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

January 31, 2024 updated by: Fortunato Ciardiello, University of Campania "Luigi Vanvitelli"

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

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.

Study Overview

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

Study Type

Interventional

Enrollment (Actual)

219

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: single arm

This is an open-label phase II study investigating 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. 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).

If at progression after the first line or after the second line, the liquid biopsy assessment indicates RAS and or BRAF mutant status, patients will be treated with FOLFOX plus bevacizumab as second line of therapy, or with regorafenib or with trifluridine-tipiracil (investigator's choice) as third line therapy.

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

Other Names:
  • Erbitux

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

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

Other Names:
  • FOLFOX

III LINE:

- Irinotecan + cetuximab

Irinotecan: 180 mg/ m² irinotecan over 1.30 h, IV infusion every 2 weeks. Cetuximab: as I line

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
RR
Time Frame: up to 59 months
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
PFS
Time Frame: from 8 weeks to 59 months (from the start of therapy until the first observation of disease progression or death due to any cause)
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)
OS
Time Frame: up to 59 months
Overall Survival
up to 59 months
AE
Time Frame: from screening up to 59 months
Safety: Adverse events graded according NCI CTCAE v 5.0
from screening up to 59 months
EORTC Core Quality of Life questionnaire EORTC QLQ C30
Time Frame: At screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression
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
DERMATOLOGY LIFE QUALITY INDEX (DLQI)
Time Frame: at screening, for each line of therapy at Week 4, at Week 25 of treatment start and at progression
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Explorative objective: RR for each line of therapy
Time Frame: from screening up to 23 months
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
Exploratory objective: cumulative PFS
Time Frame: from screening up to 23 months
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
Explorative objective: overall survival
Time Frame: from screening up to 23 months
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
Translational analyses using next generation sequencing (NGS) technologies
Time Frame: At day 1 of each line of therapy

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Fortunato Ciardiello, A.O.U. dell'Università degli studi della Campania "Luigi Vanvitelli"

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 15, 2021

Primary Completion (Estimated)

August 15, 2025

Study Completion (Estimated)

June 15, 2026

Study Registration Dates

First Submitted

March 1, 2022

First Submitted That Met QC Criteria

March 28, 2022

First Posted (Actual)

April 5, 2022

Study Record Updates

Last Update Posted (Actual)

February 1, 2024

Last Update Submitted That Met QC Criteria

January 31, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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