OrigAMI-2 - A Study of Amivantamab and mFOLFOX6 or FOLFIRI Versus Cetuximab and mFOLFOX6 or FOLFIRI as First-line Treatment in Participants With KRAS/NRAS and BRAF Wild-type Unresectable or Metastatic Left-sided Colorectal Cancer (61186372COR3001)

Studio Clinico

Patologia: Tumori del colon retto

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: III

Richiesta mandatoria di tessuto: Sì

Linee di trattamento: Prima linea

Criteri di inclusione: 

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 left-sided colorectal cancer. Participants must have unresectable or metastatic disease.
Notes:
Left-sided CRC is defined as a primary tumor that involves the splenic flexure, descending colon, sigmoid colon, rectosigmoid, or rectum. 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 for KRAS/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/NRASA59, Q61, K117, or A146 or BRAF V600. A copy of the test report documenting the WT status for KRAS/NRASand 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 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 tumor tissue.
Notes:
The most recent sample should be submitted if multiple samples exist.
Fresh tumor biopsy is required, if clinically feasible, for participants who have received neoadjuvant therapy, adjuvant therapy, or both.
When fresh tissue biopsy collection is not clinically feasible, then archival tissues collected at diagnosis (for participants without prior adjuvant or neoadjuvant therapy) or post-adjuvant or neoadjuvant treatments can be used.
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. Has not received any prior systemic therapy for unresectable or metastatic CRC.
Following prior adjuvant/neoadjuvant therapy in the non-metastatic disease is permitted. However, the last course of adjuvant or neoadjuvant chemotherapy must have concluded >12 months prior to CRC recurrence/metastases.
Adjuvant chemotherapy that included fluoropyrimidine alone or in combination with oxaliplatin or irinotecan (no more than 6 months of treatment); or radiation with radiosensitizing chemotherapy.
Neoadjuvant chemotherapy with fluoropyrimidine monotherapy.
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. eGFR based 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
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. Criterion modified per Amendment EEA-1:
11.1 While on study treatment and for women at least 15 months after, and for men at least 12 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.
Disease Characteristics
14. Criterion added per Amendment EEA-1:
Must be eligible for treatment with mFOLFOX6 (if assigned to receive mFOLFOX6) or FOLFIRI (if assigned to receive FOLFIRI) according to respective local regulatory approvals and SoC guidelines.

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.

Criteri di esclusione: 

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) or cetuximab (refer to the product label) (all participants)
    b. any component of mFOLFOX6 (refer to the product labels) (participants receiving mFOLFOX6)
    c. any component of FOLFIRI (refer to the product labels) (participants receiving FOLFIRI)
4. Participant has a history of clinically significant cardiovascular disease including, but not limited to, the following:
    a. 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 catheter-associated 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
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 surgerywhile 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 studyor 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.
8. Participant with known HER2-positive/amplified tumor.
9. Has prior exposure to any agents that target EGFR or MET (including but not limited to protein products, monoclonal antibodies, tyrosine kinase inhibitors, or antisense oligonucleotide therapy).
10. Criterion modified per Amendment EEA-1:
10.1 Participant with known complete absence of DPDactivity. Testing for DPD deficiency should be performed per local guidelines.
11. Criterion modified per Amendment EEA-1:
11.1 For a participant who is to receive FOLFIRI: known to be homozygous for the UGT1A1*28 or *6 alleles or compound or double heterozygous for the UGT1A1*28 and *6 alleles 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-PCRmeasurement 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. Had radiation therapy within 28 days before randomization. Note: Localized radiotherapy for palliative purposes must be completed at least 21 days
prior to randomization.
17. Requires a prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study (see Section 6.9.3 for prohibited therapies).
18. 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
19. 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 <80kg; 2240 mg per peso corporeo ≥80 kg) + mFOLFOX6 o FOLFIRI
• Braccio B: Cetuximab + mFOLFOX6 o FOLFIRI
Il periodo di trattamento inizierà il Giorno 1 del Ciclo 1 e continuerà come cicli di 28 giorni.

Trattamento sperimentale: 

Amivantamab SC + Folfox o Folfiri

Trattamento di controllo: 

Cetuximab + Folfox o 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) nei partecipanti trattati con amivantamab + mFOLFOX6 o FOLFIRI rispetto ai partecipanti trattati con cetuximab + mFOLFOX6 o FOLFIRI.

Obiettivi secondari dello studio: 

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

Centri partecipanti

Nord Italia

Centro Italia

Informazioni Generali

Protocollo

Numero di iscrizione a registro: 2024-513852-13

Data di inserimento: 29.04.2025

Promotore

Janssen Research & Development, LLC

Principal Investigator ITALIA

Riferimento: Dr. Info non applicabile

Telefono: 00000

Email: na@na.it

Localita: na