Clinical trial NCT05312398: CAPRI 2 GOIM Study: Investigate the Efficacy and Safety of a Bio-marker Driven Cetuximab-based Treatment Regimen
Official title: CAPRI 2 GOIM Study: Investigate the Efficacy and Safety of a Bio- Marker-driven Cetuximab-based Treatment Regimen Over 3 Treatment Lines in mCRC Patients With RAS/BRAF wt Tumors at Start of First Line
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Colorectal Adenocarcinoma
Lead sponsor: University of Campania Luigi Vanvitelli
Sponsor class: OTHER
First posted: 2022-04-05
Enrollment: 219
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 3 treatment lines in mCRC patients with RAS/BRAF wt tumors at start of first line.
Primary purpose: TREATMENT

Brief summary: This clinical program aims to evaluate the activity and efficacy of cetuximab continuation of treatment for three lines of therapy with rotation of chemotherapy (FOLFIRI, FOLFOX, irinotecan) in mCRC patients, whose tumors remain RAS/BRAF WT. The study will also evaluate the activity and efficacy of cetuximab re-introduction in combination with irinotecan as third line therapy in the concept of re-challenge for those patients that will be treated in second line with chemotherapy plus anti-angiogenic drugs (FOLFOX plus bevacizumab), having a RAS or BRAF mutant disease at the time of progression after FOLFIRI plus cetuximab first line treatment. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by liquid biopsy assessment of RAS/BRAF status.

Detailed description: Based on dynamic and longitudinal liquid biopsy assessment of RAS/BRAF status, that will be prospectively performed before each line of treatment, mCRC patients will be treated with cetuximab in combination with chemotherapy throughout three lines of therapy, as follows: FOLFIRI plus cetuximab (first line); FOLFOX plus cetuximab (second line); irinotecan plus cetuximab (third line) in case of RAS/BRAF WT at each time point of progression. If at progression after the first line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with FOLFOX plus bevacizumab as the second line of therapy. If at progression after the second line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with regorafenib or trifluridine-tipiracil (investigator's choice), as third line of therapy. Each treatment will be administered using standard doses and schedules until progression of disease or unacceptable toxicity.

This study will also evaluate the activity and efficacy of cetuximab re-introduction in combination with irinotecan as third line therapy in the concept of re-challenge for those patients that will be treated in second line with FOLFOX plus bevacizumab, having a RAS or BRAF mutant disease at the time of progression after FOLFIRI plus cetuximab first line treatment. A novel characteristic of this program is that the therapeutic algorithm will be defined at each treatment decision (first line, second line and third line) in a prospective fashion in each patient by liquid biopsy assessment of RAS/BRAF status

Eligibility criteria: Inclusion Criteria:

1. Histologically proven diagnosis of colorectal adenocarcinoma
2. Diagnosis of metastatic disease
3. RAS and BRAF wild-type status of FFPE analysis of primary colorectal cancer and/or related metastasis
4. Measurable disease according to Response Evaluation Criteria in Solid Tumors RECIST criteria, vers.1.1)
5. Male or female patients ≥ 18 years of age
6. ECOG Performance Status 0,1
7. Adequate bone marrow, liver and renal function assessed within 14 days before starting study treatment as defined by the following parameters:

   Bone marrow:
   * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
   * Hemoglobin (Hgb) ≥ 9 g/dL
   * Platelets ≥ 100 x 109/L

   Liver function:

   • Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and ALT (SGPT) ≤ 2.5 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN

   Renal function:

   • Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min
8. If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment
9. If female and of childbearing potential, or if male, agreement to use adequate contraception (e.g., abstinence, intrauterine device, oral contraceptive, or double-barrier method), during the study and until at least 3 months after last dose of study treatment administration, based on the judgment of the Investigator or a designated associate
10. Signed informed consent obtained before screening.

