OrigAMI-3 - A Study of Amivantamab and FOLFIRI Versus Cetuximab/Bevacizumab and FOLFIRI in Participants With KRAS/NRAS and BRAF Wild-type Colorectal Cancer Who Have Previously Received Chemotherapy (61186372COR3002).

Studio Clinico

Patologia: Tumori del colon retto

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: III

Linee di trattamento: Seconda linea

Criteri di inclusione: 

Age
1. Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.
Disease Characteristics
2. Have histologically or cytologically confirmed adenocarcinoma of the colon or rectum.
Participants must have recurrent, unresectable or metastatic disease.
Note: Carcinoma of the anal canal is excluded.
3. Be diagnosed to have KRAS, NRAS, and BRAFWT tumor as determined by local testing.
Both tissue- and blood-based testing is an acceptable method for the eligibility determination.
The local test must at least include and participants must be WT forKRAS/NRASG12 and G13 and BRAFV600 codons. Other KRAS/NRAScodons, as well as MSI-H/dMMR status and ERBB2/HER2 amplification status, should be determined per the local guidelines and standard practice. A participant is excluded from the study if the participant is known to have a mutation (with the exception of a silent mutation) in any of the following codons
based on local testing: KRAS/NRASG12, G13, A59, Q61, K117, or A146 or BRAFV600.
A copy of the test report documenting the WT status for KRAS/NRAS and BRAFmust be included in the participant records, and a de-identified copy must be submitted to the sponsor during the screening period.
The local test must be performed prior to randomization in accordance with local guidelines using an FDA-approved test or laboratory-developed test that is validated in a CLIA-certified laboratory (sites in the United States) or an accredited local laboratory (sites outside of the United States). In the European Union, the local test must be CE-marked or an in-house laboratory-developed test from health institutions in the European Union in accordance with Article 5(5) of the IVDR 2071/746, as amended.
4. Must agree to the submission of fresh or archival tumor tissue post-progression from the most recent therapy, if clinically feasible.
5. Have measurable disease according to RECIST v1.1. If only 1 measurable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed ≥7 days after the biopsy.
Prior Therapy Restrictions or Requirements
6. Participant must have received 1 line of systemic therapy for mCRC, with documented radiographic disease progression on or after this line of therapy. The regimen must be fluoropyrimidine-based and oxaliplatin-based therapy. Prior anti-VEGF therapy is allowed according to local regulatory approvals and SoC guidelines.
Note: Definition of 1 line of therapy equates to disease progression from 1 and only 1 prior regimen for mCRC.
Rechallenge of a same regimen after disease progression or maintenance therapy will not count as an additional line of therapy.
Recurrence from prior neoadjuvant/adjuvant chemotherapy <12 months from the last course of systemic chemotherapy is considered as 1 prior line in the metastatic setting and, with this 1 line, the participant will be eligible for the study.
Performance Status 
7. Have an ECOG PS of 0 or 1 (Appendix 8).
Renal Function
8. Have at least 1 of the following:
    a. Serum creatinine ≤1.5×ULN
    b. eGFRbased on the MDRD 4-variable formula (see Appendix 10) or directly measured creatinine clearance ≥50 mL/min
Hepatic Function
9. Participants are eligible if they have the following laboratory values:
              Hepatic metastases

Total bilirubin ≤1.5×ULN
Bilirubin in case of known congenital nonhemolytic hyperbilirubinemias such as Gilbert syndrome - isolated total bilirubin ≥1.5×ULN with conjugated (direct) bilirubin ≤1.5×ULN
Hematologic Values
10. Participants should have: (without transfusion or growth factors within 1 week of randomization):
Hemoglobin ≥9.0 g/dL, without transfusion or growth factors within 1 week
Neutrophils ≥1.5×103/μL or ≥1.0×103/μL for participants with benign ethnic neutropenia
Participants with benign ethnic neutropenia must have a source document describing the (1) persistent low neutrophil count (eg, neutrophil count <1.5×103/μL in 2 consecutive laboratory tests performed at least 2 weeks apart); (2) absence of other cytopenias, splenomegaly, or lymphadenopathy; and (3) other possible etiology of neutropenia have been ruled out.
Platelets ≥100×103/μL
Sex and Contraceptive/Barrier Requirements
11. While on study treatment and for 6 months after the last dose of study treatment, a participant must:
    - Not breastfeed or be pregnant
    - Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction
    - Wear an external condom
    - If of childbearing potential,
       o Have a negative highly sensitive (eg, beta-human chorionic gonadotropin [β-hCG]) pregnancy test at screening and within 24 hours before randomization and agree to further pregnancy tests per the SoA
        o Practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used
    - If a participant’s partner is of childbearing potential,
        o The partner must practice a highly effective method of contraception unless the participant is vasectomized
See Appendix 4 for details.
Informed Consent
12. Must sign an ICF (or their legally designated representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
13. Be willing and able to adhere to the lifestyle restrictions specified in this protocol.

