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

Overview

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.

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.