non-resectable metastatic colorectal cancer MedDRA version: 20.0 Level: LLT Classification code 10010036 Term: Colorectal carcinoma System Organ Class: 100000004864
Conditions
Sponsors
AIO-Studien-gGmbh
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Adult patients (= 18 years of age) • Cohort I: Histologically confirmed and definitively inoperable or irresectable metastatic colorectal cancer. Focus on patients with large tumor load at metastatic sites and/or symptomatic metastatic disease or • Cohort II: Chance of secondary resection with curative intent defined and reviewed by expert panel • RAS wild-type tested in ? KRAS exon 2 (codons 12/13) ? KRAS exon 3 (codons 59/61) ? KRAS exon 4 (codons 117/146) ? NRAS exon 2 (codons 12/13) ? NRAS exon 3 (codons 59/61) ? NRAS exon 4 (codons 117/146) assessed by an institution participating in and certified by the specific working group of the Deutsche Gesellschaft für Pathologie) • At least one measurable lesion according to RECIST measured within 3 weeks prior to registration • No previous chemotherapy for metastatic disease (adjuvant chemotherapy for non-metastatic disease is allowed if terminated more than 6 months ago) with exception of 1 application of FOLFOXIRI in patients with need of immediate treatment while waiting for the result of RAS mutation testing. • Performance status ECOG 0-1 • Adequate haematological, hepatic, renal, and metabolic function parameters: Leukocytes > 3000/mm³, ANC = 1500/mm3, platelets = 100,000/mm3, Hb > 9g/dl (may be transfused or treated with erythropoietin to maintain or exceed this level) Creatinine clearance = 50 ml/min or serum creatinine = 1.5 x upper limit of normal Bilirubin = 1.5 x upper limit of normal, GOT-GPT = 2.5 x upper limit of normal in absence of liver metastases, or = 5 x upper limit of normal in presence of liver metastases, AP = 5 x upper limit of normal Magnesium = lower limit of normal; calcium = lower limit of normal (may be substituted to maintain or exceed this level) • Negative pregnancy test and willingness to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly). • Before subject registration, written informed consent must be given according to ICH-GCP, and national/local regulations. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 61 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 32
Exclusion criteria
Exclusion criteria: • Past or current history of malignancies except for the indication under this study and curatively treated: - Basal and squamous cell carcinoma of the skin - In-situ carcinoma of the cervix - Other malignant disease without recurrence after at least 5 years of follow-up • Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) = 6 months before enrollment. • Clinically relevant interstitial lung disease, e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan. • History of evidence upon physical examination of CNS disease unless adequately treated (e.g. primary brain tumour, seizure not controlled with standard medical therapy, brain metastases or history of stroke). • Pre-existing neuropathy > grade 1 (NCI CTCAE), except for loss of tendon reflex • Allogeneic transplantation requiring immunosuppressive therapy. • Severe non-healing wounds, ulcers or bone fractions. • Evidence of bleeding diathesis or coagulopathy. • Patients not receiving therapeutic anticoagulation must have an INR 1,5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of randomisation. • Concomitant therapy with certain anti-viral medicines (sorivudine and brivudine or analogue compounds). • Major surgical procedure, open biopsy, nor significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study except for surgery for colorectal cancer with curative intent and central venous line placement for chemotherapy administration. • Pregnancy or breastfeeding women. • Subjects with known allergy to the study drugs or to any of its excipients. • Known DPD deficiency. • Current or recent (within the 28 days prior to starting study treatment) treatment of another investigational drug or participation in another investigational study. • Known grade III/IV allergic reaction against monoclonal antibodies. • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess efficacy (objective response rate, ORR) of adding panitumumab to FOLFOXIRI in patients with newly diagnosed metastatic colorectal cancer expressing wild-type RAS Cohort I) Definitively unresectable metastatic disease, with a focus on symptomatic metastatic disease and/or large tumor load, or Cohort II) With chance of secondary resection with curative intent according to recent S3 guidelines of the German Cancer Society. The ORR will be compared to expectations derived from historical data, which are verified by a randomised control group without the antibody. ;Secondary Objective: • To evaluate ORR in both cohorts • To evaluate secondary resection rate with curative intent for patients cohort II • To evaluate pathological response in liver surgery specimen (pretreatment biopsy of liver metastases in cohort II within the translational research program) • To evaluate disease control rate (DCR) • To evaluate progression-free survival (PFS) • To evaluate duration of response • To evaluate time to response • To evaluate overall survival (OS) • To evaluate toxicity and feasibility • To assess time to recurrence (cohort II in case of secondary resection) • To assess liver toxicity, and histopathological response rate for resected patients (central histological review, cf. appendix 6) • To assess quality of life by adding panitumumab to FOLFOXIRI. • Translational research: detection of EGFR expression, functional genetic polymorphisms of the EGFR gene, EGFR amplification, EGFR activation, EGFR signalling, epigenetics (methylation) and miRNA profiles ;Primary end point(s): Combined objective response rate for patient cohort I and II ;Timepoint(s) of evaluation of this end point: end of treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • ORR in both cohorts • Secondary resection rate with curative intent for patients cohort II • Pathological response in liver surgery specimen (pretreatment biopsy of liver metastases in cohort II within the translational research program) • DCR • PFS • Duration of response • Time to response • OS • Time to recurrence (cohort II in case of secondary resection • Toxicity and feasibility • Liver toxicity and histopathological response rate for resected patients; biopsies both from healthy liver tissue and liver metastases should be obtained for all patients of cohort II (chance of secondary resection) pre-treatment • QL (QLQ C30) With respect of quality of life, the difference in the mean value of the global quality of life dimension of the EORTC QLQ C30 is assessed, calculated as the average of all available time points from 6 weeks to 24 weeks after randomization; the effect of palliative treatment on quality of life (treatment vs. baseline); evaluation of the prognostic impact of the quality of life and comparison to performance status; correlation between response rate and quality of life and between symptomatic/asymptomatic patients and quality of life. • Translational research: detection of EGFR expression, functional genetic polymorphisms of the EGFR gene, EGFR amplification, EGFR activation, EGFR signalling, epigenetics (methylation) and miRNA profiles;Timepoint(s) of evaluation of this end point: end of trial | — |
Countries
Germany
Contacts
Public ContactCRO
Clin Assess GmbH
Outcome results
None listed