Criteri di esclusione: 

Any potential participant who meets any of the following criteria will be excluded from participating in the study:
Medical Conditions
1. Has uncontrolled illness including, but not limited to, the following:
    a. Diabetes mellitus
    b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics/antimicrobials 1 week prior to starting study treatment]) or diagnosed or suspected viral infection except as
allowed by Exclusion Criterion 14 for HIV
    c. Active bleeding diathesis. Bleeding from the primary tumor is not an exclusion.
    d. Impaired oxygenation requiring continuous oxygen supplementation
    e. Psychiatric illness/social situation that would limit compliance with study requirements
    f. Significant history of bleeding events (eg. hemoptysis, upper or lower gastrointestinal bleeding) within 6 months of randomization unless the source of bleeding has been resected or controlled
    g. History of gastrointestinal perforation within 6 months of randomization. However, if the perforation was from the primary tumor that has been surgically resected and controlled, the individual may be enrolled.
2. Has medical history of (noninfectious) ILD/pneumonitis/pulmonary fibrosis or has current ILD/pneumonitis/pulmonary fibrosis, or where suspected ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening.
3. Has known allergies, hypersensitivity, or intolerance to excipients ofany of the following:
    a. amivantamab (refer to the IB), cetuximab (refer to the product label), or bevacizumab (refer to the product label)
    b. any component of FOLFIRI (refer to the product labels)
4. Criterion (bullet g only) modified per Amendment EEA-1:
    a. 4.1 Participant has a history of clinically significant cardiovascular disease including, but not limited to, the following: Diagnosis of deep vein thrombosis or pulmonary embolism within 4 weeks prior to randomization or any of the following within 6 months prior to randomization: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically nonsignificant thrombosis, such as nonobstructive catheterassociated clots, are not exclusionary.
    b. Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). Note: Participants with cardiac pacemakers who are clinically stable are eligible.
    c. Uncontrolled (persistent) hypertension: systolic BP >180 mm Hg; diastolic BP >100 mm Hg
    d. Congestive heart failure defined as NYHA class III or IV or hospitalization for congestive heart failure (any NYHA class) within 6 months of randomization (Appendix 9)
    e. Pericarditis/clinically significant pericardial effusion
    f. Myocarditis
    g. Participants receiving bevacizumab: Participants with a history of poorly controlled hypertension or with resting blood pressure >150/100 mm Hg in the presence or absence of a stable regimen of antihypertensive therapy. Participants with history of aneurysm or artery dissection will be excluded.
5. Has or will have any of the following:
    a. An invasive operative procedure with entry into a body cavity within 4 weeks or without complete recovery before the first administration of study treatment. Thoracentesis or paracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to the first administration of study treatment as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment in the clinical judgement of the investigator.
    b. Significant traumatic injury within 3 weeks before the start of the first administration of study treatment (all wounds must be fully healed prior to Day 1).
    c. Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study treatment.
Note: Port placement for chemotherapy administration is allowed.
6. Has a prior or concurrent second malignancy other than the disease under study or one whose natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s) (see Appendix 7 for details). Prior or concurrent second malignancies must be reviewed and agreed to with the medical monitor.
Disease Characteristics
7. Participant with known dMMR/MSI-H status who has not received immunotherapy treatments.
8. Participant with known HER2-positive/amplified tumor.
9. Has prior exposure to irinotecan, any agents that target EGFR or MET (including but not limited to protein products, monoclonal antibodies, tyrosine kinase inhibitors, or antisense oligonucleotide therapy), or both.
10. Criterion modified per Amendment EEA-1:
10.1 Participant with known complete absence of DPD activity. Testing for DPD deficiency should be performed per local guidelines.
11. Criterion modified per Amendment EEA-1:
11.1 Known to be homozygous for the UGT1A1*28 or *6 alleles or is compound or double heterozygous for the UGT1A1*28 and *6 alleles per local guidelines. Participants with Gilbert syndrome must be tested for UGT1A1 per local guidelines. Testing for UGT1A1 should be done in accordance with local guidelines.
Brain and Central Nervous System Metastases
12. Has symptomatic or untreated brain metastasis.
Note: Participants with definitively, locally treated metastases that are clinically stable and asymptomatic for a least 2 weeks and who are off or receiving low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 6 weeks prior to randomization are eligible
13. Has medical history or known presence of leptomeningeal disease or spinal cord compression.
HIV Status
14. HIV-positive participants are not eligible if they meet any of the following criteria:
    a. Detectable viral load (ie, >50 copies/mL) at screening
    b. CD4+ count <300 cells/mm3 at screening
    c. AIDS-defining opportunistic infection within 6 months of screening
    d. Not receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to randomization).
Viral Hepatitis Assessments
15. Has active hepatitis ofinfectious origin at screening:
    a. Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants who are HBsAg-negative with positive antibodies to total anti-HBc) must be screened using RT-PCR measurement of HBV DNA levels.
Those who are RT-PCR-positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by RT-PCR (see Appendix 11).
    b. Known hepatitis C infection or positive serologic testing for HCV (anti-HCV) antibody.
    c. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative HCV RNA test is obtained at screening or within 3 months prior to first dose of study treatment.
    d. Other clinically active liver disease of infectious origin.
Prior/Concomitant Therapy or Clinical Study Experience
16. Has had prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives whichever is longer, before the first administration of study intervention(s). For agents with long half-lives, the maximum required time since last dose is 4 weeks. The maximum required time since last dose is 28 days.
17. Had radiation therapy within 28 days before randomization.
Note: Localized radiotherapy for palliative purposes must be completed at least 21 days prior to randomization.
18. Has toxicities from previous anticancer therapies not resolved to baseline levels or to Grade ≤1 prior to randomization (except for alopecia or post-radiation skin changes [any grade], Grade ≤2 peripheral neuropathy, and Grade ≤2 hypothyroidism stable on hormone replacement).
19. Requires a prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study (see Section 6.9.3 for prohibited therapies).
20. Received an investigational treatment (including investigational vaccines but not including anticancer therapy) or used an invasive investigational medical device within 8 weeks of randomization.
Other Exclusions
21. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

Schema di trattamento: 

• Braccio A: amivantamab SC (1.600 mg per peso corporeo <80 kg; 2.240 mg per peso corporeo ≥80 kg) + FOLFIRI
• Braccio B: cetuximab o bevacizumab (a scelta dello sperimentatore) + FOLFIRI

Trattamento sperimentale: 

Amivantamab SC+ Folfiri

Trattamento di controllo: 

Cetuximab/Bevacizumab + Folfiri

Obiettivi primari dello studio: 

L’obiettivo primario di questo studio è confrontare la PFS (Progression-Free Survival [sopravvivenza libera da progressione]) (valutata mediante revisione centrale indipendente in cieco (Blinded Independent Central Review, BICR) e l’OS (Overall Survival [sopravvivenza complessiva]) nei partecipanti trattati con amivantamab + FOLFIRI rispetto ai partecipanti trattati con cetuximab o bevacizumab (a scelta dello sperimentatore) + FOLFIRI.

Obiettivi secondari dello studio: 

Gli obiettivi secondari includono altre misure di efficacia, sicurezza e PRO (Patient-Reported Outcomes [esiti riferiti dal paziente]).

Note generali: 

Data inizio arruolamento: febbraio 2025
Data fine arruolamento: novembre 2026

Centri partecipanti

Nord Italia

Centro Italia

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2024-513853-66

Data di inserimento: 29.04.2025

Promotore

Janssen Cilag International

Principal Investigator ITALIA

Riferimento: Dr. Info non applicabile

Telefono: 00000

Email: na@na.it

Localita: na