Post-resection/ ablation chemotherapy in patients with metastatic colorectal cancer (FIRE-9 - PORT / AIO-KRK-0418). Prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of active post-resection/ ablation therapy in patients with metastatic colorectal 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

11 Nov 2021 → ongoing

Decision date (initial)

2024-11-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512174-10-00

EudraCT number

2020-006144-18

ClinicalTrials.gov

NCT05008809

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To compare the efficacy of active additive chemotherapy after definitive treatment of metastases to structured follow-up only

Conditions and MedDRA coding

metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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 rectum
4. Resected (R0 or R1) and/or effectively treated metastases (all techniques allowed) of colorectal cancer within 3-10 weeks before randomization (earlier randomisation allowed if at least 3 weeks interval between intervention and treatment start is guaranteed) AND resected primary tumor (synchronous or metachronous). In cases of synchronous metastases the interval of 3-10 weeks might be calculated following the removal of the primary tumor if this intervention was the last to address all tumor lesions
5. Absence of significant active wound healing complications (if applicable) at randomization. Resolved wound healing complications after resection/ablation are acceptable for inclusion into the trial
6. No radiographic evidence of active metastatic disease at study entry in a CT and/or MRI scan not older than 10 weeks prior randomization. Pre- surgery/ablation images are eligible for the study if all lesions have been addressed in the interval
7. ECOG performance status 0-2.
8. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results: • Absolute neutrophil count 1.5 x 109/L (1500/µL) • Hemoglobin ≥ 80 g/L (8 g/dL) • Platelet count ≥ 100 x109/L (100000/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
9. 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.
10. Proficient fluorouracil metabolism as defined: a) Prior treatment with 5-FU or capecitabine without unusual toxicity or b) If tested, normal DPD deficiency test according to the standard of the study site or c) If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine/capecitabine dosage should be reduced by 50%
11. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization 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 9 months after the last dose of Oxaliplatin or for at least 6 months after the last dose of all other 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 28

1. Treatment of metastases greater than 3 cm with radio-frequency/microwave ablation within 24 months prior to study entry if applicable.
2. Treatment of metastases greater than 5 cm with radiation (stereotactic/ brachytherapy) within 24 months prior to study entry if applicable.
3. Any previous systemic therapy is allowed for inclusion into the trial. However, if previous oxaliplatin-containing chemotherapy at any time for metastatic or localized disease was carried out, the inclusion into the trial is permitted under the condition, that a) A total duration of oxaliplatin-based therapy of six months (i.e. 12 cycles of FOLFOX / FOLFOXIRI or 8 cycles CAPOX) is not exceeded - including therapy within the FIRE-9/PORT trial b) If already more than three months of oxaliplatin-based therapy (i.e. >6 cycles of FOLFOX / FOLFOXIRI or >4 cycles CAPOX) was used, the study therapy should be started with an irinotecan-based regimen (i.e. FOLFIRI or FOLFOXIRI) However, in the case of FOLFOXIRI therapy in the trial, the above mention regulation concerning the total dosing of oxaliplatin still applies (i.e. 12 cycles of FOLFOX / FOLFOXIRI or 8 cycles CAPOX should not be exceeded - including therapy within the FIRE-9/PORT trial).
4. New York Heart Association Class III or greater heart failure by clinical judgement.
5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
6. Unstable angina pectoris.
7. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.
8. Ongoing toxicities > grade 2 NCI CTCAE
9. Active uncontrolled infection by investigator’s perspective.
10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
11. Known hypersensitivity to 5-FU, folinic acid irinotecan, oxaliplatin or capecitabine or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
12. Recent or concomitant treatment with brivudine.
13. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 5.0 (see appendix 2)).
14. Inflammatory bowel disease and/or bowel obstruction.
15. Simultaneous application of Johannis herbs preparations.
16. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
17. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization or at least to intended treatment start or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.
18. 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.
19. Medical history of malignant disease other than mCRC 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% and does not require active therapy
20. Known alcohol or drug abuse.
21. Pregnant or breastfeeding females.
22. 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.
23. Patients depended on Sponsor, investigator or study site.
24. Suspected SARS-CoV-2 infection with or without symptoms (evaluation according to local policy in respective center with respect to actual status of pandemic and with reference to the policy that would apply to patients with similar therapy outside the trial). This may include assessment of vaccination status, anamnesis, physical examination and potentially antigen and/or PCR testing.
25. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
26. Limited legal capacity.
27. Concomitant administration of strong CYP3A4 and/or UGT1A1 inducers (e.g. Rifampicin, Carbamazepin, Phenobarbital, Phenytoin or Apalutamid).
28. Planned inoculation/vaccination with a live vaccine during treatment with Oxaliplatin and/or Irinotecan, and until 6 months after treatment with Irinotecan

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) time at the 24 months follow-up defined as time from randomization to death or evidence of disease (whatever occurs first)

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

Chariteplatz 1, Mitte Mitte

City

Berlin

Postcode

10117

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

Third parties 1

Locations

1 EU/EEA country · 76 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 13 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