informed‌ ‌consent‌ ‌of‌ ‌the‌ ‌subjects‌ ‌before‌ ‌their‌ ‌inclusion‌ ‌in‌ ‌the‌ ‌trial.‌ ‌ 
4.‌ ‌Collect,‌ ‌record‌ ‌and‌ ‌report‌ ‌the‌ ‌data‌ ‌correctly.‌ ‌ 
5.‌ ‌Immediately‌ ‌report‌ ‌serious‌ ‌or‌ ‌unexpected‌ ‌adverse‌ ‌events‌ ‌to‌ ‌the‌ ‌sponsor.‌ ‌ 
6.‌‌Ensure‌‌that‌‌all‌‌persons‌‌involved‌‌will‌‌respect‌‌the‌‌confidentiality‌‌of‌‌any‌‌information‌‌about‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌trial‌ ‌subjects.‌ ‌ 
7.‌ ‌Report‌ ‌regularly‌ ‌to‌ ‌the‌‌Ethics‌‌Committee‌‌for‌‌Clinical‌‌Research‌‌on‌‌the‌‌progress‌‌of‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
trial.‌ ‌ 
Take‌‌responsibility‌‌for‌‌the‌‌preparation‌‌of‌‌the‌‌final‌‌test‌‌report,‌‌giving‌‌your‌‌agreement‌‌to‌‌it‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
with‌ ‌your‌ ‌signature.‌ ‌ 
12.3.2‌ ‌CRD‌ ‌cumplimentation‌ ‌rules‌ ‌ 
Data‌ ‌will‌ ‌be‌ ‌recorded‌ ‌in‌ ‌accordance‌ ‌with‌ ‌GCP‌ ‌through‌ ‌the‌ ‌electronic‌ ‌documentation‌ ‌system‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic‌ ‌CRD)‌ ‌at‌ ‌the‌ ‌center.‌ ‌ 
The‌‌application‌‌is‌‌designed‌‌to‌‌function‌‌entirely‌‌over‌‌the‌‌Internet.‌‌All‌‌processing‌‌steps,‌‌except‌‌for‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌actual‌ ‌input‌ ‌and‌ ‌display‌ ‌of‌‌the‌‌data,‌‌are‌‌carried‌‌out‌‌centrally‌‌on‌‌a‌‌web‌‌/‌‌database‌‌server.‌‌In‌‌
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
65‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
particular,‌ ‌data‌ ‌storage‌ ‌will‌ ‌be‌ ‌done‌ ‌only‌ ‌centrally.‌ ‌ 
The‌‌server‌‌is‌‌located‌‌at‌‌the‌‌InterHost‌‌Data‌‌Processing‌‌Center‌‌facilities‌‌in‌‌Madrid,‌‌calle‌‌Albasanz,‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
71.‌ ‌ 
For‌‌data‌‌entry‌‌and‌‌results‌‌printing,‌‌the‌‌system‌‌is‌‌based‌‌on‌‌a‌‌so-called‌‌"network‌‌interface",‌‌that‌‌is,‌‌
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
data‌ ‌entry‌ ‌forms‌ ‌and‌ ‌reports‌ ‌are‌ ‌displayed‌ ‌on‌‌the‌‌client‌‌computer‌‌as‌‌HTML‌‌pages‌‌(Hyper‌‌Text‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Markup‌ ‌Language,‌ ‌the‌ ‌standard‌ ‌language‌ ‌for‌ ‌describing‌ ‌pages‌ ‌on‌ ‌the‌ ‌Internet)‌ ‌through‌ ‌a‌ ‌web‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
browser.‌‌It‌‌is‌‌not‌‌necessary‌‌to‌‌install‌‌any‌‌user-specific‌‌software‌‌in‌‌order‌‌to‌‌use‌‌the‌‌system‌‌from‌‌the‌‌
     
 
 
 
 
 
 
 
 
   
 
 
 
 
 
investigator's‌ ‌computer.‌ ‌The‌ ‌raw‌ ‌data‌ ‌can‌ ‌be‌ ‌accessed‌ ‌directly‌ ‌through‌ ‌an‌ ‌ODBC‌ ‌database‌ ‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
further‌ ‌data‌ ‌processing.‌ ‌ 
The‌ ‌system‌ ‌checks‌ ‌the‌ ‌correctness‌ ‌of‌ ‌the‌ ‌data‌ ‌by‌ ‌ranges‌‌and‌‌performs‌‌validity‌‌and‌‌consistency‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
checks.‌ ‌Implausible‌ ‌or‌ ‌omitted‌ ‌data‌ ‌can‌ ‌be‌ ‌corrected‌ ‌or‌ ‌completed‌ ‌after‌ ‌discussion‌ ‌with‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
investigator.‌ ‌Correction‌ ‌documents‌ ‌are‌ ‌stored‌ ‌(audit‌ ‌trail).‌ ‌ 
The‌ ‌system‌ ‌has‌ ‌a‌ ‌system‌ ‌of‌ ‌keys‌ ‌and‌ ‌passwords‌ ‌that‌ ‌restricts‌ ‌access‌ ‌to‌ ‌different‌ ‌areas‌ ‌of‌ ‌the‌‌
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
application‌ ‌depending‌ ‌on‌ ‌the‌ ‌role‌ ‌assigned‌ ‌by‌ ‌the‌ ‌sponsor.‌ ‌Apart‌ ‌from‌ ‌the‌ ‌researcher,‌ ‌only‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
expressly‌‌authorized‌‌persons‌‌who‌‌have‌‌received‌‌specific‌‌training‌‌for‌‌the‌‌study‌‌may‌‌complete‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRD-e.‌ ‌ 
All‌ ‌the‌‌data‌‌collected‌‌in‌‌the‌‌e-CRDs‌‌must‌‌be‌‌able‌‌to‌‌be‌‌documented‌‌in‌‌measurement‌‌records‌‌or‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
through‌ ‌annotations‌ ‌in‌ ‌the‌ ‌patients'‌ ‌medical‌ ‌records.‌ ‌ 
Patient‌‌identification‌‌lists‌‌are‌‌stored‌‌exclusively‌‌at‌‌study‌‌centers.‌‌The‌‌study‌‌documents‌‌are‌‌archived‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
at‌ ‌the‌ ‌centers.‌ ‌Documents‌ ‌must‌ ‌be‌ ‌kept‌ ‌for‌ ‌a‌ ‌period‌ ‌of‌ ‌15‌ ‌years.‌ ‌ 
12.4.Report‌ ‌and‌ ‌Publication‌ ‌of‌ ‌the‌ ‌Clinical‌ ‌Trial‌ ‌
 
Ccomplying‌‌with‌‌the‌‌provisions‌‌of‌‌the‌‌R.D.‌‌223/2004,‌‌the‌‌results‌‌of‌‌this‌‌test‌‌will‌‌be‌‌published,‌‌both‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
positive‌ ‌and‌ ‌negative‌ ‌results‌ ‌in‌ ‌recognized‌ ‌scientific‌ ‌media.‌ ‌ 
The‌ ‌sponsor‌ ‌and‌ ‌the‌ ‌researchers‌ ‌are‌ ‌fully‌ ‌committed‌ ‌to‌ ‌publishing‌ ‌the‌ ‌results‌ ‌of‌‌the‌‌study.‌‌All‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
publications‌ ‌(eg,‌ ‌manuscripts,‌ ‌abstracts,‌ ‌oral‌ ‌/‌ ‌slide‌ ‌presentations,‌ ‌book‌ ‌chapters)‌ ‌based‌ ‌on‌ ‌this‌‌
 
 
 
 
   
 
 
 
 
 
 
 
study‌ ‌must‌ ‌be‌ ‌submitted‌ ‌to‌ ‌the‌ ‌sponsor‌ ‌for‌ ‌review‌ ‌prior‌ ‌to‌ ‌publication.‌ ‌ 
The‌‌trial‌‌will‌‌be‌‌registered‌‌in‌‌the‌‌public‌‌access‌‌database‌‌"clinicaltrials.gov"‌‌of‌‌the‌‌National‌‌Institute‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
of‌ ‌Health‌ ‌of‌ ‌the‌ ‌United‌ ‌States‌ ‌of‌ ‌North‌ ‌America.‌ ‌ 
‌
 
12.5‌ ‌Monitoring‌ ‌and‌ ‌Audit‌ ‌
 
Investigator‌ ‌responsibilities‌ ‌are‌ ‌stipulated‌ ‌in‌ ‌the‌ ‌ICH‌ ‌Guidelines‌ ‌for‌ ‌Good‌ ‌Clinical‌ ‌Practice‌ ‌(GCP).‌ ‌ 
Researchers‌‌must‌‌enter‌‌study‌‌data‌‌in‌‌the‌‌Data‌‌Collection‌‌Notebooks‌‌or‌‌other‌‌data‌‌collection‌‌system.‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
The‌‌investigator‌‌will‌‌allow‌‌monitoring‌‌visits‌‌related‌‌to‌‌the‌‌study‌‌and‌‌audits‌‌by‌‌the‌‌Sponsor‌‌or‌‌its‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
representatives,‌‌the‌‌review‌‌of‌‌the‌‌Ethics‌‌Committees,‌‌and‌‌the‌‌regulatory‌‌inspection‌‌(s)‌‌(e.g.,‌‌FDA,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EMEA)‌ ‌providing‌ ‌access‌ ‌direct‌ ‌to‌ ‌the‌ ‌facilities‌ ‌where‌ ‌the‌ ‌study‌ ‌is‌ ‌taking‌ ‌place,‌ ‌the‌ ‌original‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
documents,‌ ‌the‌ ‌data‌ ‌collection‌ ‌notebooks,‌ ‌and‌ ‌all‌ ‌other‌ ‌documents‌ ‌of‌ ‌the‌ ‌study.‌ ‌ 
The‌‌investigator,‌‌or‌‌the‌‌investigator's‌‌designated‌‌member,‌‌should‌‌be‌‌available‌‌for‌‌some‌‌time‌‌during‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the‌ ‌monitoring‌ ‌visits‌ ‌to‌ ‌review‌ ‌data‌ ‌and‌ ‌resolve‌ ‌any‌ ‌queries‌ ‌and‌ ‌to‌ ‌allow‌ ‌direct‌ ‌access‌ ‌to‌ ‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patient's‌‌source‌‌documents‌‌(e.g.,‌‌medical‌‌history,‌‌laboratory‌‌tests,‌‌ECGs)‌‌for‌‌verification‌‌of‌‌original‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
data.‌‌The‌‌data‌‌collection‌‌must‌‌be‌‌completed‌‌before‌‌each‌‌visit‌‌and‌‌must‌‌be‌‌made‌‌available‌‌to‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
sponsor's‌ ‌representative‌ ‌so‌ ‌that‌ ‌they‌ ‌can‌ ‌verify‌ ‌its‌ ‌accuracy‌ ‌and‌ ‌completeness.‌ ‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
66‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
12.6‌ ‌Protocol‌ ‌amendment‌ ‌
 
Supplements‌‌or‌‌changes‌‌to‌‌the‌‌protocol‌‌can‌‌be‌‌made‌‌exclusively‌‌by‌‌the‌‌sponsor,‌‌who‌‌must‌‌send‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
them‌ ‌to‌ ‌the‌ ‌Ethics‌ ‌Committee‌ ‌and‌ ‌the‌ ‌AEMPS‌ ‌as‌ ‌amendments‌ ‌to‌ ‌the‌ ‌protocol.‌‌ ‌
  
12.7‌ ‌Data‌ ‌management‌ ‌
 
All‌‌data‌‌(personal,‌‌clinical,‌‌economic‌‌and‌‌from‌‌studies‌‌of‌‌biological‌‌material)‌‌obtained‌‌on‌‌patients‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
will‌ ‌be‌ ‌treated‌ ‌in‌ ‌accordance‌ ‌with‌ ‌the‌ ‌Directive‌ ‌on‌‌the‌‌protection‌‌of‌‌people‌‌with‌‌respect‌‌to‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
processing‌‌of‌‌personal‌‌data‌‌and‌‌Organic‌‌Law‌‌15/1999,‌‌of‌‌13‌‌December‌‌of‌‌protection‌‌of‌‌personal‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
data.‌ ‌ 
In‌ ‌accordance‌ ‌with‌ ‌the‌ ‌provisions‌ ‌of‌ ‌the‌ ‌aforementioned‌‌legislation,‌‌patients‌‌may‌‌exercise‌‌their‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
rights‌‌of‌‌access,‌‌modification,‌‌opposition‌‌and‌‌cancellation‌‌of‌‌data,‌‌for‌‌which‌‌they‌‌must‌‌contact‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
doctor‌ ‌of‌ ‌the‌ ‌clinical‌ ‌trial.‌ ‌ 
The‌‌content‌‌of‌‌the‌‌CRD‌‌as‌‌well‌‌as‌‌the‌‌documents‌‌generated‌‌during‌‌the‌‌study‌‌will‌‌be‌‌considered‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
strictly‌ ‌confidential‌ ‌and‌ ‌will‌ ‌not‌ ‌be‌ ‌disclosed‌ ‌to‌ ‌third‌ ‌parties.‌ ‌ 
12.8‌ ‌Documentation‌ ‌
 
The‌‌researcher‌‌has‌‌the‌‌legal‌‌obligation‌‌to‌‌keep‌‌the‌‌patient‌‌identification‌‌list‌‌for‌‌the‌‌time‌‌stipulated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in‌‌art.‌‌39‌‌of‌‌RD‌‌223/2004.‌‌Likewise,‌‌the‌‌researcher‌‌must‌‌store‌‌the‌‌data‌‌of‌‌the‌‌registered‌‌patients,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
including‌‌the‌‌original‌‌or‌‌copies‌‌of‌‌the‌‌test‌‌results,‌‌the‌‌informed‌‌consents,‌‌the‌‌approval‌‌of‌‌the‌‌Ethics‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Committee,‌ ‌as‌ ‌well‌ ‌as‌‌the‌‌correspondence‌‌and‌‌any‌‌other‌‌original‌‌documents‌‌associated‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
study,‌‌during‌‌a‌‌period‌‌specified‌‌in‌‌art.‌‌39‌‌of‌‌RD‌‌223/2004.‌‌This‌‌necessary‌‌condition‌‌also‌‌applies‌‌in‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
the‌‌event‌‌that‌‌the‌‌doctor‌‌transfers‌‌the‌‌documents‌‌(together‌‌with‌‌the‌‌associated‌‌storage‌‌obligation)‌‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
   
a‌ ‌successor.‌ ‌ 
Original‌‌study‌‌patient‌‌data‌‌(medical‌‌history)‌‌should‌‌be‌‌stored‌‌according‌‌to‌‌the‌‌applicable‌‌archiving‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
period‌ ‌at‌ ‌the‌ ‌study‌ ‌centers,‌ ‌but‌ ‌not‌ ‌for‌ ‌a‌ ‌period‌ ‌of‌ ‌less‌ ‌than‌ ‌15‌ ‌years.‌ ‌ 
The‌ ‌researcher‌‌/‌‌s‌‌must‌‌guarantee‌‌that‌‌the‌‌relevant‌‌records‌‌and‌‌documents‌‌for‌‌the‌‌study‌‌and‌‌the‌‌
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
distribution‌ ‌of‌‌the‌‌study‌‌medication,‌‌that‌‌is,‌‌copies‌‌of‌‌the‌‌data‌‌collection‌‌notebooks‌‌and‌‌original‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
source‌ ‌documents,‌ ‌data‌ ‌and‌ ‌records‌‌(eg‌‌records‌‌hospital‌‌charts,‌‌clinical‌‌charts,‌‌laboratory‌‌notes;‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
memos;‌ ‌patient‌ ‌diaries‌ ‌or‌ ‌evaluation‌ ‌checklists;‌ ‌pharmacy‌ ‌supply‌ ‌records;‌ ‌data‌ ‌recorded‌ ‌from‌‌
 
 
 
 
 
 
 
 
 
 
 
 
automated‌‌instruments;‌‌certified‌‌copies‌‌or‌‌transcripts‌‌after‌‌verification‌‌as‌‌exact‌‌copies;‌‌microfiche;‌‌
 
 
 
 
 
 
 
 
 
 
 
 
photographic‌‌negatives;‌‌microfilms‌‌or‌‌magnetic‌‌media,‌‌X-rays,‌‌patient‌‌files;‌‌and‌‌records‌‌kept‌‌in‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
pharmacy,‌ ‌in‌ ‌the‌ ‌laboratories,‌ ‌and‌ ‌in‌ ‌the‌ ‌technical-medical‌ ‌departments‌ ‌involved‌ ‌in‌‌the‌‌clinical‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
study;‌‌documents‌‌related‌‌to‌‌the‌‌treatment‌‌of‌‌the‌‌patient‌‌and‌‌the‌‌count‌‌of‌‌the‌‌study‌‌drug;‌‌consents‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
informed‌ ‌signed‌ ‌originals,‌ ‌etc.])‌ ‌are‌ ‌on‌ ‌file‌ ‌by‌ ‌the‌ ‌investigator‌ ‌du‌ ‌For‌ ‌as‌ ‌long‌ ‌as‌ ‌necessary‌ ‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
comply‌‌with‌‌national‌‌and‌‌international‌‌regulations‌‌(generally‌‌15‌‌years‌‌after‌‌clinical‌‌development‌‌
 
 
 
 
 
 
 
 
 
 
 
 
has‌‌been‌‌discontinued‌‌or‌‌after‌‌final‌‌marketing‌‌approval).‌‌The‌‌researcher‌‌agrees‌‌to‌‌comply‌‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
document‌ ‌/‌ ‌record‌ ‌retention‌ ‌procedures‌ ‌by‌ ‌signing‌ ‌the‌ ‌protocol.‌ ‌ 
12.9.Finance‌ ‌
 
GEMCAD-1002‌ ‌(POSIBA)‌ ‌is‌ ‌a‌ ‌trial‌ ‌sponsored‌ ‌by‌ ‌the‌ ‌Spanish‌ ‌Multidisciplinary‌ ‌Group‌ ‌on‌‌
 
 
 
 
 
 
 
 
 
 
 
 
Digestive‌ ‌Cancer,‌ ‌a‌ ‌non-profit‌ ‌scientific‌ ‌association.‌‌The‌‌sponsor‌‌will‌‌bear‌‌the‌‌costs‌‌of‌‌the‌‌trial‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
 
(insurance,‌ ‌start-up,‌ ‌and‌ ‌trial‌ ‌monitoring).‌ ‌ 
‌ 
‌
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
67‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
13.‌ ‌REFERENCES‌ ‌
 
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patients‌‌with‌‌advanced‌‌colorectal‌‌cancer:‌‌evidence‌‌in‌‌terms‌‌of‌‌response‌‌rate.‌‌J‌‌Clin‌‌Oncol‌‌10‌‌(6):‌‌
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
896–903,‌ ‌1992.‌ ‌ 
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Almendro‌ ‌V,‌ ‌Ametller‌ ‌E,‌ ‌García-Recio‌ ‌S,‌ ‌et‌ ‌al.‌ ‌The‌ ‌role‌ ‌of‌ ‌MMP7‌ ‌and‌ ‌its‌ ‌cross-talk‌ ‌with‌‌the‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FAS/FASL‌ ‌system‌ ‌during‌ ‌the‌ ‌acquisition‌ ‌of‌ ‌chemoresistance‌ ‌to‌ ‌oxaliplatin.‌ ‌PLoS‌ ‌ONE.‌‌
 
 
 
 
 
 
 
 
 
 
 
2009;4(3):e4728.‌ ‌Epub‌ ‌2009‌ ‌Mar‌ ‌6.‌ ‌ 
‌ 
Amado‌‌RG,‌‌Wolf‌‌M,‌‌Peeters‌‌M,‌‌et‌‌al.,‌‌Wild-type‌‌KRAS‌‌is‌‌required‌‌for‌‌panitumumab‌‌efficacy‌‌in‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
patients‌ ‌with‌ ‌metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌J‌ ‌Clin‌ ‌Oncol.‌ ‌2008‌ ‌Apr‌ ‌1;26(10):1626-34.‌ ‌ 
‌ 
Avastin®,‌ ‌Summary‌ ‌of‌ ‌product‌ ‌characteristics.‌ ‌Roche‌ ‌Registration‌ ‌Limited.‌ ‌United‌ ‌Kingdom‌ ‌ 
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Baselga‌ ‌J,‌ ‌Mendelsohn‌ ‌J.‌ ‌Receptor‌ ‌blockade‌ ‌with‌ ‌monoclonal‌ ‌antibodies‌ ‌as‌ ‌cancer‌ ‌therapy.‌
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacol‌ ‌Ther.‌ ‌1994;64:203-212.‌ ‌ 
‌ 
Benvenuti‌‌S,‌‌Sartore-Bianchi‌‌A,‌‌Di‌‌Nicolantonio‌‌F,‌‌et‌‌al.‌‌Oncogenic‌‌activation‌‌of‌‌the‌‌RAS/RAF‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
signaling‌‌pathway‌‌impairs‌‌the‌‌response‌‌of‌‌metastatic‌‌colorectal‌‌cancers‌‌to‌‌anti–Epidermal‌‌Growth‌‌
 
 
 
 
 
 
 
 
 
 
 
 
Factor‌ ‌Receptor‌ ‌antibody‌ ‌therapies.‌ ‌Cancer‌ ‌Res‌ ‌2007;‌ ‌67‌ ‌(6):‌ ‌2643-2648.‌ ‌ 
‌ 
Chakravarti‌‌A,‌‌Loeffler‌‌JS,‌‌Dyson‌‌NJ.‌‌Insulin-like‌‌growth‌‌factor‌‌receptor‌‌I‌‌mediates‌‌resistance‌‌to‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
anti-epidermal‌ ‌growth‌ ‌factor‌ ‌receptor‌ ‌therapy‌ ‌in‌ ‌primary‌ ‌human‌ ‌glioblastoma‌ ‌cells‌ ‌through‌‌
 
 
 
 
 
 
 
 
 
 
 
continued‌ ‌activation‌ ‌of‌ ‌phosphoinositide‌ ‌3-kinase‌ ‌signaling.‌ ‌Cancer‌ ‌Res.‌ ‌2002‌ ‌Jan‌ ‌1;62(1):200-7‌ ‌ 
‌ 
Collett‌ ‌D.‌  ‌In‌ ‌Modelling‌ ‌Binary‌ ‌Data‌ ‌1992.‌ ‌Publishers:‌ ‌Chapman‌ ‌&‌ ‌Hall‌ ‌of‌ ‌London‌ ‌ 
‌ 
Cunningham‌‌D,‌‌Pyrhonen‌‌S,‌‌James‌‌RD,‌‌et‌‌al.‌‌Randomized‌‌trial‌‌of‌‌Irinotecan‌‌plus‌‌supportive‌‌care‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
versus‌‌supportive‌‌care‌‌alone‌‌after‌‌fluorouracil‌‌failure‌‌for‌‌patients‌‌with‌‌metastatic‌‌colorectal‌‌cancer.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Lancet‌ ‌1998;352:1413-1418.‌ ‌ 
‌ 
Cunningham‌ ‌D,‌ ‌Humblet‌ ‌Y,‌ ‌Sienna‌ ‌S‌ ‌ea.‌ ‌Cetuximab‌ ‌monotherapy‌‌plus‌‌Irinotecan‌‌in‌‌Irinotecan‌‌
 
 
 
 
   
 
 
 
 
 
 
 
refractory‌ ‌metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌N‌ ‌Engl‌ ‌J‌ ‌Med.‌ ‌2004;351:337-345.‌ ‌ 
‌ 
Dallas‌‌NA,‌‌Xia‌‌L,‌‌Fan‌‌F,‌‌Gray‌‌MJ,‌‌Gaur‌‌P,‌‌van‌‌Buren‌‌G‌‌2nd,‌‌Samuel‌‌S,‌‌Kim‌‌MP,‌‌Lim‌‌SJ,‌‌Ellis‌‌
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
LM.‌ ‌Chemoresistant‌ ‌colorectal‌ ‌cancer‌ ‌cells,‌ ‌the‌ ‌cancer‌ ‌stem‌ ‌cell‌ ‌phenotype,‌ ‌and‌ ‌increased‌‌
 
 
 
 
 
 
 
 
 
 
 
 
sensitivity‌‌to‌‌insulin-like‌‌growth‌‌factor-I‌‌receptor‌‌inhibition.‌‌Cancer‌‌Res.‌‌2009‌‌Mar‌‌1;69(5):1951-7.‌‌
 
 
 
 
 
 
 
 
 
 
 
 
Epub‌ ‌2009‌ ‌Feb‌ ‌24.‌ ‌ 
‌ 
de‌‌Gramont‌‌A,‌‌Figer,‌‌A,‌‌Seymour‌‌M,‌‌et‌‌al.‌‌Folinic‌‌acid‌‌and‌‌fluorouracil‌‌with‌‌or‌‌without‌‌oxaliplatin‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
as‌ ‌first-line‌ ‌treatment‌ ‌in‌ ‌advanced‌ ‌colorectal‌ ‌cancer.‌ ‌J‌ ‌Clin‌ ‌Oncol.‌  ‌2000;22:229-237.‌ ‌ 
‌ 
De‌‌Roock‌‌W,‌‌Piessevaux‌‌H,‌‌De‌‌Schutter‌‌J,‌‌Janssens‌‌M,‌‌De‌‌Hertogh‌‌G,‌‌Personeni‌‌N,‌‌Biesmans‌‌B,‌‌
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
Van‌‌Laethem‌‌JL,‌‌Peeters‌‌M,‌‌Humblet‌‌Y,‌‌Van‌‌Cutsem‌‌E,‌‌Tejpar‌‌S.‌‌KRAS‌‌wild-type‌‌state‌‌predicts‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
survival‌‌and‌‌is‌‌associated‌‌to‌‌early‌‌radiological‌‌response‌‌in‌‌metastatic‌‌colorectal‌‌cancer‌‌treated‌‌with‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
cetuximab.‌ ‌Ann‌ ‌Oncol.‌ ‌2008‌ ‌Mar;19(3):508-15.‌ ‌Epub‌ ‌2007‌ ‌Nov‌ ‌12‌ 
‌ 
Desbois-Mouthon‌ ‌C,‌ ‌Cacheux‌ ‌W,‌ ‌et‌ ‌al.,‌ ‌Impact‌ ‌of‌ ‌IGF-1R/EGFR‌ ‌cross-talks‌ ‌on‌ ‌hepatoma‌ ‌cell‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
68‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
sensitivity‌ ‌to‌ ‌gefitinib.‌ ‌Int‌ ‌J‌ ‌Cancer.‌ ‌2006‌ ‌Dec‌ ‌1;119(11):2557-66.‌ ‌ 
‌ 
Di‌‌Fiore‌‌F,‌‌Blanchard‌‌F,‌‌Charbonnier‌‌F,‌‌et‌‌al.‌‌Clinical‌‌relevance‌‌of‌‌K-RAS‌‌mutation‌‌detection‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic‌ ‌colorectal‌ ‌cancer‌ ‌treated‌ ‌by‌ ‌cetuximab‌ ‌plus‌ ‌chemotherapy.‌ ‌Cancer‌ ‌Res‌ ‌2006;‌ ‌66(8):‌‌
 
 
 
 
 
 
 
 
 
 
 
 
3992-3995.‌ ‌ 
‌ 
Di‌‌Fiore‌‌F,‌‌Blanchard‌‌F,‌‌Charbonnier‌‌F,‌‌et‌‌al.,‌‌Clinical‌‌relevance‌‌of‌‌KRAS‌‌mutation‌‌detection‌‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic‌ ‌colorectal‌ ‌cancer‌ ‌treated‌ ‌by‌ ‌Cetuximab‌ ‌plus‌ ‌chemotherapy.‌ ‌Br‌ ‌J‌ ‌Cancer.‌ ‌2007‌ ‌Apr‌‌
 
 
 
 
 
 
 
 
   
 
 
 
23;96(8):1166-9.‌ ‌Epub‌ ‌2007‌ ‌Mar‌ ‌20.‌ ‌ 
‌ 
Douillard‌‌JY,‌‌Cunningham‌‌D,‌‌Roth‌‌AD,‌‌et‌‌al.‌‌Irinotecan‌‌combined‌‌with‌‌fluorouracil‌‌compared‌‌with‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
fluorouracil‌‌alone‌‌as‌‌first-line‌‌treatment‌‌for‌‌metastatic‌‌colorectal‌‌cancer:‌‌a‌‌multicentre‌‌randomized‌‌
 
 
 
 
 
 
 
 
   
 
 
trial.‌ ‌Lancet.‌ ‌2000;‌ ‌355:1041-1047.‌ ‌ 
‌ 
Eisenhauer‌‌EA‌‌Therasse‌‌P,.‌‌Bogaerts‌‌J,‌‌et‌‌al.‌‌,New‌‌response‌‌evaluation‌‌criteria‌‌in‌‌solid‌‌tumours:‌‌
 
 
 
 
   
 
 
 
 
 
 
 
 
 
Revised‌ ‌RECIST‌ ‌guideline‌ ‌(version‌ ‌1.1)‌ ‌Eur‌ ‌J‌ ‌Cancer,‌ ‌2009;‌ ‌45:248-260.‌ ‌ 
‌ 
El-Shewy‌ ‌HM,‌ ‌Kelly‌ ‌FL,‌ ‌Barki-Harrington‌ ‌L,‌ ‌Luttrell‌ ‌LM.‌ ‌Ectodomain‌ ‌shedding-dependent‌‌
 
 
 
 
 
 
 
 
 
 
transactivation‌‌of‌‌epidermal‌‌growth‌‌factor‌‌receptors‌‌in‌‌response‌‌to‌‌insulin-like‌‌growth‌‌factor‌‌type‌‌I.‌‌
 
 
 
 
 
   
   
 
 
 
   
Mol‌ ‌Endocrinol.‌ ‌2004‌ ‌Nov;18(11):2727-39.‌ ‌Epub‌ ‌2004‌ ‌Jul‌ ‌22.‌ ‌ 
‌ 
Erbitux®,‌ ‌Summary‌ ‌of‌ ‌product‌ ‌characteristics.‌ ‌Merck‌ ‌KGaA,‌ ‌64271‌ ‌Darmstadt,‌ ‌Germany‌ ‌ 
‌ 
Finocchiaro‌ ‌G,‌ ‌Cappuzzo‌‌F,‌‌Jänne‌‌PA,‌‌et‌‌al.‌‌EGFR,‌‌HER2‌‌and‌‌K-RAS‌‌as‌‌predictive‌‌factors‌‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab‌‌sensitivity‌‌in‌‌colorectal‌‌cancer.‌‌ASCO‌‌Annual‌‌Meeting‌‌Proceedings‌‌Part‌‌I.‌‌Vol‌‌25,‌‌No.‌‌
 
 
 
 
 
 
 
 
 
   
 
 
 
18S‌ ‌(June‌ ‌20‌ ‌Supplement),‌ ‌2007:‌ ‌A4021.‌ ‌ 
‌ 
Friday‌ ‌BB,‌ ‌Adjei‌ ‌AA.‌ ‌K-ras‌ ‌as‌‌a‌‌target‌‌for‌‌cancer‌‌therapy.‌‌Biochem‌‌Biophys‌‌Acta‌‌2005;‌‌1756:‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
127-144.‌ ‌ 
‌ 
Gallego‌ ‌R,‌ ‌Codony-Servat‌ ‌J,‌ ‌García-Albéniz‌ ‌X,‌ ‌et‌ ‌al.‌ ‌Serum‌ ‌IGF-I,‌ ‌IGFBP-3,‌ ‌and‌ ‌matrix‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
metalloproteinase-7‌ ‌levels‌ ‌and‌ ‌acquired‌ ‌chemo-resistance‌ ‌in‌ ‌advanced‌ ‌colorectal‌‌cancer.‌‌Endocr‌‌
 
 
 
 
 
 
 
 
 
 
Relat‌ ‌Cancer.‌ ‌2009‌ ‌Mar;16(1):311-7.‌ ‌Epub‌ ‌2008‌ ‌Dec‌ ‌24.‌ ‌ 
‌ 
Goldberg‌‌RM,‌‌et‌‌al.‌‌A‌‌Randomised‌‌Controlled‌‌Trial‌‌of‌‌Fluorouracil‌‌Plus‌‌Folinic‌‌acid,‌‌FOLFOX‌‌4,‌‌
 
   
   
 
 
 
 
 
 
 
 
   
and‌‌Oxaliplatin‌‌Combinations‌‌in‌‌Patients‌‌With‌‌Previously‌‌Untreated‌‌Metastatic‌‌Colorectal‌‌Cancer;‌‌
 
 
 
 
 
 
 
 
 
 
 
J‌ ‌Clin‌ ‌Oncol‌ ‌2004:22:23-30‌ ‌ 
‌ 
Herbst‌‌RS,‌‌Shin‌‌DM.‌‌Monoclonal‌‌antibodies‌‌to‌‌target‌‌epidermal‌‌growth‌‌factor‌‌Receptor-positive‌‌
 
 
 
 
 
 
 
 
 
 
 
 
tumours:‌ ‌A‌ ‌new‌ ‌paradigm‌ ‌for‌ ‌cancer‌ ‌therapy.‌ ‌Cancer.‌ ‌2002;‌ ‌94:1593-1611.‌ ‌ 
‌ 
Horndler‌‌C,‌‌Gallego‌‌R,‌‌Alonso‌‌V‌‌et‌‌al.‌‌Co-expression‌‌of‌‌matrix‌‌metalloproteinase-7‌‌(MMP7)‌‌and‌‌
 
 
 
 
     
 
 
 
 
 
 
 
phosphorylated‌ ‌Insulin‌ ‌growth‌ ‌factor‌ ‌receptor‌ ‌I‌ ‌(pIGF-IR)‌ ‌predicts‌ ‌resistance‌ ‌to‌ ‌cetuximab‌ ‌or‌‌
 
 
 
 
   
 
 
 
 
 
 
panitumumab‌‌in‌‌wild-type‌‌KRAS‌‌and‌‌BRAF‌‌metastatic‌‌colorectal‌‌cancer.‌‌A‌‌GEMCAD‌‌study.‌‌Proc‌‌
 
 
 
 
 
 
 
 
   
 
 
 
ASCO,‌ ‌4063‌ ‌(abstr),‌ ‌2009.‌ ‌ 
‌ 
Ince‌‌WL,‌‌Jubb‌‌AM,‌‌Holden‌‌SN,‌‌et‌‌al.‌‌Association‌‌of‌ ‌k-ras,‌‌b-raf,‌‌and‌‌p53‌‌status‌‌with‌‌the‌‌treatment‌‌
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
effect‌ ‌of‌ ‌bevacizumab.‌ ‌J‌ ‌Natñ‌ ‌Cancer‌ ‌Inst‌ ‌2005;‌ ‌97:‌ ‌981-9.‌ ‌ 
‌ 
International‌ ‌Committee‌ ‌of‌ ‌Medical‌ ‌Journal‌ ‌Editors,‌ ‌Uniform‌ ‌Requirements‌ ‌for‌ ‌Manuscripts‌‌
 
 
 
 
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
69‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
Submitted‌ ‌to‌ ‌Biomedical‌ ‌Journals:‌ ‌Writing‌ ‌and‌ ‌Editing‌ ‌for‌ ‌Biomedical‌ ‌Publication.‌ ‌2004.‌‌
 
 
 
 
 
 
 
 
 
 
 
http://www.icmje.org/‌ ‌ 
‌ 
Jemal‌ ‌A,‌ ‌Murray‌ ‌T,‌ ‌Ward,‌ ‌E‌ ‌et‌ ‌al.‌  ‌Cancer‌ ‌statistics,‌ ‌2005.‌ ‌CA Cancer‌ ‌J‌ ‌Clin.‌  ‌2005;55:10-30.‌ ‌ 
‌ 
Khambata-Ford‌‌S,‌‌Garrett‌‌CR,‌‌Meropol‌‌NJ,‌‌et‌‌al.‌‌Expression‌‌of‌‌epiregulin‌‌and‌‌amphiregulin‌‌and‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K-ras‌ ‌mutation‌‌status‌‌predict‌‌disease‌‌control‌‌in‌‌metastatic‌‌colorectal‌‌cancer‌‌patients‌‌treated‌‌with‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
Cetuximab.‌ ‌J‌ ‌Clin‌ ‌Oncol‌ ‌2007;‌ ‌25:‌ ‌3230-3237.‌ ‌ 
‌ 
Kindler,‌ ‌HL,‌ ‌Shulman,‌ ‌KL.‌ ‌Metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌Curr‌ ‌Treat‌ ‌Options‌ ‌Oncol.‌ ‌
 
 
 
 
 
 
 
 
 
 
 
2001;2:459-471.‌ ‌ 
‌ 
Lievre‌ ‌A,‌ ‌Bachet‌ ‌JB,‌ ‌Le‌ ‌Corre‌ ‌D,‌ ‌et‌ ‌al.‌ ‌K-RAS‌ ‌mutation‌ ‌status‌ ‌is‌ ‌predictive‌ ‌of‌ ‌response‌ ‌to‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab‌ ‌therapy‌ ‌in‌ ‌colorectal‌ ‌cancer.‌ ‌Cancer‌ ‌Res‌ ‌2006;‌ ‌66:‌ ‌3992-3995.‌ ‌ 
‌ 
Lièvre‌ ‌A,‌ ‌Bachet‌ ‌JB,‌ ‌Boige‌ ‌V,‌ ‌et‌ ‌al.,‌ ‌KRAS‌ ‌mutations‌ ‌as‌ ‌an‌ ‌independent‌ ‌prognostic‌ ‌factor‌ ‌in‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
patients‌ ‌with‌ ‌advanced‌ ‌colorectal‌ ‌cancer‌ ‌treated‌ ‌with‌ ‌cetuximab.‌ ‌J‌ ‌Clin‌ ‌Oncol.‌ ‌2008‌ ‌Jan‌‌
 
 
 
 
 
 
 
   
 
 
 
 
20;26(3):374-9.‌ ‌ 
‌ 
Maindrault-Goebel‌ ‌F,‌ ‌Louvet,‌ ‌C,‌ ‌Andre‌ ‌T,‌ ‌et‌ ‌al.‌ ‌Oxaliplatin‌ ‌added‌ ‌to‌ ‌the‌ ‌simplified‌ ‌bimonthly‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
folinic‌ ‌acid‌ ‌and‌ ‌5-fluorouracil‌ ‌regimen‌ ‌as‌ ‌second-line‌ ‌therapy‌ ‌for‌ ‌metastatic‌ ‌colorectal‌ ‌cancer‌‌
 
 
 
 
 
 
 
 
 
 
 
 
(FOLFOX6).‌ ‌GERCOR.‌  ‌Eur‌ ‌J‌ ‌Cancer.‌  ‌1999;35:1338-1346.‌ ‌ 
‌ 
Malumbres‌‌M,‌‌Barbacid‌‌M.‌‌RAS‌‌oncogenes:‌‌the‌‌first‌‌30‌‌years.‌‌Nature‌‌Rev‌‌Cancer‌‌2003‌‌(Vol‌‌3):‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7-13.‌ ‌ 
‌ 
McLeod,‌‌HL,‌‌McKay,‌‌JA,‌‌Collie-Duguid,‌‌ES,‌‌Cassidy,‌‌J.‌‌Therapeutic‌‌opportunities‌‌from‌‌tumour‌‌
 
 
 
 
 
 
   
 
 
 
 
biology‌ ‌in‌ ‌metastatic‌ ‌colon‌ ‌cancer.‌ ‌Eur‌ ‌J‌ ‌Cancer.‌  ‌2000;36:1706-1712.‌ ‌ 
‌ 
Meropol‌‌NJ,‌‌Berlin‌‌J,‌‌Hecht‌‌JR,‌‌et‌‌al.‌‌Multicentre‌‌study‌‌of‌‌ABX-EGF‌‌monotherapy‌‌in‌‌patients‌‌with‌‌
 
 
   
 
   
 
 
 
 
 
   
 
 
metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌Proc‌ ‌Am‌ ‌Soc‌ ‌Clin‌ ‌Oncol.‌ ‌2003:22:256‌ ‌Abstract‌ ‌1026.‌ ‌ 
‌ 
Miyamoto‌ ‌S,‌ ‌Yano‌ ‌K,‌ ‌Sugimoto‌‌S,‌‌Ishii‌‌G,‌‌Hasebe‌‌T,‌‌Endoh‌‌Y,‌‌Kodama‌‌K,‌‌Goya‌‌M,‌‌Chiba‌‌T,‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ochiai‌‌A.‌‌Matrix‌‌metalloproteinase-7‌‌facilitates‌‌insulin-like‌‌growth‌‌factor‌‌bioavailability‌‌through‌‌
 
 
 
 
 
 
 
 
 
 
its‌ ‌proteinase‌ ‌activity‌ ‌on‌ ‌insulin-like‌ ‌growth‌ ‌factor‌ ‌binding‌ ‌protein‌ ‌3.‌ ‌Cancer‌ ‌Res.‌ ‌2004‌ ‌Jan‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15;64(2):665-71‌ ‌ 
‌ 
Pazdur‌‌R,‌‌Coia‌‌L,‌‌Wagman‌‌LD,‌‌Ayoub,‌‌JP.‌‌Colorectal‌‌and‌‌anal‌‌cancers.‌‌In:‌‌Cancer‌‌management:‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
multidisciplinary‌ ‌approach.‌ ‌Melville,‌ ‌NY:‌ ‌PRR,‌ ‌Inc,‌ ‌1999:149-175.‌ ‌ 
‌ 
Peréz-Soler‌ ‌R,‌ ‌Saltz‌ ‌L.‌ ‌Cutaneous‌ ‌adverse‌ ‌effects‌ ‌with‌ ‌HER1/EGFR-targeted‌ ‌agents:‌ ‌is‌ ‌there‌‌a‌‌
 
 
 
 
 
 
 
 
 
 
 
   
silver‌ ‌lining?‌ ‌J‌ ‌Clin‌ ‌Oncol.‌ ‌2005‌ ‌Aug‌ ‌1;23(22):5235-46.‌ ‌Review.‌ ‌ 
‌ 
Rothenberg‌ ‌ML,‌ ‌Oza‌ ‌AM,‌ ‌Bigelow‌ ‌RH,‌‌et‌‌al.‌‌Superiority‌‌of‌‌oxaliplatin‌‌and‌‌fluorouracil-folinic‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
acid‌ ‌compared‌ ‌with‌ ‌either‌ ‌therapy‌ ‌alone‌ ‌in‌ ‌patients‌ ‌with‌ ‌progressive‌ ‌colorectal‌ ‌cancer‌ ‌after‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFOX‌‌4‌‌and‌‌fluorouracil-folinic‌‌acid:‌‌Interim‌‌Results‌‌of‌‌a‌‌Phase‌‌III‌‌Trial.‌‌J‌‌Clin‌‌Oncol.‌‌2003;‌‌
   
 
 
 
 
 
   
 
 
   
 
 
 
21:2059-2069.‌ ‌ 
‌ 
Roudabush‌‌FL,‌‌Pierce‌‌KL,‌‌et‌‌al.,‌‌Transactivation‌‌of‌‌the‌‌EGF‌‌receptor‌‌mediates‌‌IGF-1-stimulated‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
shc‌ ‌phosphorylation‌ ‌and‌ ‌ERK1/2‌ ‌activation‌ ‌in‌ ‌COS-7‌ ‌cells.‌ ‌J‌ ‌Biol‌ ‌Chem.‌ ‌2000‌ ‌Jul‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
70‌ ‌of‌ ‌71‌ ‌ 


‌ 
‌ 
21;275(29):22583-9.‌ ‌ 
‌ 
Rougier‌‌P,‌‌Van‌‌Cutsem‌‌E,‌‌Bajetta‌‌E,‌‌et‌‌al.‌‌Randomised‌‌trial‌‌of‌‌irinotecan‌‌versus‌‌fluorouracil‌‌by‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
continuous‌‌infusion‌‌after‌‌fluorouracil‌‌failure‌‌in‌‌patients‌‌with‌‌metastatic‌‌colorectal‌‌cancer.‌‌Lancet‌ ‌
 
 
 
 
 
 
 
 
 
 
 
 
1998;‌ ‌352:‌ ‌1407-1412.‌ ‌ 
‌ 
Saltz‌ ‌LB,‌ ‌Meropol‌‌NJ,‌‌Loehrer‌‌PJ,‌‌et‌‌al.‌ ‌Phase‌‌II‌‌trial‌‌of‌‌cetuximab‌‌in‌‌patients‌‌with‌‌refractory‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
colorectal‌ ‌cancer‌ ‌that‌ ‌expresses‌ ‌the‌ ‌epidermal‌ ‌growth‌ ‌factor‌ ‌receptor.‌ ‌J‌ ‌Clin‌ ‌Oncol‌ ‌2004;‌ ‌22:‌‌
 
 
 
 
 
 
 
 
   
 
 
 
 
1201-1208.‌ ‌ 
‌ 
Tan‌ ‌X,‌ ‌Egami‌ ‌H,‌ ‌Abe‌ ‌M,‌ ‌et‌ ‌al.,‌ ‌Involvement‌ ‌of‌ ‌MMP-7‌ ‌in‌ ‌invasion‌‌of‌‌pancreatic‌‌cancer‌‌cells‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
through‌‌activation‌‌of‌‌the‌‌EGFR‌‌mediated‌‌MEK-ERK‌‌signal‌‌transduction‌‌pathway.‌‌J‌‌Clin‌‌Pathol.‌‌
 
 
 
 
 
 
 
 
 
   
 
 
2005‌ ‌Dec;58(12):1242-8.‌ ‌ 
‌ 
Therasse‌‌P,‌‌Arbuck‌‌SG,‌‌Eisenhauer‌‌EA,‌‌et‌‌al.‌‌New‌‌guideline‌‌to‌‌evaluate‌‌the‌‌response‌‌to‌‌treatment‌‌
   
 
 
 
   
 
 
 
 
 
 
 
 
 
of‌ ‌solid‌ ‌tumours.‌ ‌J‌ ‌Natl‌ ‌Cancer‌ ‌Inst.‌ ‌2000;92:205-216‌ ‌ 
‌ 
Tournigand‌‌C,‌‌Andre‌‌T,‌‌Achille‌‌E‌‌et‌‌al.‌‌FOLFIRI‌‌followed‌‌by‌‌FOLFOX6‌‌of‌‌the‌‌reverse‌‌sequence‌‌
 
 
 
 
     
 
 
 
 
 
 
 
 
 
in‌ ‌advanced‌ ‌colorectal‌ ‌cancer.‌ ‌J‌ ‌Clin‌ ‌Oncol.‌ ‌2004;22:229-237.‌ ‌ 
‌ 
Van‌ ‌Cutsem‌ ‌E,‌ ‌Kohne‌ ‌C,‌ ‌Hitre‌ ‌E,‌ ‌et‌ ‌al.‌ ‌Cetuximab‌ ‌and‌ ‌chemotherapy‌ ‌as‌ ‌initial‌ ‌treatment‌ ‌for‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
metastatic‌ ‌colorectal‌ ‌cancer.‌ ‌NEJM‌ ‌2009;360:1408-1417.‌ ‌ 
‌ 
Van‌‌Cutsem‌‌E,‌‌Nowacki‌‌M,‌‌Lang‌‌I,‌‌et‌‌al.‌‌Randomized‌‌phase‌‌III‌‌study‌‌of‌‌irinotecan‌‌and‌‌5-FU/FA‌‌
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
with‌‌or‌‌without‌‌cetuximab‌‌in‌‌the‌‌first-line‌‌treatment‌‌of‌‌patients‌‌with‌‌metastatic‌‌colorectal‌‌cancer‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(mCRC):‌ ‌The‌ ‌CRYSTAL‌ ‌trial.‌ ‌Proc‌ ‌ASCO‌ ‌2007‌ ‌(25):‌ ‌4000‌ ‌(abstract).‌ ‌ 
‌ 
Yang‌ ‌X-D,‌ ‌Jia‌ ‌XC,‌ ‌Corvalan‌ ‌JR,‌ ‌Wang‌ ‌P,‌ ‌Davis‌ ‌CG,‌ ‌Jakobovits‌ ‌A.‌ ‌Eradication‌ ‌of‌ ‌established‌‌
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
tumours‌ ‌by‌ ‌a‌ ‌fully‌‌human‌‌monoclonal‌‌antibody‌‌to‌‌the‌‌epidermal‌‌growth‌‌factor‌‌receptor‌‌without‌‌
 
   
 
 
 
 
 
 
 
 
 
 
 
concomitant‌ ‌chemotherapy.‌ ‌Cancer‌ ‌Res.‌ ‌1999;‌ ‌59:1236-1243.‌ ‌ 
‌ 
‌ ‌ 
‌ 
Single-arm,‌‌multicenter,‌‌prospective‌‌phase‌‌II‌‌clinical‌‌trial‌‌for‌‌biomarker‌‌
 
 
 
   
 
 
 
 
validation‌ ‌in‌ ‌patients‌ ‌with‌ ‌advanced‌ ‌and‌ ‌/‌ ‌or‌ ‌metastatic‌ ‌colorectal‌‌
 
 
 
 
 
   
 
 
 
cancer‌ ‌with‌ ‌non-mutated‌ ‌KRAS‌ ‌gene‌ ‌treated‌‌with‌‌chemotherapy‌‌plus‌‌
 
 
 
 
 
 
 
 
 
biweekly‌ ‌cetuximab‌ ‌as‌ ‌first-line‌ ‌therapy‌ ‌ 


Protocol:‌ ‌GEMCAD‌ ‌1002‌ ‌–‌ ‌POSIBA‌ ‌Version‌ ‌1.0‌ ‌from‌ ‌February‌ ‌23rd,‌ ‌2010‌ ‌(adaptation‌ ‌to‌ ‌Clinicaltrials.gov‌ ‌from‌ ‌May‌ ‌2021)‌ ‌ 
71‌ ‌of‌ ‌71‌ ‌ 

SAP_001.pdf: 
 
 
Clinical  Study  Statistical  Plan   
  
A  prospective,  multicentre,  single-arm,  phase  II  clinical  trial  to  evaluate  biomarkers  in  
 
advanced  and/or  metastatic  colorectal  cancer  patients  with  wild-type  KRAS/NRAS   
status   treated  with  chemotherapy  plus  bi-weekly  cetuximab  as  first-line  therapy.   
  
Protocol  Number:  GEMCAD-1002   
  
EudraCT  Number:  2010-019236-12   
  
Clinicaltrials.gov  number:  NCT01276379   
  
Acronym:  POSIBA   
  
27/JUN/2011  
 
CONFIDENTIAL  
 
 
 
 
 
 
 
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   1  of  36  
 


 
 
Signature  pages  for  clinical  study  statistical  plan  
 
I  have  read  this  report  and  confirm  that  to  the  best  of  my  knowledge  it  accurately 
describes  the  conduct  and  results  of  the  study.   
  
Signed:  Date:  /  /  Print  name:  Dr.  Carlos  Fernandez  Martos   
  
Affiliation:  GEMCAD  Chairman   
  
Signed:  Date:  /  /  Print  name:  Dr.  Joan  Maurel  Santasusana   
  
Affiliation:  GEMCAD  Scientific  Committee   
  
Signed:  Date:  /  /  Print  name:  Dr.  Xabier  García  de  Albéniz   
  
Affiliation:  Trial  Statistician  and  Coordinating  Investigator  
 
 
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   2  of  36  
 


TITLE  PAGE   
  
Study  title:  A  prospective,  multicentre,  single-arm,  phase  II  clinical  trial  to  evaluate  
 
 
 
 
 
 
  
 
 
 
 
biomarkers  in  advanced  and/or  metastatic  colorectal  cancer  patients  with  wild-type  
 
 
 
 
 
 
 
 
 
 
KRAS/NRAS  status  treated  with  chemotherapy  plus  bi-weekly  cetuximab  as  first-line  
 
 
 
 
 
 
 
 
 
 
therapy.   
  
Name  of  tested  drug:  Cetuximab   
  
Indication  studied:  Advanced  and/or  metastatic  colorectal  cancer   
  
Study  description:  A  single-arm,  prospective,  multicentre  phase  II  clinical  trial  with  
 
 
 
 
 
 
  
 
 
 
central  review  of  RAS  status  and  the  identification  of  predictive  biomarkers.  Patients  
 
 
 
 
 
 
 
 
 
 
 
 
were 
 treated  either  with  commercially  available  FOLFOX6  (m)  or  FOLFIRI  (m)  as  
 
 
 
 
 
 
 
 
 
 
 
 
single-arm 
 treatment  combined  with  cetuximab  500  mg/m 2  bi-weekly  as  first-line  
 
 
 
 
 
 
 
 
 
 
treatment.  FOLFIRI  (m)  or  FOLFOX6  (m)  was  administered  once  every  2  weeks  until  
 
 
 
 
 
 
 
 
 
  
 
 
the  completion  of  6  months  of  therapy,  or  the  presence  of  progressive  disease  (PD),  or  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
unacceptable  toxicity.   Cetuximab  was  administered  every  2  weeks  until  PD.   
  
Tumour  sample  quality  from  primary  or  metastatic  tissues  was  checked,  and  blood  
 
samples  were  collected  at  baseline  and  every  3  months  along  with  abdominopelvic  CT   
scan  imaging.  The  feasibility  of  bi-weekly  cetuximab  in  combination  with  chemotherapy  
 
(FOLFOX  or  FOLFIRI)  was  evaluated  by  means  of  progression  free  survival  (PFS),   
  
overall  survival  (OS),  objective  response  rate  (ORR),  and  reported  toxicities.  The  trial   
hypothesis  was  that  the  proposed  biomarkers  would  allow  identifying  those   patients   
who  would  benefit  the  most  from  bi-weekly  cetuximab  therapy.  KRAS  and  NRAS  
 
mutations  were  evaluated  by  pyrosequencing,  BRAF  and  PI3K  mutations  by  RT-qPCR,  
 
and  PTEN  expression  by  immunohistochemistry.  The  PFS  (time  from  the  signature  of   
the   ICF  date  to  PD  or  death)  and  OS  (time  from  the  signature  of  the  ICF  date  to  death)   
were   analysed  and  compared  between  patients  with:  wild-type  (wt)  BRAF  (wt-BRAF)  vs   
mutant   BRAF,  and  in  patients  with  increased  PI3K  pathway  activation  (PI3K  mutant  or   
loss  of   PTEN  expression)  vs  low  PI3K  pathway  activation  (wtPI3K  and  preserved  PTEN  
 
expression).   
  
Sponsor:  Grupo  Español  Multidisciplinar  en  Cáncer  Digestivo  (GEMCAD)  Spanish  
 
Multidisciplinary  Group  in  Digestive  Cancer   
  
Protocol  number:  GEMCAD  1002  -  POSIBA   
  
Clinical  Phase:  II   
  
Study  dates:  Study  initiation  date:  first  patient  enrolled  on  27/JUN/2011   
Study  completion  date  (last  patient  completed):  20/JUN/2017  
 
  
  
This  study,  including  the  archiving  of  essential  documents,  was  performed  in  
 
compliance  with  ICH  Good  Clinical  Practice  (GCP)  
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   3  of  36  
 


1.  SYNOPSIS  
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   4  of  36  
 
NAME  OF  SPONSOR:  GEMCAD   
  
NAME  OF  FINISHED  PRODUCT  N/A   
  
NAME  OF  ACTIVE  INGREDIENT(S):  CETUXIMAB  
 
Title  of  Study  
 
A  prospective,  multicentre,  single-arm,  phase  II  clinical  trial  to   
evaluate   biomarkers  in  advanced  and/or  metastatic  colorectal  cancer   
patients  with   wild-type  KRAS/NRAS  status  treated  with   
chemotherapy  plus  bi-weekly  cetuximab  as  first-line  therapy.  
 
Investigator(s)  
 
Dr.  Ramón  Rodríguez   
  
Dr.  Javier  Gallego   
  
Dr.  Rosario  Dueñas   
  
Dr.  Mª  Ángeles  Rodríguez   
  
Dr.  Joan  Maurel   
  
Dr.  Jaime  Feliu   
  
Dr.  Vicente  Alonso   
  
Dr.  Hermini  Manzano   
  
Dr.  Montse  Zanui   
  
Dr.  Carlos  Fernández-Martos   
  
Dr.  Antonieta  Salud   
  
Dr.  Jorge  Molina   
  
Dr.  Ruth  Vera   
  
Dr.  Carlos  García   
  
Dr.  Uriel  Bohn   
  
Dr.  Esther  Falcó   
  
Dr.  Carmen  Alonso   
  
Dr.  Isabel  Antón   
  
Dr.  Mireia  Gil   
  
Dr.  Miguel  Méndez   
  
Dr.  Pilar  Escudero   
  
Dr.  Verónica  Calderero   
  
Dr.  Julen  Fernández   
  
Dr.  Ana  León  
  
Dr.  Pilar  Vicente   
  
Dr.  Joaquín  Pérez  de  Olaguer   
  
Dr.  Adelaida  la  Casta   
  
Dr.  Ferrán  Losa  
 


 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   5  of  36  
 
Study  centre(s)   
  
H.  Infanta  Cristina   
  
H.G.U.  Elche   
  
H.  Jaén   
  
H.  San  Pedro  de  Alcántara   
  
H.  Clínic  de  Barcelona   
  
H.  La  Paz   
  
H.  Miguel  Servet   
  
H.  Son  Espases   
  
H.  de  Mataró  Fundación  IVO   
  
H.U.  Arnau  de  Vilanova   
  
H.P.  de  Castellón   
  
H.  de  Navarra   
  
H.  General  Yagüe/  H.U.  Burgos   
  
H.U.  Dr.  Negrin   
  
H.  Son  Llàtzer   
  
C.H.U.  Albacete   
  
H.  Sant  Jaume  de  Calella   
  
H.  de  Sagunto   
  
H.  de  Móstoles   
  
H.  Clínico  Lozano  Blesa   
  
H.  de  Barbastro   
  
Mutua  de  Terrassa   
  
Fundación  Jiménez  Díaz   
  
H.  General  de  Granollers   
  
H.  Plató   
  
H.  Universitario  de  Donostia   
  
H.  Sant  Joan  Despi  -  Moises  Broggi  
 
Objectives   
  
Primary  Objective   
  
To  evaluate  BRAF,  IGF-1RP/MMP-7  (Double-positive  Phenotype/DP),   
and  PI3K-PTEN  as  well  as  other  relevant  biomarkers  which  may  arise  
 
during  study  implementation,  to  predict  PFS  in  advanced  and/or  
 
metastatic  colorectal  cancer  patients  with  wt-RAS  tumours  treated  with  
 
standard  chemotherapy  plus  bi-weekly  cetuximab  as  first-line  therapy.   
  
Secondary  Objectives   
  
●  To  analyse  secondary  biomarkers  (MMP-7,  IGF-1,  IGFBP-3,  
 
 
 
 
 
 
 
 
amphiregulin,  and  epiregulin,  as  well  as  other  relevant  biomarkers,  
 
 
 
 
 
 
 
 
 
which  may  arise  during  the  study)  in  the  serum  and  tumour  tissues  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
predict   acquired  chemoresistance.   
  
●  OS  based  on  the  proposed  classification   
  
●  ORR  according  to  RECIST  1.1  (46)   
  
●  Safety  of  treatment  with  bi-weekly  cetuximab  at  500  mg/m 2  
 


 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   6  of  36  
 
Methodology   
  
We  conducted  a  biomarker-evaluation  phase  II  trial.  A  total  of  181  wt 
 
  
 
  
 
 
 
 
 
 
KRAS  exon  2  patients  were  evaluated  for  whole  KRAS  and  NRAS 
 
 
 
 
 
 
 
 
 
 
 
mutations  by  pyrosequencing,  BRAF  and  PI3K  mutations  by  RT-qPCR,  
 
 
 
 
 
 
 
 
 
and  PTEN  expression  by  immunohistochemistry.  Patients  were  followed 
 
 
 
 
 
 
 
 
every  3  months  with  abdominopelvic  CT-scan  imaging  and  clinical 
 
 
 
 
 
 
 
 
 
examination.  PFS  (time  from  the  signature  of  the  ICF  date  to 
 
 
 
 
 
 
 
 
 
 
 
progression  or  death)  and  OS  (time  from  the  signature  of  the  ICF  date 
 
 
 
 
 
 
 
 
 
 
 
 
 
to  death)  in  patients  with  wt-BRAF  vs  mutant  BRAF  and  in  patients  with 
 
 
 
 
 
 
 
 
 
  
 
 
increased  PI3K  pathway  activation  (PI3K  mutant  or  loss  of  PTEN 
 
 
 
 
 
 
 
 
 
 
expression)  vs  low  PI3K  pathway  activation  (wt-PI3K  and  preserved  
 
 
 
 
 
 
 
 
 
PTEN  expression)  were  evaluated.  Univariate  and  multivariable 
 
 
 
 
 
 
 
analyses  of  BRAF  and  PI3K-PTEN  together  with  well-known  clinical 
 
 
 
 
 
 
 
 
 
variables  were  performed.  Safety  was  evaluated  based  on  type, 
 
 
 
 
 
 
 
 
 
frequency,  and  intensity  of  adverse  events  related  to  the  combination 
 
 
 
 
 
 
 
 
 
 
treatment.  
 
Number  of  patients   
  
Target  events  for  primary  endpoint:   
  
Planned:  170  patients   
  
Enrolled:   
  
Analysed  for  safety:   
  
Analysed  for  efficacy:   
  
Diagnosis  and   
main   criteria  for   
inclusion  
 
Main  inclusion  criteria:   
  
Patients,  men  or  women  18  years  or  older,  with  advanced  and/or  
 
 
 
 
 
 
 
 
 
 
 
metastatic  wt-KRAS  and  NRAS  colorectal  cancer,  histologically  or  
 
 
 
 
 
 
 
 
cytologically  confirmed  and  radiologically  measurable,  with  ECOG  
 
 
 
 
 
 
 
performance  status  0  to  2  and  adequate  hepatic,  renal,  and  
 
 
 
 
 
 
 
 
 
 
haematological  function,  all  after  provision  of  the  patients’  signed  
 
 
 
 
 
 
 
 
 
informed  consent.  Patients  were  included  only  if  their  tumour  samples  
 
 
 
 
 
  
 
 
 
were  of  the  required  quality  to  perform  the  proposed  biomarker  tests.  
 
 
 
 
 
 
 
 
 
 
 
The  centralised  review  laboratory  was  responsible  for  evaluating  the  
 
 
 
 
 
 
 
 
 
quality  of   the  tumour  blocks.   
  
Main  exclusion  criteria:   
  
Patients  who  have  received  a  previous  systemic  treatment  for  their  
 
 
 
  
 
 
 
 
 
metastatic  colorectal  cancer  were  excluded  from  the  trial.  Those  who  
 
 
 
 
 
 
 
 
 
 
have  previously  undergone  metastatic  surgery  (liver,  lung,  or  other),  
 
 
 
 
 
 
 
 
 
presenting  with  central  nervous  system  metastasis  or  significant  
 
 
 
 
 
 
 
 
cardiovascular  disease  will  also  be  excluded.  
 
Test  product,   
dose   and  mode   
of   
  
administration  
 
Cetuximab  (Erbitux®  5  mg/ml  -  500  mg/m 2  every  2  weeks)  was  
 
 
 
  
 
 
 
 
 
 
administered  intravenously  with  an  infusion  pump,  gravity  drip,  or  a  
 
 
 
 
 
 
 
 
  
syringe  pump.  The  duration  of  the  cetuximab  infusion  was  120  
 
 
 
 
 
 
 
 
 
 
minutes  for  the  first  cycle,  90  minutes  for  the  second,  and  60  minutes  
 
 
 
 
 
 
 
 
 
 
 
 
 
for  the  third  and  subsequent  cycles.  Prior  to  all  cetuximab  infusions,  
 
 
 
 
 
 
 
 
 
 
 
patients  received  adequate  premedication  as  prophylaxis  against  an  
 
 
 
 
 
 
 
 
acute  hypersensitivity 
 reaction  with  an  antihistamine  and  a  
 
 
 
 
 
 
 
 
corticosteroid,  according  to  local   
  
practice.  
 


 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   7  of  36  
 
Duration  of   
treatment   
  
Cetuximab  (Erbitux®)  500  mg/m 2  bi-weekly  until  underlying   
disease   progression.  
 
Criteria  for  evaluation    
Primary:   
  
PFS  comparing  2  cohorts  of  patients,  which  will  be  defined  according  to 
the  classification  based  on  the  predictive  capacity  of  each  biomarker.   
  
Secondary:   
  
●  ORR:  incidence  of  a  complete  or  partial  response  according  to  the  
 
revised  RECIST  1.1  criteria.   
  
●  Duration  of  response  (DoR);  calculated  only  for  the  subjects  who  
 
 
 
 
 
 
 
 
 
 
 
present  an  objective  response  and  considering  the  time  from  the  
 
 
 
 
 
 
 
 
 
 
first 
 objective  response  to  radiological  disease  progression,  
 
 
 
 
 
 
 
according  to 
 the  revised  RECIST  1.1  criteria.  For  responding  
 
 
 
 
 
 
 
 
 
subjects  without  disease  progression,  DoR  are  censored  at  the  last  
 
 
 
 
 
 
 
 
 
 
date  of  assessable   disease  evaluation.  
 
 
 
●  OS:  time  from  the  signature  of  the  ICF  date  date  to  date  of  death.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For  subjects  who  have  not  died,  or  are  lost  to  follow-up  at  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
closing  date  for  data  analysis,  OS  will  be  censored  at  the  date  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
last  contact.   
  
●  Safety:  type,  frequency,  and  intensity  of  adverse  events  related  to   
the   combination  treatment.  
 


 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   8  of  36  
 
Statistical  methods   
  
Sample  size  considerations   
  
Initially,  the  number  of  patients  required  to  be  recruited  in  24  months  
 
 
 
 
 
 
 
 
 
 
 
 
was  155  and  the  total  study  duration  (recruitment  +  follow-up)  was  
 
 
 
 
 
 
 
  
 
 
considered  to  be  28  months  for  115  events  to  occur.  After  recruiting  
 
 
 
 
 
 
 
 
 
 
 
 
157  patients,  it  was  determined  that  about  70  of  these  patients  had  
 
  
 
 
 
 
 
 
 
 
 
insufficient  samples  for  biomarker  analysis  preventing  their  inclusion  
 
 
 
 
 
 
 
 
in  the  analysis  of  the  primary  objective.  Therefore,  in  order  to  reach  
 
 
 
 
 
 
 
 
 
 
 
 
the  115  events  necessary  to  evaluate  the  primary  endpoint,  the  total  
 
 
 
 
 
 
 
 
 
 
 
number  of  patients  to  be  included  in  the  trial  was  increased  up  to  240.  
 
 
 
 
 
  
 
 
 
 
 
 
 
Finally,  221  patients  were 
 considered  sufficient  to  observe  the  
 
 
 
 
 
 
 
 
 
required  number  of  events.  After  central  reviewing  and  monitoring,  
 
 
 
 
 
 
 
 
 
181  patients  with  wt-RAS  were  finally   included  for  efficacy  analysis.   
  
For  sample  size  calculation,  it  was  assumed  that  patients  could  be  
 
 
 
  
 
 
 
 
 
 
classified  into  2  groups  based  on  their  clinical  characteristics  and  their  
 
  
 
 
 
 
 
 
 
 
biomarker  profile.  The  log-rank  method  was  planned  to  be  used  for  the  
 
 
 
 
 
 
 
 
 
 
 
 
comparison  of  PFS  during  follow-up  between  the  two  groups.  A  
 
 
 
 
 
 
 
 
 
 
minimum 
 difference  in  PFS  of  20%  (50%  vs  30%)  was  expected  
 
 
 
 
 
 
 
 
 
 
 
between  the   groups  at  12  months,  given  the  following  assumptions:   
  
●  Alpha  error  (two-tailed):  5%   
  
●  Beta  error:  20%   
  
Statistical  considerations   
  
The  primary  and  the  secondary  efficacy  objectives  were  analysed   
using   per-protocol  analysis.  Patients  fulfilling  all  eligibility  criteria  and   
with  documented  wt-RAS  status  (KRAS  and  NRAS)  were  included  in   
the   efficacy  analysis.   
  
Efficacy  analysis  was  based  on  radiological  imaging  performed  
 
 
 
 
 
 
 
 
throughout  the  study  and  assessed  by  site  investigators.  Any  finding  
 
 
 
 
 
 
 
 
 
 
considered  as  non-evaluable  by  the  investigator  was  excluded  from  
 
 
 
 
 
 
 
 
 
the   analysis  (it  was  considered  as  non-existent).   
  
For  continuous  variables,  mean,  standard  error  (for  efficacy  variables),  
 
 
 
 
 
 
 
 
 
standard  deviation  (for  other  measurements),  median,  25 th  percentile,  
 
 
 
 
 
 
 
 
75 th  percentile,  minimum  and  maximum,  were  considered.  Categorical  
 
 
 
 
 
 
 
 
variables  are  presented  using  frequencies  and  percentages.   
  
The  95%  two-sided  confidence  intervals  (CI  95%)  of  Kaplan–Meier    


 
 
12-MONTHS  PFS  RISK  MODEL  DEFINITION   
  
Clinical  variables  and  biomarkers  were  used  to  build  a  score  to  predict  12-months  PFS,  by  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
using  a  multivariable  Cox  regression  model  built  with  those  clinical  variables  with  a  p≤0.15  in  
 
 
 
 
 
 
 
 
 
 
 
  
  
the  multivariable  analysis  (performance  status,  chemotherapy  regimen,  sidedness,  resectable  
 
 
 
 
 
 
 
 
 
only  liver  metastases).  Once  the  first  risk  score  was  built  adding  up  the  coefficients  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
multivariable  model  (PS>0=  0.6,  left  sided=-0.5,  resectable  liver  only  metastases=-0.4  and  
 
 
 
 
 
 
 
 
 
 
 
folfiri+cetuximab  therapy=Not  evaluable),  ROC  curves  were  computed  for  PFS  at  12  months  
 
 
 
 
 
 
 
 
 
 
 
 
using  a  logistic  regression  model.  All  4  scores  ( A.  Clinical  variables  including  PS,  sidedness  
  
 
 
 
  
 
 
 
 
 
 
 
and  resectable  only  liver  metastases,  B.  Clinical  variables  +  BRAF  mutation;  C.  Clinical  
 
 
 
 
 
 
 
 
 
 
 
 
 
variables  +  PI3K  mutation  or  PTEN  ≤3;  D.  Clinical  variables  +  DP)  had  comparable  low  areas  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
under  the  curve,  ranging  between  0.5  and  0.7,  overall:  The  AUC  of  the  score  containing  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  variables  was  0.67  (95%  CI)  (0.60-0.75).   
  
The  AUC  of  the  score  with  clinical  variables  and  BRAF  mutational  status  was  0.68  (0.61-0.75,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p-value  =  0.37).  The  AUC  of  the  score  with  clinical  variables  and  PI3KCA  mutation/PTEN  
  
 
 
 
 
 
 
 
 
 
 
 
 
status  was  0.69  (0.61-0.76,  p-value  =  0.32).  The  AUC  of  the  score  with  clinical  variables  and  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
DP   phenotype  was  0.66  (0.58-0.73,  p-value  =  0.09).   
  
SAFETY  RESULTS   
  
CONCLUSIONS   
  
DATE  OF  THE  REPORT:   
  
 
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   9  of  36  
 
 
 
quartiles  were  calculated  according  to  Brookmeyer  and  Crowley   
methods   (55,56).  Safety  data  were  analysed  throughout  the  entire   
study.   
  
In  the  first  step  to  develop  a  prediction  model  for  PFS,  univariate  Cox 
 
 
 
 
 
  
 
 
 
 
 
 
regression  analysis  including  all  clinical  variables  collected  in  the  study 
 
 
 
 
 
 
 
 
 
 
was  performed  in  order  to  identify  which  should  be  considered  for  the  
 
 
 
 
 
 
 
 
 
 
 
 
model  selection  thereafter  in  the  second  step.  All  factors  with  a  ≤0.15  p    
value  (Appendix  15.2,  item  4)  were  selected  for  the  multivariable  Cox 
 
 
 
 
 
 
 
 
 
 
 
analysis.  The  cut-off  of  ≤0.15  p-value  was  used  in  order  to  include  the 
 
 
 
 
 
 
 
 
 
 
 
 
 
presence  of  resectable  liver  metastases  as  that  is  a  well-known 
 
 
 
 
 
 
 
 
 
 
prognostic  factor  in  mCRC.  In  the  second  step  multivariable  Cox  
 
 
 
 
 
 
 
 
 
 
regression  analysis  was  performed  including  those  variables  identified 
 
 
 
 
 
 
 
 
in  the  of  univariate  analysis.  Importantly,  the  variable  treatment  
 
 
 
 
 
 
 
 
 
(FOLFIRI  vs  FOLFOX)  was  not  included  for  the  development  of  the 
 
 
 
 
 
 
 
 
 
 
 
prediction  score  because  it  was  not  a  characteristic  intrinsic  to  the 
 
 
  
 
 
 
 
 
 
 
patients.  
 


2.  TABLE  OF  CONTENTS   
  
 
 
1.  SYNOPSIS  
 
2.  TABLE  OF  CONTENTS   
  
LIST  OF  ABBREVIATIONS  &  DEFINITION  OF  TERMS  
 
3.  INVESTIGATORS  AND  STUDY  ADMINISTRATIVE  STRUCTURE  
 
4.  INTRODUCTION  
 
5.  STUDY  OBJECTIVES  
 
6.  INVESTIGATIONAL  PLAN  
 
7.  RESULTS  
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   10  of  36  
 


LIST  OF  ABBREVIATIONS  &  DEFINITION  OF  TERMS   
  
Abbreviation/   
  
Acronym  Definition   
  
5-FU  5-fluorouracil   
  
AE  Adverse  event   
  
AEMPS  Agencia  Española  de  Medicamentos  y  Productos  Sanitarios   ALT 
Alanine  aminotransferase   
  
AST  Aspartate  aminotransferase   
  
CEA  Carcinoembryonic  antigen   
  
CI  Confidence  interval   
  
CNS  Central  nervous  system   
  
CR  Complete  Response   
  
CRF  Case  report  form   
  
CrCl  Creatinine  clearance   
  
CT  Computerised  tomography   
  
CTCAE  Common  terminology  criteria  for  adverseevents   DP  Double-positive   
phenotype  (Co-expression  of  p-IGFR-1  and  MMP-7)  DoR  Duration  of  Response   
  
ECG  Electrocardiogram   
  
ECOG  PS  Eastern  Cooperative  Oncology  Group  performancestatus  
 
EGF  Epidermal  growth  factor   
  
EGFr  Epidermal  growth  factor  receptor   
  
EoT  End  of  Treatment   
  
FOLFIRI  (m)  Chemotherapy  regimen  with  irinotecanand  5-FU/leucovorin  infusion   
FOLFOX-6  (m)  Chemotherapy  regimen  with  oxaliplatin  and  5-FU/leucovorin   
infusion  GCP  Good  Clinical  Practice   
  
G-CSF  Granulocyte  colony  stimulatingfactor   
  
HIV  Human  immunodeficiency  virus   
  
ICH  International  Conference  on  Harmonisation   
  
ICF  Informed  Consent  Form   
  
IGF  Insulin-like  growth  factor   
  
IGFBP-3  Insulin-like  growth  factor-binding  protein-3   
  
IGFr  Insulin-like  growth  factor  receptor   
  
i.v.  Intravenous   
  
LDH  Lactate  dehydrogenase   
  
LLN  Lower  limit  of  normal   
  
ULN  Upper  limit  of  normal   
  
LV  Leucovorin   
  
mAb  Monoclonal  antibody   
  
mCRC  Metastatic  colorectal  cancer   
  
MMP-7  Matrix  metalloproteinase-  7   
  
MRI  Magnetic  resonance  imaging   
  
ORR  Objective  response  rate   
  
OS  Overall  survival   
  
PFS  Progression  free  survival  
 
PD  Progressive  disease   
  
PR  Partial  Response   
  
PTEN  Phosphatase  &  Tensin  homolog   
  
RBC  Red  blood  countRECISTResponse  Evaluation  Criteria  In  SolidTumours  ROC   
Receiver  operating  characteristic   
  
SAE  Serious  adverse  event   
  
SD  Stable  Disease   
  
SEOM  Sociedad  Española  de  Oncología  Médica  (Spanish  Society  of  MedicalOncology)  SIV   
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   11  of  36  
 


Site  initiation  visit   
  
StD  Standard  Deviation   
  
SUSAR  Suspected  unexpected  serious  adversereaction   
  
WBC  White  blood  count  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   12  of  36  
 


3.  INVESTIGATORS  AND  STUDY  ADMINISTRATIVE  STRUCTURE   
Table  II  shows  the  principal  study  personnel  involved.  
  
Table  II:  Principal  study  personnel  
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   13  of  36  
 
Title   
  
Name  and  affiliation  
 
Coordinating   
  
Investigator 
Dr.  Jesús  García-Foncillas  Director,  Department  of  Oncology   
Director,  Translational  Oncology  Division,  Health  Research   
Institute   Fundación  Jiménez  Día z  
 
Coordinating   
  
Investigator 
Dr.  Xabier  García-Albéniz  Department  of   
Epidemiology   Harvard  School  of  Public  Health  
 
Sponsor   
  
Dr.  Carlos  Fernández  Martos  Chairman  of  GEMCAD   
  
Grupo  Español  Multidisciplinar  en  Cáncer  Digestivo   
(GEMCAD)   Spanish  Multidisciplinary  Group  of  Digestive   
Cancer   
  
Secretari  Coloma,  64-68,  esc  B,  entlo  5º  08024  –   
Barcelona  e-mail:  secretaria@gemcad.org  Phone:  +  34   
93  434  44  12  Fax:  +  34  93  253  11  68  
 
Project   
  
Managers  
 
MFAR  Clinical  Research   
  
Federico  Nepote   
  
Robert  Morales  
 
Clinical   
  
Research   
  
Associate(s)  
 
MFAR  Clinical  Research   
  
Francisco  Roldán   
  
Isaac  Rubio   
  
Olga  Martínez   
  
Sara  Fabregas   
  
José  Luis  López   
  
Borja  Pelaez   
  
Cristina  Rusiñol   
  
Gessami  Sanchez   
  
Oscar  Peña   
  
Marina  Ruiz   
  
Alejandro  González   
  
Sonia  Diez   
  
Lucía  Carril   
  
Belén  Aranda  
 
Medical  Advisory   
  
Dr.  Joan  Maurel  Santasusana  -  H.  Clínic  Barcelona  
 
Data   
  
Management  
 
Federico  Nepote  -  MFAR  Clinical  Research   
  
Robert  Morales  -  MFAR  Clinical  Research  
 
Trial  Statistician   
  
Dr.  Xabier  García-Albéniz   
  
Department  of  Epidemiology   
  


 
 
Table  I:  Study  sites  
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   14  of  36  
 
Harvard  School  of  Public  Health  
 
Centre  name   
  
1.   
  
2.   
  
3.   
  
4.   
  
5.   
  
6.   
  
7.   
  
8.   
  
9.   
  
10.  
 
11.   
  
12.   
  
13.  
 
14.  
 
15.  
 
16.  
 
17.  
 
18.   
  
19.   
  
20.   
  
21.   
  
22.  
 
23.  
 
24.   
  
25.  
 
26.   
  
27.   
  
28.   
  
29.   
  


4.  INTRODUCTION   
  
4.1.  COLORECTAL  CANCER  (CRC)   
  
CRC  is  the  third  most  common  cancer  in  men  (746,000  cases,  10.0%  of  the  total)  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  second  most  common  in  women  (614,000  cases,  9.2%  of  the  total)  worldwide.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Almost 
 55%  of  the  cases  occur  in  more  developed  regions.  There  is  a  wide  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
geographical  variation 
 in  cancer  incidence  across  the  world,  and  the  geographical 
 
 
 
 
 
 
 
 
 
 
 
patterns  are  very  similar  in  men  and  women;  incidence  rates  vary  10-fold  in  both  sexes  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
worldwide,  the  highest  estimated  rates  being  in  Australia/New  Zealand  (ASR  44.8  and  
 
 
 
 
 
 
 
 
 
 
 
 
32.2  per  100,000  in  men  and  women,  respectively),  and  the  lowest  in  Western  Africa  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(4.5  and  3.8  per  100,000).   
  
Mortality  is  higher  (694,000  deaths,  8.5%  of  the  total)  with  more  deaths  (52%)  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
less  developed  regions  of  the  world,  reflecting  a  poorer  survival  in  these  regions.  There  
 
 
 
 
 
 
  
 
  
 
 
 
is  less  variability  in  mortality  rates  worldwide  (6-fold  in  men  and  4-fold  in  women),  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  highest  estimated  mortality  rates  in  both  sexes  in  Central  and  Eastern  Europe  (20.3  
 
 
 
 
  
 
  
 
 
 
 
 
per  100,000  for  men,  11.7  per  100,000  for  women),  and  the  lowest  in  Western  Africa  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(3.5 
 per 
 100,000 
 for 
 men 
 and 
 3.0 
 per 
 100,000 
 for 
 women).  
 
 
 
 
 
 
 
 
 
 
 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=colorectal   
  
It  is  expected  that  CRC  will  cause  about  50,630  deaths  during  2018  in  the  US.  Death  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
rate  (the  number  of  deaths  per  100,000  people  per  year)  associated  with  CRC  has  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
been  dropping  in  both  men  and  women  in  the  past  several  decades.  One  reason  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
this  is  that  the  early  diagnosis  of  colorectal  polyps  is  possible,  and  these  polyps  are  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
removed  before  they  can  develop  into  cancers  and  hinder  cancer  treatment.  In  addition,  
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  for  CRC  has  improved  over  the  last  few  decades.  As  a  result,  there  are  now  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
more  than  1   million  survivors  of  CRC  in  the  US  (1).   
  
According  to  the  Globocan  estimation  of  2012,  447,136  new  cases  of  CRC  were  
 
 
 
 
 
 
 
 
 
 
 
 
 
diagnosed  in  Europe  (second  most  common  cancer,  accounting  for  13.0%  of  all  cancers  
 
 
 
 
 
 
 
 
 
 
 
 
 
apart  from  non-melanoma  skin  cancers)  and  214,866  deaths  from  CRC  in  Europe  
 
 
 
 
 
 
 
 
 
 
 
 
(12.2% 
 of  the  total  number  of  cancer  deaths,  second  most  common  cause  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
cancer-related  deaths)  (2).  The  most  recent  data  from  REDECAN  shows  colorectal  
 
 
 
 
 
 
 
 
 
 
 
cancer  as  the  most  frequently  diagnosed  in  2015,  followed  by  prostate  (33,370  cases),  
 
 
 
 
 
 
 
 
 
 
 
 
 
lung  (28,347  cases),   breast  (27,747  cases),  and  bladder  (21,093  cases)  (3)   
  
Data  from  the  SEOM  state  that  41.441  new  cases  of  CRC  were  diagnosed  in  Spain  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2015  (16.3%  of  all  tumour  incidences),  making  CRC  the  most  diagnosed  cancer.  
 
 
 
 
 
 
 
 
 
 
 
 
Moreover,  CRC  is  the  second  most  common  cause  of  cancer  death  in  our  country,  after  
 
  
 
 
 
 
 
 
 
  
 
 
 
lung  cancer,  with  over  15,449  deaths  in  2014  (4).   
  
Out  of  the  newly  diagnosed  cases,  15–20%  correspond  to  patients  with  metastatic  
 
disease  at  the  time  of  diagnosis  (5)  and  up  to  50%  of  all  patients  eventually  present  with   
metastatic  disease  (5,6).  Generally,  CRC  is  curable  if  diagnosed  at  an  early  stage,  and  it  
 
is  confined  to  the  intestinal  mucosa,  with  a  5-year  survival  rate  of  93%  (7).  However,  the  
 
5-year  survival  rate  decreases  to  67%  if  the  tumour  spreads  to  adjacent  organs  and   
lymph   nodes,  and  it  is  only  8%  in  patients  with  disseminated  metastatic  disease  (5,7).   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   15  of  36  
 


4.1.1.  CRC  treatment   
  
Historically,  the  median  survival  rate  of  patients  with  metastatic  disease  has  been  11–13  
 
 
 
 
 
 
 
 
 
 
 
 
 
months  after  treatment  with  a  combination  of  the  fluoropyrimidine,  5-fluorouracil  (5-FU),  
 
 
 
  
 
 
 
 
 
 
and  leucovorin  (LV)  (8).  The  introduction  of  oxaliplatin  and  irinotecan  in  advanced  
 
 
 
 
 
 
 
 
 
 
 
 
colorectal  chemotherapy  has  improved  the  frequency  and  extent  of  clinical  response  
 
 
 
 
 
 
 
 
 
 
 
compared  with  that  achieved  with  5-FU/LV  alone,  and  it  has  enhanced  progression  free  
 
 
 
 
 
 
 
  
 
 
 
 
survival  (PFS)  and  overall  survival  (OS).  Current  research  is  focused  on  optimising  this  
 
 
 
 
 
 
 
  
 
 
 
 
systemic  chemotherapeutic  regimen.   
  
Irinotecan,  a  specific  DNA  topoisomerase  I  inhibitor,  has  shown  significant  activity  as  a 
  
 
 
  
 
 
 
 
 
  
single  agent  in  the  treatment  of  patients  with  CRC  refractory  to  5-FU  (9,10).  
 
 
 
 
 
 
 
 
 
 
 
 
 
Furthermore, 
 the  addition  of  irinotecan  to  the  combination  therapy  with  5-FU/LV  
 
 
 
 
 
 
 
 
 
 
 
(FOLFIRI  regimen)  significantly  improves  OS,  response  rate,  and  time  until  progression  
 
 
 
 
 
 
 
 
 
 
 
in  the  therapy  of   previously  untreated  mCRC  compared  to  5-FU/LV  alone  (11).   
  
Oxaliplatin,  a  platinum  analogue,  causes  the  inter-  and  intra-strand  cross-linking  of  DNA,  
  
 
 
 
 
 
 
 
 
 
 
thereby  preventing  DNA  replication.  It  is  effective  and  well  tolerated  when  administered  
 
 
 
   
 
 
 
 
 
 
with  LV  as  a  bolus  and  an  infusion  (FOLFOX  regimen);  however,  neutropenia  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
sensory  neuropathies  are  more  frequent  with  this  combination  than  with  treatment  with  
 
 
 
 
 
 
 
 
 
 
 
 
5-FU  and  LV  alone  (12,13,14,15,16).  In  recent  years  there  has  been  significant  progress  
 
 
 
 
 
 
 
 
 
 
 
 
 
in  the  treatment  of  mCRC,  which  has  resulted  in  the  improvement  of  patient  life  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
expectancy.   
  
Therapies  targeted  against  vascular  endothelial  growth  factor  receptor  and  epidermal  
 
growth  factor  receptor  (EGFr)  have  been  recently  established  in  mCRC  treatment.   
  
It  has  been  proved  that  targeted  therapies,  specifically  designed  to  inhibit  carcinogenic  
 
 
 
 
 
 
 
 
 
 
 
 
biochemical  processes,  are  effective  in  the  treatment  of  mCRC.  Cetuximab  (Erbitux®),  a  
 
 
 
  
 
 
 
 
 
  
chimeric  monoclonal  antibody  targeted  against  EGFr,  has  been  approved  by  the  FDA  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
use  in  combination  with  irinotecan  for  the  treatment  of  EGFr-expressing  mCRC  in  
 
 
 
 
 
 
 
 
 
 
 
 
patients  who  are  refractory  to  irinotecan-based  chemotherapy.  It  has  also  been  
 
 
 
 
 
 
 
 
 
 
 
approved  as  a  single  agent  for  the  treatment  of  EGFr-expressing  recurrent  mCRC  in  
 
  
 
 
 
 
 
 
 
 
 
 
patients  who  are  intolerant  to  irinotecan-based  chemotherapy  (17,18,19,20).  Within  the  
 
 
 
 
 
 
 
 
 
 
European  Union 
 (Erbitux®  SmPC),  cetuximab  is  indicated  for  the  treatment  of  
 
 
 
 
 
 
 
 
 
 
 
EGFr-expressing  wt-RAS  mCRC:   
  
●  in  combination  with  irinotecan-based  chemotherapy,   
  
●  as  first-line  therapy  in  combination  with  FOLFOX,  
 
●  as  a  single  agent  in  patients  refractory  to  oxaliplatin  and  irinotecan-based  therapy  
 
and  who  are  intolerant  to  irinotecan.   
  
Bevacizumab  (Avastin®)  is  another  selective  product  that  binds  to  and  neutralises  the  
 
 
 
 
 
 
 
 
 
 
 
 
biologic  activity  of  human  vascular  endothelial  growth  factor-A,  a  protein  with  a  crucial  
 
 
 
 
 
 
 
  
 
  
 
role  in  tumour  angiogenesis.  Bevacizumab,  in  combination  with  fluoropyrimidine-based  
 
 
 
 
 
 
 
 
 
chemotherapy,  is  indicated  for  the  treatment  of  mCRC  (Avastin®  SmPC).   
  
There  are  2  monoclonal  antibodies  targeted  against  EGFR:  panitumumab  and  cetuximab.   
  
Panitumumab  is  presently  indicated  for  the  treatment  of  wt-RAS  mCRC  in  adult   
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   16  of  36  
 


patients:  ●  as  first-line  therapy  in  combination  with  FOLFOX  or  FOLFIRI,  ●  as   
second-line  therapy  in  combination  with  FOLFIRI  for  patients  who  have   received   
first-line  fluoropyrimidine-based  chemotherapy  (excludingirinotecan),  ●  as  monotherapy   
after  the  failure  of  fluoropyrimidine-,  oxaliplatin-,  and  irinotecan  containing   
chemotherapy  regimens  for  the  treatment  of  EGFr-expressing  mCRC  in   patients  who   
are  refractory  to  fluoropyrimidine-,  oxaliplatin-,  and  irinotecan-based   chemotherapy   
(Vectibix®  SmPC).   
  
The  monoclonal  antibody,  cetuximab,  was  approved  by  the  EMEA  in  July  2008  as  first   
line  treatment  of  mCRC  in  patients  who  fulfil  the  criteria  detailed  below.   
  
Cetuximab  is  currently  indicated  for  the  treatment  of  patients  with  EGFr-expressing  wt   
RAS  mCRC:   
  
●  in  combination  with  irinotecan-based  chemotherapy,   
  
●  as  first-line  therapy  in  combination  with  FOLFOX,   
  
●  as  a  single  agent  in  patients  who  have  failed  oxaliplatin-  and  irinotecan-based  
 
therapy  and  who  are  intolerant  to  irinotecan  (Erbitux®  Datasheet).   
  
Therefore,  the  current  indication  for  cetuximab  as  first-line  treatment  in  patients  with  
 
 
 
 
 
 
 
 
 
 
 
 
EGFr-expressing  wt-RAS  mCRC,  reflected  in  the  SPC,  was  established  after  the  
 
 
 
 
 
 
 
 
 
 
 
CRYSTAL  and  OPUS  clinical  trials,  and  it  was  verified  that  cetuximab  could  be  used  in  
 
 
 
 
 
  
 
 
 
 
 
 
  
routine  clinical  practice  in  combination  with  irinotecan  and  oxaliplatin  chemotherapy  
 
 
 
 
 
 
 
 
 
 
regimens  as  first-line  treatment.   
  
The  PRIME  study  results,  published  in  NEJM  (Douillard  and  cols,  Sep  2013) ,  showed  
 
 
 
 
 
 
 
 
 
 
 
 
 
that  patients  with  mutations  of  KRAS  exon  3  and  exon  4  or  of  NRAS  exon  2,  exon  3,  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
and  exon  4  do  not  benefit  from  treatment  with  FOLFOX  and  panitumumab  compared  
 
  
 
 
 
 
 
 
 
 
 
 
with  FOLFOX  alone.  The  FIRE-3  study,  presented  at  ESMO  2013,  confirms  the  same  
 
 
 
 
 
 
 
 
 
 
 
 
 
findings 
 with  FOLFIRI+cetuximab  vs.  FOLFIRI+bevacizumab.  Therefore,  patients  
 
 
 
 
 
 
 
enrolled  in  this 
 current  trial  were  evaluated  for  mutational  status  of  the  mentioned  
 
 
 
 
 
 
 
 
 
 
 
 
 
genes  at  the  indicated   exons.  
 
4.1.2.  CRYSTAL  study   
  
The  CRYSTAL  study  was  designed  to  evaluate  the  efficacy  of  adding  cetuximab  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFIRI  as  first-line  treatment  of  mCRC.  It  is  a  phase  III  trial  comparing  FOLFIRI  vs  
 
 
 
 
 
  
  
 
 
 
 
 
 
FOLFIRI+cetuximab.  Sample  size  was  1,198  patients,  randomised  1:1  according  to  
 
 
 
 
 
 
 
 
 
 
geographical  site  location  and  Eastern  Cooperative  Oncology  Group  performance  status  
 
 
 
 
 
 
 
 
 
 
(ECOG  PS).  The  CRYSTAL  study  design  contemplated  PFS  as  the  primary  objective  
 
 
 
 
 
 
 
 
 
 
 
 
and  OS,  response,  and  safety  as  secondary  objectives.  Efficacy  analysis  of  KRAS  
 
 
 
 
 
 
 
 
 
 
 
 
status  was   retrospectively  performed.   
  
Updated  survival  data  on  the  wt-KRAS  status  of  CRYSTAL  study  patients  treated  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
the  combination  of  FOLFIRI+cetuximab  were  presented  at  the  2009  ECCO/ESMO  
 
 
 
 
 
 
 
 
 
 
conference  in  Berlin  (21)  and  in  ASCO  GI  2010  (22)  after  a  longer  follow-up  period  and  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
a   higher  number  of  KRAS  determinations  than  in  the  original  publication:  45%  to  89%   
  
(21,22).  Significant  improvements  in  outcomes  features  were  observed  for  the  first  time  
 
 
 
 
 
 
 
 
 
 
 
 
including  ORR  (57.3%  vs  39.7%,  p<0.0001;  OR:  2.07,  CI95%:  1.52-2.83),  PFS  (9.9  vs 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4  months,  p=0.012;  HR:  0.70,  CI95%:  0.67-0.95),  and  OS  (23.5  vs  20  months,  
 
 
 
 
 
 
 
 
 
 
 
 
 
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p=0.0094;  HR:  0.8;  CI  95%:  0.67–0.95)  (21,22).   
  
These  data,  along  with  data  on  their  BRAF  mutational  status  (determined  in  83%  of  the  
 
patients)  (22)  confirms  the  superiority  of  the  combination  of  standard  chemotherapy  with  
 
cetuximab  in  wt-KRAS  patients,  in  terms  of  efficacy.  These  results  proved  superior  in  wt   
KRAS  and  wt-BRAF  patients,  and  the  presence  of  mutated  BRAF  worsened  the  results,  
 
regardless  of  the  treatment  used.  Therefore,  the  authors  concluded  that  BRAF  mutation  
 
is  a  negative  prognostic  factor  in  mCRC.   
  
4.1.3.  OPUS  20  study   
  
The  OPUS  20  study  is  a  randomised  phase  II  trial,  comparing  FOLFOX  vs  
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFOX+cetuximab  as  first-line  treatment  of  mCRC.  The  sample  size  was  292  patients,  
 
 
 
 
 
 
 
 
 
 
 
 
randomised  1:1  according  to  ECOG  PS.  The  OPUS  20  study  design  contemplated  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
superiority  of  response  rate  in  the  experimental  arm  as  the  primary  objective.  Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
analysis  of  KRAS  status  was  retrospective,  as  was  in  the  CRYSTAL  study.   
  
Updated  data  on  the  efficacy  of  the  FOLFOX-4+cetuximab  combination  in  wt-KRAS   
patients,  following  an  increment  in  the  number  of  patients  who  underwent  mutational  
 
status  determination  were  presented  at  the  ECCO/ESMO  2009  conference  (23)  and  
 
ASCO  GI  2010  (24).  A  higher  number  of  patients  with  KRAS  status  determination  93.5%   
vs  69.1%  in  the  original  publication)  was  reported  then.  The  OPUS  20  study   
re-confirmed   that  the  addition  of  cetuximab  to  FOLFOX  in  wt-KRAS  is  beneficial  in   
terms  of  PFS   (FOLFOX+cetuximab  arm:  8.3  vs.  7.2  months;  HR  0.57;  CI  95%   
0.38–0.86,  p=0.0064)  indicating  a  43%  reduction  in  the  risk  of  PD,  and  ORR   
(FOLFOX+cetuximab:  57.3%  vs   34%,  p=0.027;  OR:  2.55;  CI  95%:  1.38–4.72).  Benefit   
on  OS  was  not  statistically   demonstrated  with  median  OS  of  22.8  vs.  18.5  months   
(p=0.38)  (23,24).   
  
Results  of  a  meta-analysis  on  treatment  efficacy  after  adding  cetuximab  as  first-line  
 
  
 
 
 
 
 
 
 
 
 
mCRC  chemotherapy  in  the  CRYSTAL  and  OPUS  20  trials  were  presented  at  these  
 
 
 
 
 
 
 
 
 
 
 
 
 
conferences  (25).  This  study  involved  independent  data  on  845  wt-KRAS  mCRC  
 
 
 
 
 
 
 
 
 
 
 
patients  (666  patients  from  the  CRYSTAL  trial  and  179  patients  from  the  OPUS  20  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
trial).  The  analysis  showed  that  cetuximab  addition  offers  a  clear  benefit  in  the  ORR  
 
 
 
 
 
 
 
  
 
 
 
 
 
(with  an  odds   
  
ratio  above  2)  and  an  increase  in  PFS  for  wt-KRAS  patients  (the  risk  of  PD  was  reduced  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
by  34%;  HR  0.66;  p<0.001).  Moreover,  the  study  also  demonstrated  a  significant  
 
 
 
 
 
 
 
 
 
 
 
 
increment  in  the  OS  of  wt-KRAS  patients  who  received  cetuximab  (HR  0.81;  p=0.0062)  
 
 
 
 
 
 
 
 
 
 
 
 
 
(Table  6)  (26).   
  
HR/odds  ratio  95%  CI  p-value  Heterogenicity  p-value   
  
OS  0.81  0.69–0.94  0.0062  0.6696   
  
PFS  0.66  0.55–0.80  <0.0001  0.3332   
  
ORR  2.16  1.64–2.86  <0.0001  0.5568   
  
4.2.  RATIONALE  FOR  THE  STUDY   
  
Advanced  and/or  mCRC  is  a  heterogeneous  condition,  and  the  classification  of  
 
 
 
 
 
 
 
 
 
 
 
advanced  and/or  mCRC  patients  is  currently  poor.  Approximately  20%  of  the  patients  
 
 
 
 
 
 
 
 
 
 
 
 
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present  with  advanced  and/or  mCRC  at  early  stages  (<5  nodes  in  the  liver  and  size  <5  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
cm),  and  are  suitable  for  local  treatment  (surgery  or  local  ablative  therapy).  Additionally,  
 
 
 
 
 
 
 
 
 
 
 
 
 
10–15%  of  the  patients  show  a  poor  functional  status  (ECOG  PS>2)  or  exhibit  disability  
 
 
 
 
  
 
 
 
 
 
 
 
 
secondary  to  geriatric  syndromes  and/or  comorbidity  with  conditions  that  oppose  any  
 
 
 
 
 
 
 
 
 
 
 
strategy  other  than  supportive  care.  The  rest  of  the  patients  (patients  unsuitable  for  
 
 
 
 
 
 
 
 
 
 
 
 
 
radical  surgery)  represent  the  patient  population  treated  with  palliative  therapy.  Despite  
 
 
 
 
 
 
 
 
 
 
 
this,  not  all  patients  display  the  same  prognosis.  Patients  with  an  ECOG  PS  of  0–1  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lactate  dehydrogenase  (LDH)  levels  <  upper  limit  of  normal  (ULN;  intermediate  risk  
 
 
 
  
 
 
 
 
 
 
 
patients)  have  shown  better  PFS  and  OS  independent  of  the  therapy  in  all  previous  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
randomised   clinical  trials  (11,13,27).   
  
The  CRYSTAL  study  shows  that  FOLFIRI+cetuximab  in  wt-KRAS  patients  improves  
 
 
 
 
 
 
 
 
 
 
PFS  when  compared  with  FOLFIRI  treatment  alone.  Presently,  the  selection  of  patients  
 
 
 
 
 
 
 
 
 
 
 
 
to  undergo  cetuximab  treatment  was  based  on  KRAS  mutational  status,  which  enabled  
 
 
 
 
 
 
 
 
 
 
 
 
us 
 to  identify  those  patients  who  would  not  respond  to  therapy.  Other  activity  
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarkers   remained  to  be  evaluated.   
  
PTEN   
  
The  cytoplasmic  expression  of  PTEN  is  inversely  associated  with  PFS  in  CRC.  There  
 
 
 
 
 
 
 
 
 
 
 
 
 
are  2  primary  retrospective  studies  that  evaluated  PTEN  expression  in  patients  treated  
 
 
 
 
 
 
 
 
 
 
 
 
with   cetuximab.  However,  this  biomarker  had  not  yet  been  prospectively  evaluated.   
  
Bi-weekly  cetuximab  regimen   
  
The  cetuximab  standard  administration  regimen  implies  a  weekly  infusion  of  this  drug.   
Bi  weekly  administration  (i.e.  every  fortnight)  presents  2  advantages:  it  is  more   
convenient   for  the  patients  and  allows  health  systems  to  save  resources.    
However,  this  benefit  would  be  even  more  significant  in  the  case  of  treatment  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab  based  chemotherapy  regimens,  as  most  chemotherapy  regimens  combined  
 
 
 
 
 
 
 
 
 
with  cetuximab  are  administered  every  fortnight.   
  
This  possibility  has  been  studied  via  clinical  trials,  and  it  has  been  previously  
 
demonstrated  that  the  pharmacokinetics  and  pharmacodynamics  of  weekly  and   
bi-weekly  regimens  are  equivalent.  Phase  II  clinical  trials  of  cetuximab  in  combination   
with   chemotherapy  provide  data  confirming  the  hypothesis  that  the  toxicity  and  efficacy   
of  the   bi-weekly  regimen  are  similar  to  those  of  the  weekly  regimen.   
  
The  decision  for  using  the  bi-weekly  cetuximab  regimen  in  this  trial  was  based  on  the  
 
findings  described  below:   
  
Results  of  a  multicentre,  prospective,  uncontrolled  clinical  trial,  which  evaluated  the  
 
 
 
 
 
 
 
 
 
 
 
safety  profiles  of  70  patients  treated  with  irinotecan+cetuximab  at  500  mg/m 2  every  
 
 
 
 
 
 
 
 
 
 
 
 
fortnight, 
 were  presented  at  the  ASCO  GI  2008  conference.  Grade  3  and  grade  4  
 
 
 
 
 
 
 
 
 
  
 
  
toxicities  included  neutropenia  (6%),  diarrhoea  (6%),  asthenia  (7%),  and  acne-like  skin  
 
 
 
 
 
 
 
 
 
 
 
rash  (11.4%).  A  total  of  29  patients  were  eligible  for  the  treatment,  and  the  PFS  at  12  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
months  was  52%.  The  authors  concluded  that  bi-weekly  cetuximab  is  as  effective  and  
 
 
 
 
 
 
 
 
  
 
 
 
safe  as  the  standard   weekly  therapy  (28).   
  
An  exploratory  clinical  trial  of  bi-weekly  therapy  with  irinotecan  and  cetuximab  was  
 
 
 
 
 
 
 
 
 
 
 
 
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conducted  in  mCRC  patients,  who  had  received  at  least  one  previous  chemotherapy  
 
 
 
 
 
 
 
 
 
 
 
 
cycle.  In  this  trial,  a  total  of  40  patients  were  treated  with  irinotecan  at  180  mg/m 2  and  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab  at  500  mg/m 2  every  2  weeks  in  21-day  cycles  until  unacceptable  toxicity  or  
 
 
 
 
  
 
 
 
 
 
 
 
 
PD.  OR  was  22.5%  (2  complete  and  7  partial  responses).  Disease  control  rate  was  
 
 
 
 
 
 
  
 
 
 
 
 
 
60%.  Time 
 to  progression  was  3.4  months  and  OS  was  8  months.  The  bi-weekly  
 
 
 
 
 
 
 
 
 
  
 
 
 
regimen  demonstrated  good  tolerability.  Grade  3  and  grade  4  adverse  events  (AEs)  
 
 
 
 
  
 
  
 
 
 
were  observed  in  12  patients.  These  study  findings  show  that  bi-weekly  regimen  is  
 
 
 
 
 
 
 
 
 
 
 
 
 
similar  to   weekly  administration  schedule  in  terms  of  toxicity  and  efficacy  (29).   
  
A  single-centre  clinical  trial  was  conducted  on  74  patients  with  refractory  mCRC  treated  
 
 
 
 
 
 
 
 
 
 
 
 
 
with  irinotecan  and  cetuximab  at  500  mg/m 2  every  2  weeks.  Median  treatment  duration,  
 
 
 
 
 
 
 
  
 
 
 
 
ORR,  median  time  to  progression,  and  median  OS  were  4.3  months,  25%,  5.4  months,  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
and  8.9  months,  respectively.  Treatment  was  well  tolerated  (30).   
  
A  study  was  conducted  on  mCRC  patients,  which  retrospectively  compared  the  efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
and  safety  of  cetuximab  combined  with  irinotecan,  administered  either  weekly  or  bi  
 
 
 
 
 
 
 
 
 
 
 
 
weekly.  In  this  study,  patients  in  the  first  group  (n=32)  received  an  initial  dose  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab  at  400  mg/m 2 ,  followed  by  a  weekly  infusion  of  cetuximab  at  250  mg/m 2 . 
 
 
 
 
 
  
 
 
 
 
 
 
 
Patients  in  the  second  group  (n=18),  received  cetuximab  at  500  mg/m 2  bi-weekly.  ORR,  
 
 
 
 
 
 
 
 
 
 
 
 
 
PFS,  OS,  and  toxicity  were  compared  in  both  groups.  All  patients  had  received  
 
 
 
 
 
 
 
 
 
 
 
 
 
irinotecan  and  5-FU,  and  most  patients  had  previously  received  oxaliplatin.  Median  
 
 
 
 
 
 
 
 
 
 
 
follow-up  duration  for  all  patients  was  34.2  months.  PFS  and  OS  at  7  months  were 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
similar  in  both  groups.  Results  considering  the  proportion  of  patients  with  the  variable  
 
 
 
 
 
 
 
 
 
 
 
 
 
"disease  control 
 (complete  response  plus  partial  response  plus  those  with  stable  
 
 
 
 
 
 
 
 
 
 
 
disease)"  were  not  statistically  significant  (56.3%  weekly  cetuximab  patients  vs  77.8%  
 
 
 
 
 
 
 
 
 
 
 
bi-weekly  cetuximab  patients,  p=0.21),  and  when  treatment  toxicity  was  evaluated,  no  
 
 
 
 
 
 
 
 
 
 
 
patient  experienced  an  allergic  reaction  to  cetuximab,  nor  were  any  treatment-related  
 
 
 
 
 
 
 
 
 
 
 
deaths  reported;  the  most  significant  AE  was  dermatological  toxicity,  and  only  1  patient  
 
 
 
 
 
 
 
 
 
 
  
 
in  each  group  presented  with  a  grade  3  AE.  These  study  findings  indicated  that  the  
 
 
 
 
  
  
 
 
 
 
 
 
 
efficacy  of  weekly  and  bi  weekly  cetuximab  regimens  is  similar  without  increasing  
 
 
 
 
 
 
 
 
 
 
 
 
toxicity  in  association  with   irinotecan  (31).   
  
A  phase  I  clinical  trial  reported  that  cetuximab  at  500  mg/m 2  administered  bi-weekly  
 
  
 
 
 
 
 
 
 
 
 
 
shows  the  same  pharmacokinetic  profile  as  the  approved  weekly  regimen,  and  that  
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab 
 at  500  mg/m 2 
 can  be  administered  safely  bi-weekly  with  a  similar  
 
 
 
 
 
 
 
 
 
 
 
 
pharmacodynamic  profile,  concluding  that  the  bi-weekly  could  be  considered  as  an  
 
 
 
 
 
 
 
 
 
 
 
alternative  to  the  weekly   regimen  (32).   
  
These  reports  support  that  the  bi-weekly  and  weekly  cetuximab  administration  regimens  
 
are  equivalent  in  terms  of  efficacy  and  toxicity.   
  
At  the  time  of  trial  initiation,  there  was  no  published  information  on  the  usage  of  the  bi   
weekly  cetuximab  regimen  in  combination  with  oxaliplatin  (FOLFOX-6);  however,  there  
 
were  several  ongoing  clinical  trials  to  evaluate  this  treatment  regimen.  Experience  
 
gathered  from  daily  clinical  practice  at  some  hospitals  suggested  a  benefit  of  the  bi   
weekly  regimen  over  the  weekly  administration  schedule,  indicating  that  it  is  more  
 
convenient  for  patients  and  allows  health  systems  to  save  resources.  Therefore,  the  
 
sponsor  in  this  study  ultimately  left  the  choice  of  FOLFOX  or  FOLFIRI  treatment  to  the  
 
principal  investigators  (PIs)  at  each  centre,  according  to  their  own  experience  in  the  
 
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treatment  of  the  condition.  There  are  prior  data  on  the  efficacy  of  the  combination  of  
 
oxaliplatin  with  cetuximab-based  regimens,  and  no  difference  among  oxaliplatin   
regimens   has  been  reported.  Moreover,  the  added  convenience  of  combining  the   
FOLFOX-6   regimen  with  the  bi-weekly  administration  schedule  justifies  its  use  in  this   
study.  
 
After  demonstrating  differences  in  clinical  benefits  obtained  with  bi-weekly  cetuximab  
 
 
 
 
 
 
 
 
 
 
treatment  among  mCRC  patients,  considering  KRAS  mutational  status,  it  was  justified  to  
 
 
 
 
 
 
 
  
 
 
 
conduct  a  clinical  trial  with  the  secondary  objective  of  evaluating  the  cetuximab  toxicity  
  
 
 
 
 
 
 
 
 
 
 
 
profile  when  administered  as  a  bi-weekly  regimen.   
  
Justification  of  the  investigational  biomarkers   
  
Biomarker  evaluation  constitutes  one  of  the  fundamental  development  fields  at  
 
 
 
 
 
 
 
 
 
 
GEMCAD.  Biomarkers  currently  play  an  important  role  in  the  detection  and  treatment  of  
 
 
 
 
 
 
  
 
 
 
 
 
patients  with 
 CRC.  Biomarkers  also  direct  diagnostic  and  treatment  modalities  by  
 
 
 
 
 
 
 
 
 
 
 
facilitating  the  selection  of  therapeutic  drugs  across  a  broad  spectrum  of  patients.  There  
 
 
 
 
 
 
  
 
 
 
 
 
are  attempts 
 to  personalise  chemotherapy  based  on  the  presence  or  absence  of  
 
 
 
 
 
 
 
 
 
 
 
 
specific  biomarkers.  Therefore,  the  design  of  the  trial,  from  the  very  beginning,  included  
 
 
 
 
 
 
 
 
 
 
 
 
 
the  primary  endpoint 
 to  identify  the  potential  role  of  relevant  biomarkers  in  patient  
 
 
 
 
 
 
 
 
 
 
 
 
 
characterisation  and   treatment  selection.   
  
Role  of  insulin  growth  factor  receptor  (IGFr)  pathway  in  mCRC   
  
IGFr  is  overexpressed  in  CRC.  Neither  IGFr  amplification  nor  mutation  have  been  found  
  
 
 
 
 
 
 
 
 
 
 
 
in  CRC;  however,  it  is  probable  that  mechanisms  underlying  IGFr  transcriptional  
 
 
 
 
 
 
 
 
 
 
 
activation  are  involved  in  oncogenesis.  IGFr  activation  results  in  EGFr  phosphorylation  
 
 
 
 
 
 
 
 
 
 
 
by  an  autocrine/paracrine  pathway  through  the  cleavage  of  ligands  similar  to  EGF,  such  
 
 
 
 
 
 
 
 
 
 
 
 
 
as 
 heparin-binding 
 EGF, 
 amphiregulin, 
 tumour 
 necrosis 
 factor 
 alpha, 
 or  
 
 
 
 
 
 
 
 
 
metalloproteinases  (33,34).   
  
Matrix  metalloproteinase  (MMP)-7  and  its  relation  to  the  IGF  pathway   
  
MMP-7  is  a  metalloproteinase  secreted  within  the  tumour  microenvironment  by   
neoplastic   cells,  generally  facilitating  tumour  invasion,  tumour  progression,  and   
metastasis.  It  can   degrade  IGFr  pathway  proteins,  such  as  the  proapoptotic  insulin-like   
growth  factor  binding  protein  (IGFBP)-3  (35),  and  activate  EGFr  (36).  In  addition,   
activated  EGFr  can   stimulate  MMP-7  expression.  Several  in  vitro  studies  correlate  IGFr   
pathway  activation   with  resistance  to  EGFr  inhibitors  (37,38).   
  
In  vitro  observation  has  shown  that  MMP-7  increases  after  48  hours  of  oxaliplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment  in  the  native  cell  line  HT-29,  and  that  baseline  MMP-7  levels  are  4-fold  higher  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in  oxaliplatin-resistant  HT-29  cells  than  in  native  HT-29  cells  (39).  We  hypothesised  that  
 
 
 
 
 
 
 
 
 
 
 
 
 
chemotherapy  or  hypoxia  may  increase  MMP-7.  In  fact,  under  hypoxic  conditions,  MMP   
  
7  expression  was  found  to  be  upregulated  (40).   
  
It  has  been  observed  that  PD  in  untreated  CRC  patients  increases  MMP-3,  which  is   
associated  with  a  reduction  in  IGFBP-3  levels  (41).  IGFBP-2  level  in  oxaliplatin-resistant  
 
HT-29  cells  was  higher  than  that  in  native  HT-29  cells.  This  increment  in  IGFBP-2  level   
  
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may  induce  apoptosis  by  downregulating  IGF-1RP  and  pAKT;  however,  this  may  not  be  
 
 
 
 
 
 
 
 
 
 
 
 
 
possible  in  double-positive  resistant  HT-29  cells  (IGF-1RP+  and  MMP-7+).  Recently,  an  
 
 
 
 
 
 
 
 
 
 
 
increase  in  IGFr-1  phosphorylation  was  reported  by  Dallas  et  al.  (2009)  in  this  resistant  
 
 
 
 
 
 
 
 
 
 
  
 
 
phenotype.  We  consider  that  after  treatment  with  oxaliplatin,  IGFBP  induces  apoptosis  
 
 
 
 
 
 
 
 
 
 
 
through  IGFr-1  phosphorylation  inhibition  in  HT-29  cells,  unlike  in  resistant  HT-29  cells  
 
 
 
 
 
 
 
 
 
 
 
 
due  to  the  constitutive  activation  of  MMP-7.   
  
In  the  clinical  setting,  our  group  retrospectively  investigated  the  role  of  IGF-1RP  and   
MMP-7  in  patients  with  advanced  primary  or  mCRC  treated  with  cetuximab  or  
 
panitumumab  as  second-  or  third-line  therapy  (42).  A  total  of  168  tissue  samples  were  
 
available  for  the  analysis  of  RAS  and  BRAF  mutational  status,  and  MMP-7  and  IGF-1RP  
 
expression.  There  were  no  significant  differences  in  the  ORR  (18.8%  vs  15.0%),  PFS   
(3.3   vs  3.0  months),  and  OS  (7.8  vs  7.0  months)  among  the  total  and  selected  cohorts.   
MMP  7  and  IGF-1RP  expression  was  observed  in  49%  and  52%  of  patients,   
respectively.  The   co-expression  of  MMP-7  and  IGF-1RP  (“double-positivity”  group)  was 
noted  in  27/104  wt  RAS  patients  (26%)  and  in  15/71  wt-BRAF  patients  (24%).   
  
There  was  no  correlation  between  RAS  and  BRAF  mutational  status  and  
 
 
 
 
 
 
 
 
 
 
 
double-positivity 
 (p=0.52).  In  the  subgroup  of  patients  with  wt-RAS  and  BRAF,  the  
 
 
 
 
 
 
 
 
 
 
 
 
double-positivity  group  showed  a  lower  ORR  than  the  group  without  double-positivity  
 
 
  
 
 
 
 
 
 
 
(p=0.002);  they  also  showed  a  declining  median  PFS  of  91  days  vs  121  days  (p=0.09)  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
and  a  poor  median  OS 
 of  196  days  (CI  95%:  175–215)  vs  294  days  (CI  95%:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
182–344)(p=0.002).   
  
BRAF   
  
Both  prognostic  and  predictive  roles  of  BRAF  mutation  in  mCRC  have  been  established.  
 
 
 
 
 
 
 
  
 
 
 
 
BRAF  mutation  is  present  in  5–8%  of  mCRC  cases.  A  retrospective  analysis  of  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prognostic  and  predictive  potential  of  this  mutation  was  conducted  in  patients  included  
 
 
 
 
 
 
 
 
 
 
 
 
in  the  OPUS  20  study.  The  proportion  of  patients  with  mutated  BRAF  was  7.9%,  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
this  mutation  was  associated  with  OS  (HR:  1.82;  CI  95%:  1.36–2.43)  but  not  with  PFS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(HR:  1.14;  CI  95%:  0.86–1.52).  In  studies  conducted  by  Di  Nicolantonio  et  al.  (43)  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laurent–  Puig  et  al.  (44)  to  evaluate  the  prognostic  and  predictive  roles  of  BRAF  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mutation,  the  results  indicated  that  BRAF  mutation  was  associated  with  lower  OS  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
PFS.  Our  own  data  confirm  these  findings.  Our  interest  in  investigating  this  biomarker,  
 
 
 
 
 
 
 
 
 
 
 
 
 
other  than  to 
 identify  it  as  a  new  prognostic  biomarker,  lies  in  determining  its  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
significance  among  other  prognostic  biomarkers  (establishing  a  scoring  system)  as  
 
 
 
 
 
  
 
 
 
proposed  in  this  protocol.   
  
PTEN   
  
PTEN,  like  BRAF,  is  another  component  of  the  MAPK  signalling  pathway;  therefore,  its  
 
 
  
 
 
 
 
 
 
 
 
 
mutational  status  may  affect  cetuximab  efficacy.  In  the  study  by  Laurent–Puig  et  al.  (44),  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
this  biomarker  was  also  evaluated.  PTEN  expression  was  absent  in  19.9%  of  wt-KRAS  
 
 
 
 
 
 
 
 
 
 
 
 
 
patients,  and  was  associated  with  both  PFS  and  OS.  Furthermore,  another  study  (45)  
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluated  the  predictive  role  of  PTEN  expression  loss  in  mCRC  patients  treated  with  
 
 
 
 
 
 
 
 
 
 
 
 
 
irinotecan+cetuximab.  This  study  demonstrated  that  the  loss  of  PTEN  expression  was  
 
 
 
 
 
 
 
 
 
 
 
associated  with  lower  PFS  (p=0.005).   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   22  of  36  
 


Consequently,  we  consider  that  PTEN  expression,  along  with  BRAF,  is  another  
 
 
 
 
 
 
 
 
 
 
 
biomarker  that  is  worth  investigating  for  the  characterisation  of  the  MAPK  signalling  
 
 
 
 
 
 
 
 
 
 
 
 
pathway  in  this  protocol.   
  
Other  biomarkers   
  
The  list  of  investigated  biomarkers  was  left  open  to  avoid  proposals  being  outdated;  
 
 
 
 
 
 
 
 
 
 
 
 
 
however,  based  on  GEMCAD  preclinical  studies  and  recent  publications,  no  other  
 
 
 
 
 
 
 
 
 
 
 
biomarker  of  interest  was  identified  at  the  time  of  database  closure.  
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   23  of  36  
 


5.  STUDY  OBJECTIVES   
  
5.1.  PRIMARY  OBJECTIVE   
  
∙  To  evaluate  BRAF,  IGF-1RP/MMP-7  (DP)  and  PI3K-PTEN  biomarkers  to  predict  PFS  
 
 
 
 
 
 
 
 
 
 
 
 
in 
 advanced 
 and/or 
 wt-KRAS/NRAS 
 mCRC 
 patients 
 treated 
 with 
 standard  
 
 
 
 
 
 
 
 
 
chemotherapy  along  with  bi-weekly  cetuximab  as  first-line  therapy.   
  
∙  To  identify  new  biomarkers,  which  may  predict  PFS  in  wt-KRAS/NRAS  patients  
 
treated  with  chemotherapy  and  bi-weekly  cetuximab  as  first-line  therapy.  ∙  The  need  to   
identify  additional  biomarkers  of  cetuximab  efficacy  originates  from   the  low  predictive   
value  of  the  current  biomarker  classification,  based  on  KRAS   mutational  status,   
regarding  the  efficacy  of  bi-weekly  cetuximab  administration  in  patients   with  the   
investigational  condition.   
  
o  The  proposed  biomarkers  were:   
  
▪  BRAF  mutation   
  
▪  IGF-1RP/MMP-7  (DP)   
  
▪  PI3K-PTEN   
  
∙  The  identification  of  additional  biomarkers,  which  determine  the  efficacy  of  bi  weekly   
cetuximab,  will  provide  the  scientific  community  with  additional  stratification   factors  for   
the  design  of  clinical  trials  and  facilitate  the  selection  of  patients  for  bi-weekly   cetuximab   
therapy.   
  
5.2.  SECONDARY  OBJECTIVES   
  
●  To  analyse  secondary  biomarkers  (MMP-7,  IGF-1,  IGFBP-3,  amphiregulin,  and  
 
epiregulin  as  well  as  other  relevant  biomarkers,  which  may  arise  during  trial  
 
implementation)  in  the  serum  and  tumour  tissue,  to  predict  acquired  chemoresistance.  ●   
OS  based  on  the  proposed  classification.   
  
●  Objective  response  rate  (ORR)  according  to  RECIST  1.1  (46) .  ●  To  describe  the   
safety  profile,  including  AE  incidence  and  significant  changes  in   laboratory  parameters   
after  the  bi-weekly  administration  of  cetuximab  at  500  mg/m 2  q2w   as  first-line  therapy.   
  
●  To  evaluate  the  ORR,  duration  of  response  (DoR),  and  OS  in  wt-KRAS/NRAS   mCRC   
patients  treated  with  bi-weekly  cetuximab  in  combination  with  FOLFOX6  (m)  or  FOLFIRI   
(m)  as  a  first-line  chemotherapy  regimen,  according  to  the  expression  of   the  proposed   
biomarkers.  
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   24  of  36  
 


6.  INVESTIGATIONAL  PLAN   
  
 
 
Table  2:  Schedule  of  examinations  and  procedures   
  
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   25  of  36  
 
Study  procedures  
 
Selection   
  
Study   
   
treatment   
  
Safety  
   
follow-up c  
 
Long-te 
rm  
  
follow-u 
p m  
 
≤28   
days   
from   
   
cycle  1  
 
≤7  days  
   
from   
  
cycle  1  
 
Every  2   
   
weeks  a,  b  
 
(30±3   
   
days)  
 
Informed  consent   
  
X  
 
 
 
 
 
 
 
 
 
Eligibility  criteria  review   
  
X  
 
 
 
 
 
 
 
 
 
Clinical  and  medical  history   
  
X  
 
 
 
 
 
 
 
 
 
Physical  examination   
  
X   
  
 
 
X   
  
X  
 
 
 
ECG   
  
X  
 
 
 
 
 
 
 
 
 
Vital  signs   
  
X   
  
 
 
X   
  
X  
 
 
 
Weight  
  
X   
  
 
 
X   
  
X  
 
 
 
Height   
  
X  
 
 
 
 
 
 
 
 
 
Body  surface  area  calculation   
  
 
 
X   
  
X  
 
 
 
 
 
ECOG  PS j   
  
 
 
X   
  
X   
  
X  
 
 
 
AE  evaluation d   
  
 
 
X  
 
 
 
Concomitant  medication d   
  
 
 
X  
 
 
 
Survival  assessment   
  
 
 
 
 
 
 
X  
 
 
 
Laboratory  tests  
 
Pregnancy  test e   
  
 
 
X  
 
 
 
 
 
 
 
Clinical  safety  blood  tests f   
  
X   
  
X   
  
X   
  
X   
  
X  
 
Serum  CEA k   
  
X   
  
 
 
Every  3  months  until  PD   
  
Serum  biomarkers   
  
X   
  
 
 
Every  3  months  until  PD  
 
Paraffin  embedded  tumour  block l   
  
X  
 
 
 
 
 
 
 
 
 
Imaging  evaluation  of  response  
 
CT  scan  (MRI  optional) g   
  
X   
  
 
 
Every  3  months  until  PD  
 
Response  evaluation  according  to   
the   revised  RECIST  1.1  criteria i  
 
 
 
 
 
Every  3  months  until  PD  
 
Bi-weekly  cetuximab   
  
 
 
 
 
Until  PD  
 
 
 
 
 


 
 
Evaluations  schedule  –  Footnotes  
  
a.  Bi-weekly  cetuximab  administered  through  an  i.v.  infusion  at  a  500  mg/m 2  dose,  every  2  weeks  according  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
to  the  indications  established  in  this  protocol.  Cetuximab  was  given  at  least  1  hour  prior  to  chemotherapy  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
administration.  A  treatment  cycle  was  defined  as  the  14-day  period  subsequent  to  the  treatment  start  with  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cetuximab+FOLFIRI  (m)/FOLFOX-6  (m).   
  
b.  Treatment  cycles  may  be  delayed  longer  than  the  normal  2  weeks  due  to  bi-weekly  cetuximab  or  
 
FOLFIRI  (m)/FOLFOX-6  (m)  related  toxicity.   
  
c.  Safety  follow-up  visit  performed  30±3  days  after  the  last  administration  of  the  investigational  product.  d.   
Adverse  events  and  concomitant  medication  are  recorded  continually,  until  the  safety  follow-up  visit.   SAEs   
and  significant  AEs  were  followed  up  until  resolution  or  stabilisation.   
  
e.  Women  of  reproductive  age  underwent  a  serum  or  urine  pregnancy  test  ≤72  hours  prior  to  
 
investigational  treatment  initiation.   
  
f.  Haematology  tests:  complete  haemogram,  including  WBC  differential  count  and  platelet  count.   
Biochemistry  tests:  sodium,  potassium,  magnesium,  chloride,  bicarbonate,  creatinine,  albumin,  glucose,  
 
calcium,  phosphorus,  AST,  ALT,  ALP,  LDH,  total  protein,  total  bilirubin,  uric  acid,  and  blood-urea-nitrogen.  g.   
Tumour  imaging  evaluations  through  CT  scan  or  MRI  were  performed  at  selection,  and  then  every   12   
weeks  until  PD.   
  
h.  If  thoracic  CT  scan  at  selection  did  not  show  any  chest  abnormality,  chest  X-ray  imaging  were  performed  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
in  subsequent  evaluations.  A  CT  scan  was  performed  to  confirm  any  abnormality  identified  upon  chest  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-ray  imaging  performed  after  selection,  and  all  subsequent  evaluations  were  thoracic  CT  imaging.  
 
i.  Response  evaluation  was  conducted  according  to  the  revised  RECIST  1.1  criteria,  every  12±1  weeks  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
until  PD.  Subject  follow-up  was  performed  regardless  of  discontinuation  or  a  delay  in  treatment.  j.  ECOG  PS  
 
 
 
 
 
 
 
 
 
  
  
  
 
 
evaluation  (on  day  1  of  each  treatment  cycle).   
  
k.  Tumour  evaluation  and  serum  CEA  test  was  performed  every  12  weeks  and  at  the  follow-up  visit  only  in  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
subjects  who  have  withdrawn  from  the  trial  for  reasons  different  from  PD,  and  in  those  who  have  not  had  a  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
serum  CEA  test  in  the  previous  12  weeks.   
  
l.  Paraffin  embedded  tumour  block  was  sent  to  the  central  laboratory  (Fundación  Jiménez  Díaz)  at  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
selection.  The  centralised  evaluation  laboratory  perform  a  tumour  block  quality  assessment.  It  was  
 
 
 
 
 
 
 
 
 
 
 
 
 
compulsory  that  KRAS  and  NRAS  mutational  status  (wtKRAS  and  NRAS)  was  confirmed  by  a  validated  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
laboratory  before   the  inclusion  of  any  subject.   
  
m.  Follow-up  of  all  subjects  who  permanently  discontinued  the  treatment  before  disease  progression  (e.g.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
due  to  unacceptable  toxicities)  was  conducted  to  evaluate  PFS  (i.e.,  tumour  imaging)  every  12±  1  week  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
until  PD  or  until  the  end  of  study  (unless  the  reason  for  study  discontinuation  was  total  consent  withdrawal).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After  PD,  all  subjects  underwent  a  follow-up  assessment  of  disease  status,  subsequent  cancer  therapy,  and  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
survival  assessment  every  12  ±  1weeks  until  the  end  of  study  (maximum  of  24  months).   
  
n.  Blood  samples  for  biomarker  analysis  were  withdrawn  before  the  study  treatment  initiation  and  every   12   
weeks  ±  1  weeks  until  PD.   
  
 
 
Table  3:  SDV  schedule   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   26  of  36  
 
Form   
  
Variables  
 
Eligibility   
  
Pathology  report,  staging,  prior  treatment.  
 
Demographics   
  
Date  of  birth,  ECOG  PS,  ICF   
  
(signature,  date,  and  completion)  
 
Primary  tumour   
  
Diagnosis  date,  location,  staging  and  surgery  
 
Adjuvant  or  neoadjuvant   
  
treatment  
 
Yes/No  
 
KRAS/NRAS   
  
Central  reviewing  
 
Baseline  biochemistry  and   
SAE   biochemistry   
  
LDH,  creatinine,  bilirubin,  and  CEA  
 
Baseline  haematology  and   
SAE   haematology   
  
Haemoglobin,  platelets,  and  leukocytes  
 


 
 
 
 
If  all  the  aforementioned  variables  were  reviewed  by  the  CRA  for  all  patients  included  in  
 
the  site,  then  dose  modifications  and  minor  toxicities  were  also  reviewed.   
  
6.5  STATISTICAL  METHODS  PLANNED  IN  THE  PROTOCOL  &  DETERMINATION  
 
OF  SAMPLE  SIZE   
  
6.5.1  STATISTICAL  AND  ANALYTICAL  PLANS   
  
6.5.1.1.  Primary  endpoint   
  
To  quantify  if  the  biomarkers  BRAF,  IGF-1RP/MMP-7  (DP),  DP  and  PIK3CA-PTEN  
 
  
 
 
 
 
 
 
 
 
improve  the  prediction  of  12-months  progression-free  survival  (PFS)  over  the  use  of  just  
 
 
 
 
 
 
 
 
 
 
 
 
 
clinical  variables  in  the  study  population  we  compared  the  area  under  the  curve  (AUC)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of  a  ROC  curve  using  scores  composed  by  clinical  variables  with  the  AUC  of  scores  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with  the  clinical  variables  plus  each  of  the  biomarkers.   
  
PFS  was  defined  as  the  time  from  the  signature  of  the  ICF  date  to  the  radiological  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
progression  date  or  death  (whatever  occurs  first).  Subjects  who  had  not  shown  PD  and  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
had  not  died  at  database  closing  were  censored  on  the  last  date  of  radiological  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
assessment.  Subjects  who  had  concluded  study  treatment  before  48  weeks,  due  to  any  
 
 
 
 
 
 
 
 
 
 
 
 
 
cause,  underwent  follow-up  every  12  weeks  as  described  in  the  protocol.  Subjects  who  
 
 
 
 
 
 
 
 
 
 
 
 
 
had  undergone  metastatic  surgery  were  not  censored  on  the  surgery  date  but  were   
  
followed  up  every  12  weeks  until  progression  was  documented.  Subjects  who  received  
 
 
 
 
 
 
 
 
 
 
 
 
other  treatment  schemas  maintaining  the  same  strategy  (chemotherapy  +  monoclonal  
 
 
 
 
 
 
 
  
 
antibody)  without  documented  PD,  were  not  censored  at  the  time  of  the  change  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
treatment.  Progression  to  first  line  for  these  patients  was  considered  when  applicable  
 
 
 
 
 
 
 
 
 
 
 
 
according  RECIST,  independently  of  treatment  received.  If  by  any  cause,  the  baseline  
 
 
 
 
 
  
 
 
 
 
 
CT  scan  was  the  only  imaging  evaluation  performed  (e.g.,  subject  refusal  to  stay  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
study   or  lost  to  follow-up),  the  case  was  censored  on  the  inclusion  date  +1  day.   
  
Two  groups  with  a  higher  and  lower  likelihood  for  tumor  progression  until  12  months  
 
 
  
 
 
 
 
 
 
 
 
 
 
were 
 determined  based  on  the  designated  classification  of  clinical  variables  and  
 
 
 
 
 
 
 
 
 
 
 
following   proposed  biomarker  categories  :   
  
1.  wt-BRAF  vs  mutant  BRAF   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   27  of  36  
 
Metastasis   
  
Nº  affected  organs  and  hepatic  M1  (number  and  size)  
 
CT  scans  or  MRI   
  
All  variables  (date,  lesions  measure,  location,  new   
lesions)   and  RECIST  criteria  
 
AEs   
  
Grade  and  need  of  SAE  communication  
 
Treatment   
  
Start  date,  number  of  cycles,  end  date  and  reason  of   
EOT  
 
Progression   
  
Date  of  progression  and  reason  
 
Death   
  
Date  of  death  and  reason  
 


2.  wtPI3K  and  PTEN  >3  vs  mutant  PI3K  or  PTEN  ≤3   
  
3.  Non-DP  vs  DP   
  
6.5.1.2.  Secondary  endpoints   
  
●  Serum  and  tumor  tissue  secondary  biomarkers  evaluated  to  predict  acquired  
 
chemo-resistance  including  BRAF  and  PI3K.   
  
●  ORR  was  defined  as  the  incidence  of  a  complete  or  partial  response  according  to   the   
revised  RECIST  1.1  criteria.   
  
●  DoR  (calculated  only  for  the  subjects  who  present  an  Overall  Response):  Time  from  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  first  assessment  of  Overall  Response  to  radiologically-confirmed  PD  
 
 
 
 
 
 
 
 
 
according  to  the  revised  RECIST  1.1  criteria.  For  subjects  who  showed  response  
 
 
 
 
 
 
 
 
 
 
 
 
and  did  not  show  progression,  DoR  was  censored  on  the  last  date  of  assessable  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
disease  evaluation  reported  in  the  eCRF  of  the  study.   
  
●  OS:  Time  from  the  signature  of  the  ICF  date  to  date  of  death.  For  subjects  who  did  not  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
die  or  were  lost  to  follow-up  on  the  closing  date  for  data  analysis,  OS  was  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
censored  on  the  date  of  last  contact.   
  
●  Safety:  Type,  frequency,  and  intensity  of  AEs  related  to  the  combination  treatment.  
 
