Use of the chemotherapy FOLFIRI and cetuximab if given with treatment breaks or continuously in patients with newly diagnosed metastatic colorectal cancer without previous treatment.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Charite Universitaetsmedizin Berlin KöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-11-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck Healthcare Germany GmbH

External identifiers

EU CT number

2025-522377-12-00

WHO UTN

U1111-1319-8357

ClinicalTrials.gov

NCT07004413

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Others, Efficacy, Pharmacogenetic, Safety

To demonstrate superior Time To Failure of Strategy (TFS) in RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus cetuximab in first-line mCRC for 8 cycles followed by a planned treatment break and re-induction if progressive disease occurs during treatment holidays compared to continuous treatment.

Secondary objectives 4

1. To assess efficacy and tumor response kinetics
2. To define and validate circulating tumor DNA (ctDNA) by detection with the Guardant360 liquid biopsy assay as screening and monitoring biomarker for response and resistance towards FOLFIRI plus cetuximab as part of a complementary interventional clinical performance study
3. To assess safety and tolerability
4. To assess quality of life during and after treatment

Conditions and MedDRA coding

metastatic colorectal cancer

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patient’s signed informed consent
2. Histologically confirmed, UICC stage IV unresectable adenocarcinoma of the colon or rectum
3. Locally confirmed RAS/BRAF wild-type tumor status (KRAS and NRAS exon 2, 3, 4, BRAF exon 11/15)
4. Centrally confirmed RAS/BRAF wild-type status by liquid biopsy during screening phase
5. Age ≥18 at the time of written informed consent
6. ECOG performance status ≤1
7. Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria
8. Archival tumor tissue available
9. Adequate bone marrow function (all of the following): a. Leukocytes ≥ 3.0 x 10E9/L with neutrophils ≥ 1.5 x 10E9/L b. Thrombocytes ≥ 100 x 10E9/L c. Hemoglobin ≥ 8 g/dL
10. Adequate hepatic function (all of the following): a. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) b. ALAT and ASAT ≤ 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT ≤ 5 x ULN) c. INR < 1.5 and aPTT < 1.5 x ULN (patients without anticoagulation). Therapeutic anticoagulation is allowed if INR and aPTT have remained stable within the therapeutic range (INR: 2.0 – 3.5; aPTT: 1.5 – 2.5 x ULN).
11. Adequate renal function: a. Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50 mL/min
12. Proficient fluorouracil metabolism as defined: a. Prior treatment with 5-FU or capecitabine without unusual toxicity b. If tested, normal DPD deficiency test according to the standard of the study site c. If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50%
13. Women of childbearing potential (WOCBP) and men must agree to use highly effective contraceptive measures (Pearl index <1; e.g. combined oral and intravaginal, transdermal, injectable or implantable hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner) or practice true abstinence from any heterosexual intercourse (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject) for the duration of the study treatment and for at least 6 months after last administration of study medication. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
14. For men: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.

Exclusion criteria 28

1. Proof of a RAS or BRAF mutation (KRAS/NRAS exons 2, 3, 4 or BRAF exon 15) in the tumor (proven in the primary tumor or metastasis) or liquid biopsy during screening phase.
2. Participation in a clinical study or experimental drug treatment within 30 days prior to written informed consent or within a period of 5 half-lives of the substances administered in a clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest or simultaneous participation in another study while taking part in the study
3. Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, cetuximab, irinotecan and chemically related substances and/or hypersensitivity to any of the components in the formulations of the aforementioned substances, including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE grade ≥ 3.
4. Known hypersensitivity to Chinese hamster ovary cell (CHO) –cellular products or other recombinant human or humanized monoclonal antibodies
5. Patients with known brain metastases or leptomeningeal disease. In case of clinical suspicion of brain metastasis, a cranial CT or MRI must be performed to rule out brain metastasis before study inclusion.
6. History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhea
7. Symptomatic peritoneal carcinosis
8. Severe, non-healing wounds, ulcers or bone fractures
9. Requirement for immunization with live vaccine including attenuated live vaccine from at least 4 weeks before begin of induction treatment until 6 months after the administration of IMPs.
10. Hemorrhagic diathesis or known thrombophilia
11. Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
12. Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before written informed consent.
13. Treatment with nucleoside analogues including sorivudine or brivudine within 28 days before begin of induction treatment or requirement for concomitant antiviral treatment with sorivudine or brivudine or analogues
14. History of a second primary malignancy during the past 5 years before written informed consent or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively.
15. Active alcohol or drug abuse
16. Any other significant medical, psychiatric or social condition not covered by the above criteria, which, in the investigator’s judgement, may pose a safety risk, impair protocol compliance or interfere with reliable assessment of study outcomes
17. Pernicious anemia or other types of anemia caused by vitamin B12 deficiency
18. Concomitant use with St. John’s wort
19. Absent or restricted legal capacity
20. Acute or chronic New York Heart Association Class III or greater heart failure by clinical judgement.
21. Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and cerebral vascular accident (including TIA)/stroke within the past 12 months before randomization
22. Unstable angina pectoris
23. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.
24. Active uncontrolled infection by investigator’s perspective.
25. Pre-existing pulmonary fibrosis or immune pneumonitis
26. Additional cancer treatment (chemotherapy, radiation, immunotherapy or hormone treatment) during the study treatment. Mistletoe therapy does not represent an exclusion criterion.
27. Patients who are institutionalized by order of court or public authority
28. Patients who might be dependent on the sponsor/investigator or the trial site

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to Failure of Strategy, which is defined as the time from randomization to failure of the treatment strategy. Failure of the treatment strategy is defined as o Disease progression on treatment o Death o Unacceptable toxicity o Occurrence of resistance mechanisms by ctDNA analysis

Secondary endpoints 5

1. Efficacy: • Progression-free survival (PFS)1 to PFSN (defined as each PFS from treatment start with FOLFIRI+cetuximab to the first disease progression in the respective treatment period) • TFS stratified by ctDNA-guided progression or radiological progression • Overall survival (OS) • Objective response rate (ORR)
2. Tumor response kinetics: • Dynamics of the tumor markers CEA and CA19-9 • Early tumour shrinkage, as determined by radiological imaging • Depth of radiological tumor response, as determined by radiological imaging
3. Circulating tumour DNA (ctDNA): • Prospective validation to use ctDNA based RAS/BRAF mutational analysis in addition to tissue-based RAS testing to exclude RAS/BRAF mutant tumors from treatment using the Guardant360 liquid biopsy assay • Define a threshold in ctDNA change predicting progressive disease during treatment break using the Guardant360 liquid biopsy assay • Validate the formerly defined ctDNA threshold using the Guardant360 liquid biopsy assay to induce re-use of FOLFIRI + Cetuximab
4. Safety: • Type, incidence, severity, and causal relationship to IMPs of non-serious adverse events and serious adverse events (severity evaluated according to CTCAE version 5.0)
5. Quality of life: • QoL as assessed with the QoL questionnaire EQ-5D-5L

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Charite Universitaetsmedizin Berlin KöR

Sponsor organisation

Charite Universitaetsmedizin Berlin KöR

Address

Chariteplatz 1, Mitte Mitte

City

Berlin

Postcode

10117

Country

Germany

Scientific contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

PD Dr. med. Arndt Stahler

Public contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

PD Dr. med. Arndt Stahler

Third parties 27

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications