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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05008809
• Other study ID #: FIRE-9 - PORT
• Secondary ID: AIO-KRK-04182020
• Status: Recruiting
• Phase: Phase 3
• Start date: December 6, 2021
• Est. completion date: November 2030

Study information

• Verified date: July 2023
• Source: Charite University, Berlin, Germany
• Contact: Dominik Modest, Prof. Dr.
• Phone: +49 30 450
• Email: dominik.modest[@]charite.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 507
• Est. completion date: November 2030
• Est. primary completion date: November 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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 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:

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. Previous chemotherapy at any time for metastatic or localized disease with > 6 cycles of FOLFOX (or FOLFOXIRI) or > 4 cycles of CAPOX/XELOX. Any other pretreatment is permitted, including unlimited use of antibodies, fluoropyrimidines and irinotecan.

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, leucovorin, irinotecan or oxaliplatin 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.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• mFOLFOX6
Oxaliplatin: 85 mg/m², 2h IV infusion on d1 Leucovorin: 400 mg/m², 1-2 h IV infusion on d1 5-FU: (optional: 400 mg/m² bolus, 2-5 min IV infusion), 2400 mg/m², 46 h IV infusion on d1 Cycles are repeated on day 15. A total of up to 12 cycles are administered.
• mFOLFOXIRI
Oxaliplatin: 85 mg/m², 2h IV infusion on d1 Irinotecan: 150 mg/m², 90 min IV infusion on d1 Leucovorin: 400 mg/m², 1-2 h IV infusion on d1 5-FU: 2400 mg/m², 46 h IV infusion on d1 Cycles are repeated on day 15. A total of up to 12 cycles are administered.

Locations

Country	Name	City	State
Germany	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	Gemeinschaftspraxis Münster	Münster
Germany	Universitätsklinikum Münster	Münster
Germany	Friedrich-Ebert-Krankenhaus Neumünster	Neumünster
Germany	Lukaskrankenhaus Neuss	Neuss
Germany	Klinikum Nürnberg	Nürnberg
Germany	Pi.Tri-Studien GmbH Offenburg	Offenburg
Germany	Klinikum Passau	Passau
Germany	Schwerpunktpraxis Penzberg	Penzberg
Germany	Ernst von Bergmann Klinikum Potsdam	Potsdam
Germany	Studienzentrum Onkologie Ravensburg	Ravensburg
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	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

Sponsors (3)

Lead Sponsor	Collaborator
Dominik Paul Modest	German Research Foundation, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS) time	time from randomization to death or evidence of disease relapse/progression (whatever occurs first)	24 months
Secondary	Overall survival (OS)	time from randomization to the date of death of any cause	at least 5 years after randomization
Secondary	Control ol lesions	Local or distant control of lesions according to ablative technique (surgery vs. ablation vs. radiation)	up to 5 years after randomization
Secondary	(Serious) Adverse Events	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)	up to 2 years after randomization
Secondary	Quality of life (QoL)	Quality of life (QoL) as assessed with the QoL questionnaire EQ-5D-5L	up to 5 years after randomization