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

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ClinicalTrials.gov Identifier: NCT05312398
Recruitment Status : Active, not recruiting
First Posted : April 5, 2022
Last Update Posted : February 1, 2024
Sponsor:
Information provided by (Responsible Party):
Fortunato Ciardiello, University of Campania "Luigi Vanvitelli"

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.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Adenocarcinoma Drug: Cetuximab Drug: FOLFIRI Drug: FOLFOX regimen Drug: Irinotecan Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 219 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 3 treatment lines in mCRC patients with RAS/BRAF wt tumors at start of first line.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 15, 2021
Estimated Primary Completion Date : August 15, 2025
Estimated Study Completion Date : June 15, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Cetuximab

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.

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

Other Name: Erbitux

Drug: 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


Drug: 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

Other Name: FOLFOX

Drug: Irinotecan

III LINE:

- Irinotecan + cetuximab

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





Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. OS [ Time Frame: up to 59 months ]
    Overall Survival

  3. AE [ Time Frame: from screening up to 59 months ]
    Safety: Adverse events graded according NCI CTCAE v 5.0

  4. 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

  5. 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.


Other Outcome Measures:
  1. 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

  2. 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

  3. 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

  4. 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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05312398


Locations
Show Show 25 study locations
Sponsors and Collaborators
University of Campania "Luigi Vanvitelli"
Investigators
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Principal Investigator: Fortunato Ciardiello A.O.U. dell'Università degli studi della Campania "Luigi Vanvitelli"
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Responsible Party: Fortunato Ciardiello, Principal Investigator, University of Campania "Luigi Vanvitelli"
ClinicalTrials.gov Identifier: NCT05312398    
Other Study ID Numbers: CAPRI2-MS062202-0123
First Posted: April 5, 2022    Key Record Dates
Last Update Posted: February 1, 2024
Last Verified: January 2024

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Irinotecan
Cetuximab
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological