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.
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.
Primary outcome:
1. Progression-free survival (PFS) time (Time Frame - 24 months):
time from randomization to death or evidence of disease relapse/progression (whatever occurs first)
Secondary outcome:
1. Overall survival (OS) (Time Frame - at least 5 years after randomization):
time from randomization to the date of death of any cause
2. Control ol lesions (Time Frame - up to 5 years after randomization):
Local or distant control of lesions according to ablative technique (surgery vs. ablation vs. radiation)
3. (Serious) Adverse Events (Time Frame - 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)
4. Quality of life (QoL) (Time Frame - up to 5 years after randomization):
Quality of life (QoL) as assessed with the QoL questionnaire EQ-5D-5L
- Experimental: Treatment
Active treatment with mFOLFOXIRI or mFOLFOX6 q2w up to six months followed by structured Follow-up for up to five years after randomization - No Intervention: Control
Structured Follow-up for up to five years after randomization
- mFOLFOX6 (Leucovorin, Oxaliplatin, 5-fluorouracil (FU)):
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 (Leucovorin, Oxaliplatin, 5-FU, Irinotecan):
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.
Quelle: ClinicalTrials.gov
