Clinical trial NCT05008809: Post-resection/Ablation Chemotherapy in Patients With Metastatic Colorectal Cancer (FIRE-9 - PORT / AIO-KRK-0418)
Official title: Post-resection/Ablation Chemotherapy in Patients With Metastatic Colorectal Cancer Prospective, Randomized, Open, Multicenter Phase III Trial to Investigate the Efficacy of Active Post-resection/Ablation Therapy in Patients With Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: Colorectal Cancer
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: German Research Foundation
name: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
First posted: 2021-08-17
Enrollment: 507
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: open-label, randomized, controlled, multicenter, phase III study with two parallel arms
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression-free survival (PFS) time
timeFrame: 24 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: at least 5 years after randomization
measure: Control ol lesions
timeFrame: up to 5 years after randomization
measure: (Serious) Adverse Events
timeFrame: up to 2 years after randomization
measure: Quality of life (QoL)
timeFrame: up to 5 years after randomization
Other outcomes:
Locations:
city: Amberg
country: Germany
facility: Klinikum St. Marien Amberg
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Helios Klinikum Emil von Behring
city: Berlin
country: Germany
facility: MVZ Onkologischer Schwerpunkt am Oskar-Helene-Heim
city: Berlin
country: Germany
facility: Vivantes Klinikum am Urban Berlin
city: Berlin
country: Germany
facility: Vivantes Klinikum Spandau Berlin
city: Bochum
country: Germany
facility: St. Josef-Hospital Bochum
city: Bonn
country: Germany
facility: Johanniterkrankenhaus Bonn
city: Bremen
country: Germany
facility: Diakonie-Krankenhaus Bremen
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt
city: Deggendorf
country: Germany
facility: DONAUISAR Klinikum Deggendorf
city: Dessau
country: Germany
facility: Städtisches Klinikum Dessau
city: Dresden
country: Germany
facility: Onkologische-Gemeinschaftspraxis Dresden
city: Dresden
country: Germany
facility: Onkozentrum Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Essen
country: Germany
facility: Kliniken Essen-Mitte
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: KHNW Frankfurt
city: Frankfurt
country: Germany
facility: Markus-Krankenhaus Frankfurt
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Fürth
country: Germany
facility: Gemeinschaftspraxis internistische Onkologie Fürth
city: Georgsmarienhütte
country: Germany
facility: Niels-Stensen Kliniken Georgsmarienhütte
city: Gießen
country: Germany
facility: Praxis Hämatologie Onkologie Gießen
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Herne
country: Germany
facility: St. Anna Hospital Herne
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Ingolstadt
country: Germany
facility: Klinikum Ingolstadt GmbH
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Köln
country: Germany
facility: Kliniken der Satdt Köln
city: Landshut
country: Germany
facility: Klinikum Landshut
city: Landshut
country: Germany
facility: VK&K Studien Landshut
city: Leer
country: Germany
facility: Studienzentrum UnterEms Leer
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Leverkusen
country: Germany
facility: Klinikum Leverkusen
city: Lippe
country: Germany
facility: Klinikum Lippe
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Marburg
country: Germany
facility: OnkoNet Marburg GmbH
city: Marburg
country: Germany
facility: Philipps-Universität Marburg
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf Mönchengladbach
city: München
country: Germany
facility: Klinikum der Universität München
city: München
country: Germany
facility: Klinikum rechts der Isar TU München
city: München
country: Germany
facility: München Klinik Bogenhausen
city: München
country: Germany
facility: München Klinik Neuperlach
city: Münster
country: Germany
facility: Gemeinschaftspraxis Münster
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Neumünster
country: Germany
facility: Friedrich-Ebert-Krankenhaus Neumünster
city: Neuss
country: Germany
facility: Lukaskrankenhaus Neuss
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg
city: Offenburg
country: Germany
facility: Pi.Tri-Studien GmbH Offenburg
city: Passau
country: Germany
facility: Klinikum Passau
city: Penzberg
country: Germany
facility: Schwerpunktpraxis Penzberg
city: Potsdam
country: Germany
facility: Ernst von Bergmann Klinikum Potsdam
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder Regensburg
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Reutlingen
country: Germany
facility: Kreiskliniken Reutlingen
city: Rheine
country: Germany
facility: Mathias Spital Rheine
city: Rosenheim
country: Germany
facility: RoMed Klinikum Rosenheim
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
city: Schwäbisch Hall
country: Germany
facility: DIAK Klinikum Schwäbisch Hall
city: Siegen
country: Germany
facility: Marienkrankenhaus Siegen
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Stuttgart
country: Germany
facility: Marienhospital Stuttgart
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wetzlar
country: Germany
facility: Klinikum Wetzlar
city: Wolfsburg
country: Germany
facility: Onkologisches Zentrum Wolfsburg-Helmstedt
city: Wuppertal
country: Germany
facility: Petrus-Krankenhaus Wuppertal
city: Würzburg
country: Germany
facility: Gemeinschaftspraxis Würzburg
Study officials:
affiliation: Charite University, Berlin, Germany
name: Dominik Modest, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Raschzok N, Stintzing S, Heinemann V, Rauch G, Ricke J, Guckenberger M, Kurreck A, Alig AHS, Stahler A, Bullinger L, Schmelzle M, Schoning W, Lurje G, Krenzien F, Haase O, Rau B, Gebauer B, Sauer IM, Pratschke J, Modest DP. FIRE-9 - PORT / AIO-KRK-0418: a prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of adjuvant/additive chemotherapy in patients with definitely-treated metastatic colorectal cancer. BMC Cancer. 2022 Apr 2;22(1):359. doi: 10.1186/s12885-022-09422-6.