CAPRI 2 GOIM Study: Investigate the Efficacy and Safety of a Bio-marker Driven Cetuximab-based Treatment Regimen

Metastatic Colorectal Adenocarcinoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05312398
• Other study ID #: CAPRI2-MS062202-0123
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 15, 2021
• Est. completion date: June 15, 2026

Study information

• Verified date: January 2024
• Source: University of Campania "Luigi Vanvitelli"
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 219
• Est. completion date: June 15, 2026
• Est. primary completion date: August 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Metastatic Colorectal Adenocarcinoma

Intervention

Drug:
• Cetuximab
I LINE: - FOLFIRI + cetuximab FOLFIRI: 200 mg L-folinic acid with 180 mg/ m² irinotecan over 1.30 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on cycle 1 day 1), then 250 mg/m2 once weekly thereafter II LINE: - FOLFOX + cetuximab FOLFOX: 200 mg L-folinic acid given concurrently with 85 mg/ m² oxaliplatin over 2 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: as I line THIRD LINE: - Irinotecan + cetuximab Irinotecan: 180 mg/ m² irinotecan over 1.30 h, IV infusion every 2 weeks. Cetuximab: as I line
• FOLFIRI
I LINE: - FOLFIRI + cetuximab FOLFIRI: 200 mg L-folinic acid given concurrently with 180 mg/ m² irinotecan over 1.30 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: 400 mg/m2 initial dose (120-minute IV infusion on cycle 1 day 1), then 250 mg/m2 once weekly thereafter
• FOLFOX regimen
II LINE: - FOLFOX + cetuximab FOLFOX: 200 mg L-folinic acid given concurrently with 85 mg/ m² oxaliplatin over 2 h IV infusion, followed by a 400 mg/ m² IV bolus of fluorouracil followed by 2400 mg/ m² fluorouracil IV infusion over 46 h every 14 days. Cetuximab: as I line
• Irinotecan
III LINE: - Irinotecan + cetuximab Irinotecan: 180 mg/ m² irinotecan over 1.30 h, IV infusion every 2 weeks. Cetuximab: as I line

Locations

Country	Name	City	State
Italy	Ente Ecclesiastico Ospedale Generale Regionale 'F. Miulli'	Acquaviva Delle Fonti	BA
Italy	A.O.U. Ospedali Riuniti	Ancona	AN
Italy	IRCCS Istituto Tumori 'Giovanni Paolo II'	Bari	BA
Italy	Ospedale Sacro Cuore di Gesù - FATEBENEFRATELLI	Benevento	BN
Italy	P.O. Antonio Perrino	Brindisi	BR
Italy	Ospedale IRCCS 'Saverio de Bellis'	Castellana Grotte	BA
Italy	A.R.N.A.S. Garibaldi - P.O. Garibaldi-Nesima	Catania	CT
Italy	A.O.U. Mater Domini	Catanzaro	CZ
Italy	P.O. 'Vito Fazzi'	Lecce	LE
Italy	Istituto Europeo di Oncologia	Milano	MI
Italy	A.O.U. Cagliari - Presidio Policlinico D. Casula	Monserrato	CA
Italy	A.O.U. dell'Università degli studi della Campania "Luigi Vanvitelli"	Napoli
Italy	Istituto Nazionale Tumori 'Fondazione G. Pascale'	Napoli
Italy	Istituto Oncologico Veneto IRCCS	Padova	PD
Italy	A.O.U. Policlinico 'P. Giaccone'	Palermo	PA
Italy	A.O.U. Pisana	Pisa	PI
Italy	A.O. San Carlo	Potenza	PZ
Italy	A.S.P. Ragusa - Ospedale Maria Paternò Arezzo	Ragusa	RG
Italy	A.U.S.L. - IRCCS di Reggio Emilia - P.O. Arcispedale S.Maria Nuova	Reggio Emilia	RE
Italy	A.O. San Camillo-Forlanini	Roma	RM
Italy	Fondazione Policlinico Universitario 'Agostino Gemelli' IRCCS	Roma	RM
Italy	Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	FG
Italy	Ospedale San Giuseppe Moscati	Statte	TA
Italy	A.O. Ordine Mauriziano	Torino	TO
Italy	A.O. 'Pia Fondazione Cardinale G. Panico'	Tricase	LE

Sponsors (1)

Lead Sponsor	Collaborator
University of Campania "Luigi Vanvitelli"

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Explorative objective: RR for each line of therapy	the response rates for each line of therapy of RAS/BRAF WT mCRC patients who will be treated in a continuum of care strategy with cetuximab across all three therapy lines	from screening up to 23 months
Other	Exploratory objective: cumulative PFS	the cumulative progression free survivals of RAS/BRAF WT mCRC patients who will be treated in a continuum of care strategy with cetuximab across all three therapy lines	from screening up to 23 months
Other	Explorative objective: overall survival	overall survival of RAS/BRAF WT mCRC patients who will be treated in a continuum of care strategy with cetuximab across all three therapy lines	from screening up to 23 months
Other	Translational analyses using next generation sequencing (NGS) technologies	Molecular profiles of tumor tissue and liquid biopsy samples (somatic mutations identified in tumor tissue by next generation sequencing) and surrogate markers of treatment activity (changes in molecular profile of liquid biopsies). Translational analyses of tumor biomarkers will be performed; These include mutation in RAS, BRAF, PI3KCA; amplification of HER2, MET and loss of PTEN expression, all of which are implicated in resistance to anti-EGFR treatment.; Moreover, 324 genes NGS panels will provide information regarding potential predictive and prognostic biomarkers of colorectal cancer disease.; Fecal samples will be used for gut microbioma analysis, to understand how the composition of gut microbiome could influence treatment outcome and tolerability.	At day 1 of each line of therapy
Primary	RR	Response rate (RR) for each line of treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients with RAS/BRAF wild type (WT) mCRCregimen over 3 treatment lines in patients with RAS/BRAF wild type (WT) mCRC at start of first line therapy	up to 59 months
Secondary	PFS	Progression free survival (PFS) for each line	from 8 weeks to 59 months (from the start of therapy until the first observation of disease progression or death due to any cause)
Secondary	OS	Overall Survival	up to 59 months
Secondary	AE	Safety: Adverse events graded according NCI CTCAE v 5.0	from screening up to 59 months
Secondary	EORTC Core Quality of Life questionnaire EORTC QLQ C30	The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items	At screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression
Secondary	DERMATOLOGY LIFE QUALITY INDEX (DLQI)	The DLQI consists of 10 questions concerning patients' perception of the impact of skin diseases on different aspects of their health-related quality of life over the last week.	at screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression