Pre-Operative Treatment in rEseCTable cOlon canceR (PROTECTOR/FIRE-10; AIO-KRK-0620; IAG-VO-0323) Prospective, randomized, open-label, multicenter Phase III trial to investigate the efficacy of preoperative systemic therapy in advanced colon cancer

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] - Digestive System Diseases [C06]

Trial duration

1 Apr 2025 → ongoing

Decision date (initial)

2024-11-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To compare the efficacy of preoperative chemotherapy before surgery to surgery followed by stage-guided adjuvant therapy

Conditions and MedDRA coding

Colon cancer staged T3-4 and/or nodal positive by CT and/or MRI scan without distant metastases.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patient’s signed informed consent.
2. Patient’s age ≥18 years at the time of signing the informed consent.
3. Histologically confirmed adenocarcinoma of the colon or upper rectum.
4. 4. Confirmed mismatch-repair proficient and/or microsatellite stable tumor. Both Immunohistochemistry and PCR can be used for diagnosis.
5. Intent for curative surgery
6. Predicted T3 or T4 stage and or nodal positivity (N+) in a computed tomography and/or magnetic resonance imaging scan of the abdomen/pelvis as assessed by the local study team. • T3-4 defined as invasion of surrounding tissue structures or organs • N+ defined as regional lymph node(s) without fat hilus and short axis diameter of ≥1 cm
7. Absence of clear distant metastases assessed by the investigator based on respective routine evaluations within 6 weeks prior to inclusion into the trial (preferred: computed tomography of thorax and abdomen. Alternatively magnetic resonance images, sonography and x-rays might be used for assessment).
8. Absence of significant active wound healing including severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
9. ECOG performance status 0-2.
10. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results: • Absolute neutrophil count  1.5 x 109/L (1,500/µL) • Hemoglobin ≥ 80 g/L (8 g/dL) with or without transfusion • Platelet count ≥ 100 x109/L (100,000/µL) without transfusion • Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN) • Aspartate aminotransferase (AST/GOT) ≤ 3.0 × ULN. • Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ≥ 50 mL/min or serum creatinine ≤ 1.5 x ULN
11. Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
12. Proficient fluorouracil metabolism as defined: Prior treatment with 5-FU or capecitabine without unusal toxicity or If tested, normal DPD deficiency test according to the standard of the study site or 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% and patients are allowed into the trial.
13. For women of childbearing potential (WOCBP): negative pregnancy test within 7 days before treatment initiation and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 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 22

1. Ileus or directly imminent ileus as assessed by the local study team. Patients with treated and resolved ileus are allowed into the trial.
2. Previous chemotherapy for colorectal cancer of any stage
3. New York Heart Association Class III or greater heart failure by clinical judgement.
4. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
5. Unstable angina pectoris.
6. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.
7. Ongoing toxicities > grade 2 NCI CTCAE, in particular peripheral neuropathy.
8. Active uncontrolled infection by investigator’s perspective.
9. Known hypersensitivity to 5-FU, folinic acid, capecitabine, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
10. Recent or concomitant treatment with brivudine.
11. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 5.0 (see appendix)).
12. Simultaneous application of St. John’s Wort preparations.
13. Pernicious or other megaloblastic anemia caused by vitamin B12 deficiency.
14. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization that may interfere with systemic therapy as judged by the investigator.
15. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications., including but not limited to: - Simultaneous application of live vaccines during treatment with irinotecan and for at least 6 months after the last dose. - 5-FU must not be given in combination with brivudin, sorivudin and analogues to patients homozygous for DPD and patients known with completely missing DPD activity. - Severe diarrhoea.
16. Medical history of malignant disease other than colorectal cancer with the following exceptions: - patients who have been disease-free for at least three years before randomization - patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer - patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ≥ 90% at the time of inclusion (assessed and documented by the investigator) and does not require active therapy
17. Known alcohol or drug abuse.
18. Pregnant or breastfeeding females.
19. Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
20. Patients depended on Sponsor, investigator or study site.
21. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
22. Limited legal capacity.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Disease-free survival (DFS) - defined as no surgery, no resection, incomplete resection, disease recurrence (new metastases or local relapse) and death from any cause from the time of randomization. In case of no surgery,no resection, or incomplete resection (defined as R2 resection = macroscopic tumor rest), the timepoint of the respective event will be set to two weeks after randomization to avoid time-bias in favor of the experimental/neoadjuvant therapy arm.

Investigational products

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

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Charite Universitaetsmedizin Berlin KöR

Sponsor organisation

Charite Universitaetsmedizin Berlin KöR

Address

Augustenburger Platz 1, Wedding Wedding

City

Berlin

Postcode

13353

Country

Germany

Scientific contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

Prof. Dr. Dominik Modest

Public contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

Prof. Dr. Dominik Modest

Locations

1 EU/EEA country · 80 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

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

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