Exclusion Criteria:

1. Any contraindication to the use of cetuximab, Irinotecan, 5-FU, oxaliplatin, folinic acid,bevacizumab, trifluridine-tipiracil, regorafenib
2. Active uncontrolled infections, active disseminated intravascular coagulation or history of interstitial lung disease
3. Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix
4. Pregnancy (exclusion to be ascertained by a beta hCG test)
5. Breastfeeding
6. Fertile women (\<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception•
7. Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before inclusion in the study, Grade III or IV heart failure (NYHA classification)
8. Cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin
9. Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
10. Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
11. Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or during participation in the study
12. Known or clinically suspected brain metastases
13. History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
14. Severe, non-healing wounds, ulcers or bone fractures
15. Uncontrolled hypertension
16. Marked proteinuria (nephrotic syndrome)
17. Known DPD deficiency (specific screening not required)
18. Known history of alcohol or drug abuse
19. A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study
20. Absent or restricted legal capacity

Primary outcomes:
measure: RR
timeFrame: up to 59 months
Secondary outcomes:
measure: PFS
timeFrame: from 8 weeks to 59 months (from the start of therapy until the first observation of disease progression or death due to any cause)
measure: OS
timeFrame: up to 59 months
measure: AE
timeFrame: from screening up to 59 months
measure: EORTC Core Quality of Life questionnaire EORTC QLQ C30
timeFrame: At screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression
measure: DERMATOLOGY LIFE QUALITY INDEX (DLQI)
timeFrame: at screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression
Other outcomes:
measure: Explorative objective: RR for each line of therapy
timeFrame: from screening up to 23 months
measure: Exploratory objective: cumulative PFS
timeFrame: from screening up to 23 months
measure: Explorative objective: overall survival
timeFrame: from screening up to 23 months
measure: Translational analyses using next generation sequencing (NGS) technologies
timeFrame: At day 1 of each line of therapy
Locations:
city: Ancona
country: Italy
facility: A.O.U. Ospedali Riuniti
state: AN
city: Acquaviva Delle Fonti
country: Italy
facility: Ente Ecclesiastico Ospedale Generale Regionale 'F. Miulli'
state: BA
city: Bari
country: Italy
facility: IRCCS Istituto Tumori 'Giovanni Paolo II'
state: BA
city: Castellana Grotte
country: Italy
facility: Ospedale IRCCS 'Saverio de Bellis'
state: BA
city: Benevento
country: Italy
facility: Ospedale Sacro Cuore di Gesù - FATEBENEFRATELLI
state: BN
city: Brindisi
country: Italy
facility: P.O. Antonio Perrino
state: BR
city: Monserrato
country: Italy
facility: A.O.U. Cagliari - Presidio Policlinico D. Casula
state: CA
city: Catania
country: Italy
facility: A.R.N.A.S. Garibaldi - P.O. Garibaldi-Nesima
state: CT
city: Catanzaro
country: Italy
facility: A.O.U. Mater Domini
state: CZ
city: San Giovanni Rotondo
country: Italy
facility: Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza
state: FG
city: Lecce
country: Italy
facility: P.O. 'Vito Fazzi'
state: LE
city: Tricase
country: Italy
facility: A.O. 'Pia Fondazione Cardinale G. Panico'
state: LE
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
state: MI
city: Palermo
country: Italy
facility: A.O.U. Policlinico 'P. Giaccone'
state: PA
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS
state: PD
city: Pisa
country: Italy
facility: A.O.U. Pisana
state: PI
city: Potenza
country: Italy
facility: A.O. San Carlo
state: PZ
city: Reggio Emilia
country: Italy
facility: A.U.S.L. - IRCCS di Reggio Emilia - P.O. Arcispedale S.Maria Nuova
state: RE
city: Ragusa
country: Italy
facility: A.S.P. Ragusa - Ospedale Maria Paternò Arezzo
state: RG
city: Roma
country: Italy
facility: A.O. San Camillo-Forlanini
state: RM
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS
state: RM
city: Statte
country: Italy
facility: Ospedale San Giuseppe Moscati
state: TA
city: Torino
country: Italy
facility: A.O. Ordine Mauriziano
state: TO
city: Napoli
country: Italy
facility: A.O.U. dell'Università degli studi della Campania "Luigi Vanvitelli"
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori 'Fondazione G. Pascale'
Study officials:
affiliation: A.O.U. dell'Università degli studi della Campania "Luigi Vanvitelli"
name: Fortunato Ciardiello
role: PRINCIPAL_INVESTIGATOR
References: