Post-resection/Ablation Chemotherapy in Patients With Metastatic Colorectal Cancer (FIRE-9 - PORT / AIO-KRK-0418)

Phase 3

Recruiting

• Conditions: Colorectal Cancer
• Interventions: Drug: mFOLFOX6; Drug: mFOLFOXIRI; Drug: FOLFIRI; Drug: CAPOX

• Registration Number: NCT05008809
• Lead Sponsor: Dominik Paul Modest

Brief Summary

This is an open-label, randomized, controlled, multicenter, phase III study with two parallel arms. Patients with metastatic colorectal cancer after definite interventional therapy of all lesions are randomized in a 2:1 fashion (favoring active therapy) to investigate the efficacy, patient reported quality of life and safety of mFOLFOXIRI/mFOLFOX-6 as additive treatment (Arm A) versus active follow-up/surveillance (Arm B).

Detailed Description

The trial will consist of both a clinical and translational part. During the study, re-assessments (radiologic assessment, blood and QoL) will be conducted for all trial subject of the trial every 3 months. Tumor biopsies will be collected at screening (baseline sample) and in case of relapse of disease if a new tumor sample is obtained.

The objective of the re-assessments is detection of relapse either radiologically or within the translational material (blood samples with ctDNA dynamics and tumor - if available from relapses). CT scans of thorax/abdomen and/or MRI scans will be performed every 3 months within the 2 years after randomization. After the first two relapse-free years, intervals should be stretched to 6 months in the third and following years after study start. Structured follow-up for up to 60 months after randomization should be maintained for both arms.

Patients in Arm A receive additive study drug intervention (mFOLFOXIRI or mFOLFOX-6) for up to six months (12 cycles) after randomization with additional clinical and safety assessments.

Study Timeline

• Study First Submitted: 2021-08-06
• Study First Submitted QC: 2021-08-12
• Study First Posted: 2021-08-17
• Study Start: 2021-12-06
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-16
• Last Update Posted: 2024-10-18
• Primary Completion: 2027-11
• Study Completion: 2030-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 507

Inclusion Criteria

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:

    1. Prior treatment with 5-FU or capecitabine without unusual toxicity or
    2. If tested, normal DPD deficiency test according to the standard of the study site or
    3. 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.

Exclusion Criteria

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

   1. 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
   2. 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 anemia 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 depending 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	mFOLFOX6	Active treatment with mFOLFOXIRI or mFOLFOX6 or FOLFIRI q2w or CAPOX q3w up to six months followed by structured Follow-up for up to five years after randomization
Treatment	mFOLFOXIRI	Active treatment with mFOLFOXIRI or mFOLFOX6 or FOLFIRI q2w or CAPOX q3w up to six months followed by structured Follow-up for up to five years after randomization
Treatment	FOLFIRI	Active treatment with mFOLFOXIRI or mFOLFOX6 or FOLFIRI q2w or CAPOX q3w up to six months followed by structured Follow-up for up to five years after randomization
Treatment	CAPOX	Active treatment with mFOLFOXIRI or mFOLFOX6 or FOLFIRI q2w or CAPOX q3w up to six months followed by structured Follow-up for up to five years after randomization

Primary Outcome Measures

Name	Time	Method
Progression-free survival (PFS) time	24 months	time from randomization to death or evidence of disease relapse/progression (whatever occurs first)

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	at least 5 years after randomization	time from randomization to the date of death of any cause
Control ol lesions	up to 5 years after randomization	Local or distant control of lesions according to ablative technique (surgery vs. ablation vs. radiation)
(Serious) Adverse Events	up to 2 years after randomization	Type, incidence, severity, and causal relationship to active chemotherapy of non-serious adverse events and serious adverse events (severity evaluated according to CTCAE version 5.0)
Quality of life (QoL)	up to 5 years after randomization	Quality of life (QoL) as assessed with the QoL questionnaire EQ-5D-5L

Trial Locations

Locations (79)

Klinikum St. Marien Amberg; 🇩🇪 Amberg, Germany

Helios Klinikum Bad Saarow; 🇩🇪 Bad Saarow, Germany

Klinikum Bayreuth; 🇩🇪 Bayreuth, Germany

Charité Universitätsmedizin Berlin; 🇩🇪 Berlin, Germany

Helios Klinikum Emil von Behring; 🇩🇪 Berlin, Germany

MVZ Onkologischer Schwerpunkt am Oskar-Helene-Heim; 🇩🇪 Berlin, Germany

Vivantes Klinikum am Urban Berlin; 🇩🇪 Berlin, Germany

Vivantes Klinikum Spandau Berlin; 🇩🇪 Berlin, Germany

St. Josef-Hospital Bochum; 🇩🇪 Bochum, Germany

Johanniterkrankenhaus Bonn; 🇩🇪 Bonn, Germany

Diakonie-Krankenhaus Bremen; 🇩🇪 Bremen, Germany

Klinikum Chemnitz; 🇩🇪 Chemnitz, Germany

Klinikum Darmstadt; 🇩🇪 Darmstadt, Germany

DONAUISAR Klinikum Deggendorf; 🇩🇪 Deggendorf, Germany

Städtisches Klinikum Dessau; 🇩🇪 Dessau, Germany

Onkologische-Gemeinschaftspraxis Dresden; 🇩🇪 Dresden, Germany

Onkozentrum Dresden; 🇩🇪 Dresden, Germany

Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

Kliniken Essen-Mitte; 🇩🇪 Essen, Germany

Universitätsklinikum Essen; 🇩🇪 Essen, Germany

KHNW Frankfurt; 🇩🇪 Frankfurt, Germany

Markus-Krankenhaus Frankfurt; 🇩🇪 Frankfurt, Germany

Universitätsklinikum Frankfurt; 🇩🇪 Frankfurt, Germany

Universitätsklinikum Freiburg; 🇩🇪 Freiburg, Germany

Gemeinschaftspraxis internistische Onkologie Fürth; 🇩🇪 Fürth, Germany

Niels-Stensen Kliniken Georgsmarienhütte; 🇩🇪 Georgsmarienhütte, Germany

Praxis Hämatologie Onkologie Gießen; 🇩🇪 Gießen, Germany

Universitätsmedizin Göttingen; 🇩🇪 Göttingen, Germany

Universitätsklinikum Halle; 🇩🇪 Halle, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

St. Anna Hospital Herne; 🇩🇪 Herne, Germany

Universitätsklinikum des Saarlandes; 🇩🇪 Homburg, Germany

Klinikum Ingolstadt GmbH; 🇩🇪 Ingolstadt, Germany

Universitätsklinikum Jena; 🇩🇪 Jena, Germany

Kliniken der Satdt Köln; 🇩🇪 Köln, Germany

Klinikum Landshut; 🇩🇪 Landshut, Germany

VK&K Studien Landshut; 🇩🇪 Landshut, Germany

Studienzentrum UnterEms Leer; 🇩🇪 Leer, Germany

Universitätsklinikum Leipzig; 🇩🇪 Leipzig, Germany

Klinikum Leverkusen; 🇩🇪 Leverkusen, Germany

Klinikum Lippe; 🇩🇪 Lippe, Germany

Klinikum Ludwigsburg; 🇩🇪 Ludwigsburg, Germany

Klinikum Magdeburg; 🇩🇪 Magdeburg, Germany

Universitätsmedizin Mainz; 🇩🇪 Mainz, Germany

OnkoNet Marburg GmbH; 🇩🇪 Marburg, Germany

Philipps-Universität Marburg; 🇩🇪 Marburg, Germany

Johannes Wesling Klinikum Minden; 🇩🇪 Minden, Germany

Kliniken Maria Hilf Mönchengladbach; 🇩🇪 Mönchengladbach, Germany

Klinikum der Universität München; 🇩🇪 München, Germany

Klinikum rechts der Isar TU München; 🇩🇪 München, Germany

München Klinik Bogenhausen; 🇩🇪 München, Germany

München Klinik Neuperlach; 🇩🇪 München, Germany

Klinikum Passau; 🇩🇪 Passau, Germany

Schwerpunktpraxis Penzberg; 🇩🇪 Penzberg, Germany

Gemeinschaftspraxis Münster; 🇩🇪 Münster, Germany

Friedrich-Ebert-Krankenhaus Neumünster; 🇩🇪 Neumünster, Germany

Pi.Tri-Studien GmbH Offenburg; 🇩🇪 Offenburg, Germany

Krankenhaus Barmherzige Brüder Regensburg; 🇩🇪 Regensburg, Germany

Universitätsklinikum Regensburg; 🇩🇪 Regensburg, Germany

Kreiskliniken Reutlingen; 🇩🇪 Reutlingen, Germany

Mathias Spital Rheine; 🇩🇪 Rheine, Germany

RoMed Klinikum Rosenheim; 🇩🇪 Rosenheim, Germany

Universitätsklinikum Münster; 🇩🇪 Münster, Germany

Lukaskrankenhaus Neuss; 🇩🇪 Neuss, Germany

Klinikum Nürnberg; 🇩🇪 Nürnberg, Germany

Studienzentrum Onkologie Ravensburg; 🇩🇪 Ravensburg, Germany

Ernst von Bergmann Klinikum Potsdam; 🇩🇪 Potsdam, Germany

Universitätsmedizin Rostock; 🇩🇪 Rostock, Germany

DIAK Klinikum Schwäbisch Hall; 🇩🇪 Schwäbisch Hall, Germany

Marienkrankenhaus Siegen; 🇩🇪 Siegen, Germany

Klinikum Stuttgart; 🇩🇪 Stuttgart, Germany

Marienhospital Stuttgart; 🇩🇪 Stuttgart, Germany

Krankenhaus der Barmherzigen Brüder Trier; 🇩🇪 Trier, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Klinikum Wetzlar; 🇩🇪 Wetzlar, Germany

Onkologisches Zentrum Wolfsburg-Helmstedt; 🇩🇪 Wolfsburg, Germany

Petrus-Krankenhaus Wuppertal; 🇩🇪 Wuppertal, Germany

Gemeinschaftspraxis Würzburg; 🇩🇪 Würzburg, Germany