| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum (metastatic colorectal cancer), primarily non-resectable or with surgery refused by the patient |
|
| E.1.1.1 | Medical condition in easily understood language |
| metastatic colorectal cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Prospective investigation of overall survival from randomisation to third-line treatment (OS3) under cetuximab rechallenge versus an anti-EGFR-free treatment in patients that have responded to first-line treatment with cetuximab in combination with FOLFIRI or FOLFOX or FOLFOXIRI with CR or PR of any duration or SD ≥ 6 months |
|
| E.2.2 | Secondary objectives of the trial |
•ORR1, 2 & 3 (assessment of ORR 1 & ORR 2 only if the pat. was already incl. in part 1 of the study)
•PFS1, 2 & 3 (assessment of PFS 1 & PFS 2 only if the pat. was already incl. in part 1 of the study)
•(OS1) from randomisation to 1st-line treat. (assessment only if the pat. was already incl. in part 1 of the study)
•Investigation of early tumour shrinkage and depth of response during st-line and 3rd-line treat.
•Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance to an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)
•Prospective validation of a biomarker score (AREG/EREG)
•Prospective analysis of tumour marker evolution (CEA and CA 19-9)
•Recording of the safety and tolerance (NCI-CTCAE v. 4.03 criteria) of the 1st-line and 3rd-line treat. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Criteria for inclusion in the study (Part 1 and 2)
- Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer), metastases primarily non-resectable or surgery refused by the Patient
-RAS wild-type tumour status (KRAS and NRAS exon 2, 3, 4), proven in the primary tumour or metastasis prior to each randomisation time point.
Only for inclusion in part 2: If a repeated tumour biopsy is infeasible or poses an unacceptable risk to the patient as assessed by the investigator, RAS wild-type tumour status determined in liquid biopsy in Laboratory for Immunological Molecular Biology, Universitätsklinikum Knappschafts-krankenhaus Bochum GmbH permitted.
-Age ≥18
-ECOG performance status 0-1
-Patients suitable for chemotherapy administration
-Patient's written declaration of consent obtained
-Estimated life expectancy > 3 months
-Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation)
-Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of tumour material (patients directly included in part 2 of the study in whom primary tumour material is no longer available may be included in the study. Molecular profiling of blood samples is optionally performed.
-Females of childbearing potential (FCBPs) and men must agree to use highly effective contraceptive measures (Pearl index <1) or practice true abstinence from any heterosexual intercourse (true abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject) for the duration of the study treatment and for at least 6 months after last administration of study medication. A woman will be considered as being of childbearing potential unless she is at least 50 years old and moreover has gone through menopause for at least 2 years or has been surgically sterilised.
-Adequate haematopoietic function: Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L, Thrombocytes ≥ 100 x 109/L, Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
- Adequate hepatic function: Serum bilirubin ≤ 1.5 x upper limit of normal,
ALAT and ASAT ≤ 2.5 x ULN (in the presence of hepatic metastases, ALAT and ASAT ≤ 5 x uULN)
-INR < 1.5 and aPTT < 1.5 x ULN (patients without anticoagulation). Therapeutic anticoagulation is allowed if INR and aPTT have remained stable within the therapeutic range for at least 2 weeks.
-Adequate renal function: Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50ml/min.
- adequate cardiac function: ECG and echocardiogram with a LVEF of ≥55%
Inclusion criterion solely for Part 1:
-No previous chemotherapy for metastatic disease. Patient with need of immediate treatment (high tumour load, symptoms) may have received one application of FOLFIRI prior to study entry
-Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy of the primary tumour in curative treatment intention ≥ 6 months
-Any relevant toxicities of prior treatments must have resolved
Additional inclusion criteria solely for Part 2:
-Prior first-line treatment of the metastatic colorectal cancer with cetuximab or panitumumab in combination with FOLFIRI or FOLFOX or FOLFOXIRI; data available for the duration of treatment and the response within the context of first-line treatment
-Within the maintenance arms, re-induction of the primary treatment strategy with irinotecan + cetuximab is allowed as part of first-line strategy. In this context, 2nd-line treatment is defined as the introduction of a new agent that was not part of the 1st-line therapy
-Proof of a RAS wild-type tumour (KRAS and NRAS exons 2, 3, 4) in a biopsy of the primary tumour (or any metastasis) or liquid biopsy (RAS wild-type status in liquid biopsy as determined in Laboratory for Immunological Molecular Biology, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH), within 4 weeks before randomisation
-CT examinations with evidence of response (partial response [PR] or complete response [CR]) or alternatively stable disease (SD) ≥ 6 months according to RECIST Version 1.1 criteria as best response within the context of the first-line treatment with cetuximab or panitumumab in combination with FOLFIRI or FOLFOX or FOLFOXIRI
Note for clarification: CR and PR as best response do not require duration of response for ≥ 6 months, this is only required in case of SD as best response.
-Last administration of any anti-EGFR substance ≥ 4 months before randomisation 2
-At least one documented progression during first-line and second-line treatment |
|
| E.4 | Principal exclusion criteria |
-Proof of a RAS mutation (KRAS/NRAS, exons 2, 3, 4 in the tumour (proven in the primary tumour or metastasis) or liquid biopsy (permitted only prior to Part 2) or absence of testing for RAS mutation- Primarily resect. metast. and the pat. wishes for resection
-≥ Grade II heart failure (NYHA classification)
-Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and cerebral vascular accident/stroke within the past 12 months before rando. 1 or before rando. 2, unstable angina pectoris, serious cardiac arrhythmia accord. to investigator’s judgement requiring medication
-Pre-existing pulmonary fibrosis or immune pneumonitis
-Pregnancy (absence of pregnancy to be ascertained by a negative beta hCG test) or breast feeding
-Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
-Addit. cancer treat. (chemotherapy, radiation, immunotherapy or hormone treatment) during the study treat. in 1st-line and 3rd-line treat. (treat. that are conducted as part of an anthroposophic or homeopathic treatment approach, e.g. mistletoe therapy does not represent an excl. criterion)
-Previous chemotherapy for the CRC with the exception of adjuvant treat., complet. at least 6 months before entering the study (exclusion criterion solely for part 1)
-Toxicity > Grade 1 that has not yet resolved, attributed to a previous treat. or measure for treat. of the mCRC. However, alopecia (all grades) and oxaliplatin-induced neurotoxicity ≤ Grade 2 are accept. (exclusion criterion only for part 2)
-Participation in a clinical study or experimental drug treat. within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in a clinical study or during an experimental drug treat. prior to inclusion in the study, depending on which period is longest or simultaneous participation in another study while taking part in the study
-Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, capecitabine, cetuximab, irinotecan, bevacizumab and chemically related substances and/or hypersensitivity to any of the components in the formulations of the aforementioned substances, including known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade ≥ 3.
-Known hypersensitivity to Chinese hamster ovary cell (CHO) – cellular products or other recombinant human or humanised monoclonal antibodies
-Pat. with known brain metast.. In case of clinical suspicion of brain metastasis a cranial CT or MRI must beperformed to rule out brain metastasis before study inclusion.
-History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhoea
-Symptomatic peritoneal carcinosis
-Severe, non-healing wounds, ulcers or bone fractures
-Pat. with active infection requiring systemic therapy
-Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
-Active or chronic Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive; serologic tests required)
-Requirement for immunisation with live vaccine incl. attenuated live vaccine from at least 4 weeks before start of study treatment until 6 months after the administration of chemotherapeutic substances.
-Haemorrhagic diathesis or known thrombophilia
-Known complete DPD deficiency (specific screening recommended according to the recommendations of the SmPC in effect for 5-FU or capecitabine, respectively; patients with a known complete DPD deficiency must be excluded; patients with a known partial DPD deficiency may be included at the discretion of the investigator)
-Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
-Treatment with nucleoside analogues including sorivudine/brivudine within 28 days before study enrollment/requirement for concomitant antiviral treatment with sorivudine/brivudine/analogues
-History of a sec. primary malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively
-Known history of alcohol or drug abuse
-Any other severe acute or chronic concomitant disease or medical condition including psychiatric conditions (includ. recent i.e. within the past year or active suicidal ideation or behavior) or laboratory abnormalities that may increase the risk associated with study participation or study treat. administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the pat. inappropriate for entry into this study.
-Absent or restricted legal capacity |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Randomisation 1:
Overall survival from randomisation to third-line treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The anlaysis of the primary endpoint (OS3) is event driven and will be performed when 196 events have occurred. At this point, entry to part 2 will be closed. |
|
| E.5.2 | Secondary end point(s) |
Randomisation 1:
Time to first progression (PFS1) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The anlaysis of the secondary endpoint (PFS1) will be performed when 359 events have occurred or to final analysis. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 139 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 150 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
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