6.5.1.3.  Analysis  population   
  
Efficacy  variables  were  analysed  in  all  subjects  who  provided  their  informed  consents,  
 
 
 
 
 
 
 
 
 
 
 
 
were  included  in  the  trial  and  did  not  present  significant  protocol  deviations  throughout  
 
 
 
 
 
 
 
 
 
 
 
 
 
the  study  period.   
  
An  intention-to-treat  analysis  in  all  patient  enrolled  into  the  study  was  not  performed  
 
 
 
 
 
 
 
 
 
 
 
 
 
because  the  primary  study  objective  was  to  evaluate  the  predictive  value  of  the  three  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
biomarker  BRAF,  IGF-1RP/MMP-7  (Double-positive  Phenotype/DP)  and  PI3K-PTEN  on  
 
 
 
 
 
 
 
 
PFS  in  wt-RAS  CRC  patients  receiving  standard  chemotherapy  plus  bi-weekly  
 
 
 
 
 
 
 
 
 
 
cetuximab  as  first-line  therapy,  but  patients  with  significant  protocol  deviations  (e.g.  
 
 
 
 
 
 
 
 
 
 
 
RAS  mutations,  missing  biomarker  data  and  those  not  receiving  cetuximab  treatment)  
 
 
 
 
 
 
 
 
 
 
 
could  not  contribute   to  the  investigation  of  the  primary  objective.   
  
All  patients  who  received  study  medication  were  included  in  the  safety  analysis.  .   
  
6.5.1.4.  Covariate  analysis   
  
The  following  baseline  characteristics  were  studied  by  biomarkers  in  orther  to  properly  categorise  the  
 
sample:   
  
●  Gender   
  
●  Age   
  
●  Primary  Tumour  location  and  sideness  (ascending  colon,  transverse  colon,  descending  colon,  
 
sigma  and  rectum)   
  
●  Stage  of  the  disease   
  
●  Surgery  of  the  primary  tumor   
  
●  ECOG  Performance  Status   
  
●  Number  of  metastatic  organs   
  
●  Specific  locations  of  metastasis  including  number,  size  and  loctation  node,  lung,  peritoneal  and  
 
liver  (considering  also  those  patients  with  only  resectable  liver  metastases  for  comparison)  ●  Mean   
values  of  haemathological  tests  including  leucocytes,  haemoglobin,  platelets,.  ●  Baseline  LDH  levels   
>450   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   28  of  36  
 


●  Mean  ALP  and  Mean  CEA   
  
●  Chemotherapy  (FOLFOX+Cetuximab  /FOLFIRI+Cetuximab)   
  
These  groups  have  been  used  for  univariate  and  multivariable  analysis  in  order  to  
 
 
 
 
 
 
 
 
 
 
 
 
 
evaluate  efficacy  variables  such  as  ORR  and  PFS.  Disease  response  was  clinically  
 
 
 
 
 
 
 
 
 
 
 
 
assessed  by  the  investigator  based  on  the  radiological  imaging  data  collected  
 
 
 
 
 
 
 
 
 
 
 
throughout  the  study.  Any  finding  considered  as  non-assessable  by  the  investigator  was  
 
 
 
 
 
 
 
 
 
 
 
 
excluded   from  the  analysis  (it  was  considered  as  non-existent).   
  
For  continuous  variables,  mean,  standard  error  (for  efficacy  variables),  standard   
deviation   (for  other  measurements),  median,  25 th  percentile,  75 th  percentile,  minimum   
and   maximum,  were  evaluated.  Categorical  variables  were  presented  using   
frequencies  and  percentages.  
 
The  95%  two-sided  confidence  intervals  (95%CIs)  of  Kaplan–Meier  quartiles  for  time  to  
 
 
 
 
 
 
 
 
 
 
 
 
event  variables  were  calculated  according  to  Brookmeyer  and  Crowley  methods  
 
 
 
 
 
 
 
 
 
 
(Brookmeyer,  1982).  The  95%  two-sided  CIs  for  the  Kaplan–Meier  estimates  at  various  
 
 
 
 
 
 
 
 
 
 
 
 
time  points  were  calculated  according  to  the  methods  described  by  Collett  (Collett,  
 
 
 
 
 
 
 
 
 
 
 
 
1992).   
  
Safety  data  were  analysed  throughout  the  entire  study  and  presented  by  descriptive  
 
analysis.   
  
6.5.1.5.  Analysis  of  main  study  variables   
  
The  primary  efficacy  analysis  of  this  trial  was  performed  based  on  all  subjects  who  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
provided  their  informed  consents,  were  included  in  the  trial,  and  did  not  present  
 
 
 
 
 
 
 
 
 
 
 
 
 
significant   protocol  deviations  throughout  the  study  period.  .   
  
Continuous  and  ordinal  variables  between  independent  groups  were  compared  using  
 
 
 
 
 
 
 
 
 
 
the  Wilcoxon  rank-sum  test  and  proportions  were  compared  with  Fisher’s  exact  test.  
 
 
 
 
 
 
 
 
 
 
 
 
Clinical  endpoints  were  ORR,  DoR,  PFS,  and  OS.  Tumour  assessments  by  CT  scans  
 
 
 
 
 
 
 
 
 
 
 
 
 
were  performed  every  3  months  until  PD.  Patients  without  a  second  CT  scan  evaluation  
 
 
  
 
 
 
 
  
 
 
 
 
were   not  assessable  for  ORR.   
  
PFS  was  defined  as  the  time  of  the  signature  of  the  ICF  date  until  PD  or  death  from  any  
 
cause.  Patients  who  did  not  experience  PD  or  death  were  censored  on  the  date  of  last  
 
examination.  For  more  information  regarding  censoring  see  in  Section  7.5.1.1.  OS  was   
defined  as  the  time  from  the  signature  of  the  ICF  date  to  death  from  any  cause.  Patients   
lost  to  follow-up  or  still  in  the  study  at  database  closure  have  been  censored  at   the  date   
last  known  to  be  alive.   
  
Survival  analyses  including  PFS  and  OS  were  performed  using  Kaplan–Meier  methods.  
 
 
 
 
 
 
 
 
 
 
 
Cox  proportional  hazards  regression  with  the  Efron  method  for  ties  was  used  to  identify  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
prognostic  factors  for  PFS  and  OS.   
  
Multivariable  analysis  was  performed  using  subject-matter  knowledge  and  deciding  a  
 
 
 
 
 
 
 
 
  
priori  the  variables  to  adjust  by  age  (>65  years),  sex,  tumour  site  (right  vs  left),  surgery  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of  primary  tumour,  liver  only  metastases  (<3  nodules  and  <5  cm  vs  >3  nodules  or  >5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cm), 
 ECOG  PS,  LDH  (>450  U/L)  and  CEA,  BRAF  mutational  status,  and  type  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
therapy.  This 
 analysis  was  later  adjusted  by  variables  with  p-values  <0.10  in  the  
 
 
 
 
 
 
 
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   29  of  36  
 


univariate  analysis  via 
 the  automated  stepwise  selection  of  variables  (p-value  for  
 
 
 
 
 
 
 
 
 
 
 
variable  entry  into  the  model  was  0.2  and  p-value  to  keep  the  variable  in  the  model  was  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
0.1)..  All  p-values  were  two  sided.   
  
The  proposed  sample  size  ensures  establishing  a  consistent  multivariable   
analysis.  Clinical  variables  and  biomarkers  were  used  to  build  scores  intended  to   
predict  12-  months  PFS  as  following:  
 
1.  A  multivariable  Cox  model  was  built  with  those  clinical  variables  that  in  the  univariate  
  
 
 
 
 
 
 
 
 
 
  
 
 
analysis  had  a  p-value≤0.15  (PS,  chemo  regimen,  sidedness,  resectable  liver  
 
 
 
 
 
 
 
 
 
 
metastases).   
  
2.  A  score  was  established  for  each  patient  by  adding  up  the  regression  coefficients  of  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the  multivariable  Cox  model  present  in  these  patients.  If  for  example  PS>0  was  a  
 
 
 
 
 
 
 
  
 
 
 
  
negative  predictor  for  PFS  (i.e.  regression  coefficient  is  negative;  e.g.  -0.5)  and  left  
 
 
 
 
 
 
  
 
 
 
 
 
side  tumour  was  a  positive  prognostic  factor  (regression  coefficient  was  positive,  e.g.  
 
 
  
 
 
 
 
 
 
 
 
0.6)  then  for  a  patient  with  PS>0  and  left  sided  tumour  the  two  scores  were  added  (-   
  
0.5  +  0.6=0.1).  If  a  patients  has  PS=0  then  the  score  to  be  added  is  0,  as  it  is  the   
case   for  right  sided  tumour  in  the  example.   
  
3.  Using  a  logistic  regression  model  for  the  outcome  12-months  PFS,  a  ROC  curve  was  
 
computed  to  choose  the  score  cut  point  that  classifies  most  patients  correctly  4.  Patients   
were  dichotomized  according  to  that  cut  point.   
  
5.  Steps  2  to  4  were  repeated,  adding  each  of  the  three  biomarkers.   
  
6.  Definition  of  the  discriminating  power  of  the  4  scores  for  prognosis  of  or  12-months  
 
PFS  according  to  these  results  were  compared  via  ROC  curves.   
  
7.  Determination  of  the  most  suitable  score  for  12-months  PFS  according  to  these  
 
results.   
  
The  four  scores  included  in  the  first  multivariate  model  using  clinical  factors  where  
 
 
 
 
 
 
 
 
 
 
 
 
 
PS>0, 
 chemotherapy  with  FOLFIRI  and  cetuximab,  left  sided  and  resectable  liver  
 
 
 
 
 
 
 
 
 
 
 
metastases 
 were  considered  (Score  1).  The  additional  scores  considered  the  four  
 
 
 
 
 
 
 
 
 
 
 
clinical  factors  above  plus  the  status  of  each  biomarkers  (Score  2:  BRAF  mutation;  
 
 
 
 
 
 
 
 
 
 
 
 
 
Score  3:  PI3K  mutant   or  PTEN  <=3)  and  Score  4:  Double-positive  Phenotype  (DP).   
  
All  analyses  were  performed  using  SAS  V9.3  (SAS  Institute,  Cary,  NC,  USA)  statistical  
 
software.   
  
6.5.2.  DETERMINATION  OF  SAMPLE  SIZE   
  
It  was  the  aim  of  the  study  to  identify  two  groups  based  on  the  well-established   
categories   of  clinical  variables  and  the  proposed  biomarkers  which  are  prognostic   
regarding  PFS.  The  sample  size  should  be  sufficient  detect  a  clinically  relevant   
difference  in  PFS  with  a   log-rank  test  between  the  two  groups,  given  the  following   
assumptions:   
  
●  The  difference  in  PFS  at  12  months  between  the  two  groups  is  at  least  20%  (i.e.  50%  vs  30%)  
 
corresponding  to  a  hazard  ration  of  1.79  assuming  an  exponential  distribution.   ●  Alpha  error   
(two-tailed):  5%   
  
●  Beta  error:  20%   
  
●  Monthly  recruitment:  8  patients   
  
●  Percentage  of  patients  with  classification=  0:  40%   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   30  of  36  
 


Initially,  the  number  of  patients  required  to  be  recruited  in  24  months  was  155  for  115  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
events  to  occur.  Assuming  a  10%  proportion  of  potentially  non-assessable  patients,  a  
 
 
 
  
 
 
 
 
 
  
total  of  170  patients  were  needed  to  be  included.  After  recruiting  157  patients,  it  was  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
determined  that  about  70  of  these  patients  had  insufficient  samples  for  biomarker  
 
 
 
 
 
 
 
 
 
 
 
 
analysis  preventing  their  inclusion  into  the  analysis  of  the  primary  objective  Therefore,  
 
 
 
 
 
 
 
 
 
 
 
 
in  order  to  observe  the  115  events  necessary  to  evaluate  the  primary  endpoint,  the  total  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
number  of  patients  was  increased  up  to  221  recruited  in  47  months  (4–5  patients  per  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
month).  Finally,   the  total  study  duration  was  70  months  (recruitment  +  follow-up).   
  
 
 
7.  RESULTS  
 
Table  4  Disposition  of  patients   
  
 
 
 
 
Table  5  Protocol  deviations   
  
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   31  of  36  
 
Patients  enrolled   
  
 
 
Received  at  least  one  cycle  of  study  treatment   
  
 
 
Evaluable  patients   
  
 
 
End  of  study  (evaluable  population)  
 
Death   
  
 
 
Lost  to  follow-up   
  
 
 
Censored  at  database  closure   
  
 
 
Study  completion  (24  months  of  follow-up  after  
  
PD)   
  
 
 
Deviation  type   
  
Total  
 
Informed  consent  form   
  
 
 
Efficacy  criteria   
  
 
 
Eligibility  criteria   
  
 
 
Incorrect  dosing  regimen   
  
 
 
Other   
  
 
 
Safety   
  
 
 


 
 
Table  6.  Baseline  characteristics  by  biomarker   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   32  of  36  
 
 
 
wtBRAF   
  
(n=161)  
 
Mutant   
  
BRAF   
  
(n=20)  
 
p-value*  
 
wtPI3K   
and  
 
PTEN   
>3   
  
(n=69)  
 
Mutant  PI3K   
  
or  PTEN  ≤3   
  
(n=98)  
 
p   
  
value*  
 
Non-DP   
  
(n=158)   
  
DP  (n=23)   
  
p   
  
value*  
 
Female   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean  age  (SD)   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary  location  
 
Ascending  colon   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transverse  colon   
  
 
 
 
 
 
 
 
 
 
 
 
 
Descending  colon   
  
 
 
 
 
 
 
 
 
 
 
 
 
Sigmoid  colon   
  
 
 
 
 
 
 
 
 
 
 
 
 
Rectum   
  
 
 
 
 
 
 
 
 
 
 
 
 
Stage  
 
I   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
II   
  
 
 
 
 
 
 
 
 
 
 
 
 
III   
  
 
 
 
 
 
 
 
 
 
 
 
 
IV   
  
 
 
 
 
 
 
 
 
 
 
 
 
Surgery  of  the   
  
primary  tumour   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance  status  
 
0   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1   
  
 
 
 
 
 
 
 
 
 
 
 
 
2   
  
 
 
 
 
 
 
 
 
 
 
 
 
Number  of  metastatic  organs  
 
0   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1   
  
 
 
 
 
 
 
 
 
 
 
 
 
2   
  
 
 
 
 
 
 
 
 
 
 
 
 
3   
  
 
 
 
 
 
 
 
 
 
 
 
 
4+   
  
 
 
 
 
 
 
 
 
 
 
 
 
Liver  metastasis  
 
0   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤3,  ≤5  cm   
  
 
 
 
 
 
 
 
 
 
 
 
 
>3  or  >5  cm   
  
 
 
 
 
 
 
 
 
 
 
 
 
Node  metastases 1   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lung  metastases 1   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peritoneal   
  
metastases 1   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


●
Fisher’s  exact  test  for  categorical  variables  and  Wilcoxon  rank-sum  test  for  ordinal  or  continuous  data  
1 
 
 
Missing  in  one  patient  
2 
  The  patient  does  not  have  metastasis  in  any  other  location,  and  those  in  the  liver  are   
≤3   in  number  and  ≤5  cm  in  size .  
 
Table  7.  MEASUREMENTS  OF  TREATMENT  COMPLIANCE   
  
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   33  of  36  
 
Patients  with   
only  
 
resectable  liver   
  
metastases 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy  
 
FOLFOX+Cetuximab   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOLFIRI+Cetuximab   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean  Leucocytes   
  
(SD)   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean   
Haemoglobin  
 
(SD)   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean  Platelets  (SD)   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean  ALP  (SD)   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH  >450   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean  CEA  (SD)   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total   
  
(n=)  
 
Treatment  disposition  
 
Received  at  least  one  injection  (safety  population)   
  
 
 
Efficacy  population   
  
 
 
Received  at  least  12  cycles  of  cetuximab   
  
 
 
Received  at  least  12  cycles  of  chemotherapy+cetuximab    
 
 
Received  less  than  12  cycles  of  cetuximab   
  
 
 
Received  3  or  less  administrations  of  combination   
  
 
 
 
 
FOLFOX+cetuximab   
  
 
 
FOLFIRI+cetuximab   
  
 
 
End  of  Treatment  (EOT)   
  
 
 
Reasons  for  end  of  treatment  
 
 
 
PD   
  
 
 
PI  decision  (24  due  to  surgery,  2  radiotherapy,  2   
complete  response,  49  others)   
  
 
 


 
 
 
 
Table  8:  Patients  excluded  from  the  efficacy  or  safety  analysis   
  
 
 
 
 
Table  9.  Response  Rates  (efficacy  population)  based  on  BRAF  status   
  
 
 
Figure  1.  Progression  free-survival   
  
Progression  free  survival  (PFS)  based  on  the  analysis  of  X  patients  showed  a  median  of 
X  (95%  CI:  X  -  X)  months.  
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   34  of  36  
 
Patient  decision  
  
 
 
Toxicity  (related  to  treatment)   
  
 
 
AE  (unrelated  to  treatment)   
  
 
 
No  data  of  EOT  available   
  
 
 
Pat.  #   
  
Hospital   
  
Reason  for  exclusion  from  efficacy  analysis  
 
Valid   
   
for   
   
safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best  Response   
  
N=  all  patients  (%)   
  
N=  wt-BRAF  (%)   
  
N=  mutant-BRAF  (%)  
 
Complete  response   
(CR)   
  
 
 
 
 
 
 
Partial  response  (PR)   
  
 
 
 
 
 
 
Stable  disease  (SD)   
  
 
 
 
 
 
 
Disease   
Progression   (PD)   
  
 
 
 
 
 
 
Not  evaluable  (NE)   
  
 
 
 
 
 
 
Overall  response   
  
 
 
 
 
 
 
Disease  Control  Rate   
  
 
 
 
 
 
 


 
 
Figure  2.  Overall  survival   
  
When  OS  was  evaluated,  an  estimated  median  of  X  (95%  CI:  X  -  X  months  was  
 
reported.   
  
 
 
The  median  OS  of  wt-BRAF  patients  was  X  (95%  CI:  X  -  X)  months  and  for  that  of  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
mutant  BRAF  patients  was  X  (95%  CI:  X  -  X  months  (adjusted  HR:X,  CI  95%  X–  X;  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
p-value=X).  
 
 
 
Table  10.  General  toxicity  profile  (AEs+SAEs+SUSARs)  
 
 
 
 
 
 
 
Table  12.  Toxicity  profile  post  treatment  beginning  (AEs+SAEs+SUSARs)  
 
 
 
 
 
 
 
Table  13.  Toxicity  profile  post  treatment  beginning  related  to  treatment  
 
 
 
 
 
 
 
 
 
 
(AEs+SAEs+SUSARs)  
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   35  of  36  
 
Adverse  event  
 
Any  grade  
 
Grade  3  
 
Grade  4  
 
Grade  5  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse  event  
 
Any  grade  
 
Grade  3  
 
Grade  4  
 
Grade  5  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse  event  
 
Any  grade  
 
Grade  3  
 
Grade  4  
 
Grade  5  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 


 
 
 
 
Table  14.  Toxicity  profile  post  treatment  beginning  related  to  treatment  with  
 
 
 
 
 
 
 
 
 
 
 
Cetuximab  (AEs+SAEs+SUSARs)  
 
 
 
 
 
 
 
 
 
GEMCAD  1002  -  EudraCT:  2010-019236-12  -  Clinical  Study  Statistical  Plan  Page   36  of  36  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse  event  
 
Any  grade  
 
Grade  3  
 
Grade  4  
 
Grade  5  
 
N  (%)  
 
N  (%)  
 
N  (%)  
 
N  (%)