| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Avelumab added to FOLFIRI plus cetuximab followed by avelumab maintenance in patients with previously untreated RAS/BRAF wild-type metastatic colorectal cancer - the phase II FIRE-6-avelumab study |
|
| 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 | 100000004864 |
|
| 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 |
The primary objective of the study is to assess the efficacy of FOLFIRI plus cetuximab in
combination with avelumab followed by avelumab maintenance therapy in patients with
previously untreated RAS/BRAF wild-type mCRC. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the efficacy and safety profile of the tested treatment strategy
• To assess the feasibility of the tested treatment strategy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum with metastases (mCRC), metastases primarily non resectable
or surgery refused by the patient
2. RAS wild-type tumour status (KRAS and NRAS, exon 2, 3, 4) and BRAF wild-type tumour status (V600, exon 15) (proven in the primary
tumour or metastasis)
3. Adult patients ≥ 18 years
4. ECOG performance status 0-1
5. Patients suitable for chemotherapy administration
6. Patient's written declaration of consent obtained
7. Estimated life expectancy > 3 months
8. Presence of at least one measurable reference lesion according to the RECIST v1.1 criteria
9. Tumour tissue available for molecular and genetic profiling regarding BRAF/RAS mutation status and MSI Status
10. Females of childbearing potential (FCBPs) must agree to use highly effective contraceptive measures (Pearl index <1) or practice true abstinence from any heterosexual intercourse (true abstinence is acceptable if this is in line with the patient’s preferred and usual lifestyle) for the duration of study treatment and at least 6 months after the last study treatment. A woman will be considered as being of childbearing potential unless she is at least 50 years old and has gone through menopause for at least 2 years or has been surgically sterilised.
11. Males must agree to use condoms or practice true abstinence from any heterosexual intercourse (true abstinence is acceptable if this is in line
with the patient’s preferred and usual lifestyle) for the duration of study treatment and at least 6 months after the last study treatment. Male
patients must refrain from donating sperm during the study until 6 months after the administration of the last study medication.
12. Adequate bone marrow function:
a) Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
b) Thrombocytes ≥ 100 x 109/L
c) Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
13. Adequate hepatic function:
a) Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
b) ALT and AST ≤ 2.5 x ULN (in the presence of hepatic metastases, ALT and AST ≤ 5 x ULN)
c) 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.
14. Adequate renal function: Creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50 mL/min
15. Adequate cardiac function: ECG and echocardiogram with a LVEF of ≥ 55%
16. 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.
17. Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy of the primary tumour in curative treatment intention ≥ 6 months.
18. Any relevant toxicities of prior treatments must have resolved
19. Patient covered by health insurance |
|
| E.4 | Principal exclusion criteria |
1. Proof of a RAS mutation (KRAS or NRAS, exons 2, 3, 4) or BRAF mutation (V600 in exon 15) in the tumour (proven in primary tumour
or metastasis) or absence of testing for RAS or BRAF mutations
2. Primarily resect metastases and the patient wishes for resection
3. ≥ Grade II heart failure (NYHA classif)
4. Myocardial infarct, balloon angioplasty (PTCA) with or without stenting + cerebral vascular accident/stroke within the past 12 months before start of study treatm, unstable angina pectoris, serious cardiac arrhythmia according to investigator’s judgem. requiring medic.
5. Pre-existing pulmonary fibrosis or immune pneumonitis
6. Active autoimmune disease that might be negatively affected by an immune checkpoint inhibitor. Patients diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosup. treatment are eligible.
7. Prior organ transpl., incl allogeneic stem cell transpl.
8. Current use of immunosuppressive medi, except for the following:
a) Intranasal, inhaled, topical steroids, or local steroid inject (e.g., intra-articular inject);
b) System corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
c) Steroids as premedic. for hypersens reactions (e.g., CT scan premedi).
9. Pregnancy (absence of pregnancy to be ascertained by a negative β-HCG test) or breast feeding
10. Medi or psychol impairments assoc. with restricted ability to give consent or not allowing conduct of the study
11. Add cancer treatm (chemoth., radiation, immunoth or hormone treatm.) during the study treatm in first-line
(treatm that are conducted as part of an anthroposophic or homeopathic treatm approach, e.g. mistletoe therapy do not represent an excl.cr.)
12. Previous chemoth. for the Color. cancer with the exception of adjuvant treatm., compl at least 6 months bef. entering the study
13. Adv. drug reaction > NCI CTCAE Grade1 that has not yet resolved, attributed to a previous treatm or measure for treatm of the CRC. However, alopecia (all grades) and oxaliplatin-induced neurotox ≤ grade 2 are acceptable.
14. Participat in a clinic study or experim. drug treatm within 30 days prior to study incl. or within a period of 5 half-lives of the
substances admin. in a clinical study or during an experimental drug treatm prior to incl. in the study, depending on which
period is longest or simultaneous participation in another study while taking part in the study
15. Known hypersensitivity or allergic react to any of the following substances: folinic acid, 5-FU, irinotecan, cetuximab,
avelumab and chemically related substances and/or hypersens to any of the components in the formulations of the aforementioned
subst, incl known hypersensitivity reactions to monoclonal antibodies NCI CTCAE Grade ≥ 3.
16. Known hypersensitivity to Chinese hamster ovary cell (CHO) – cellular products or other recombinant human or humanised monocl antibodies
17. Patients with known brain metastases. In case of clinical suspicion of brain metastasis a cranial MRI or CT must be performed to rule out brain metastasis bef. study inclus.
18. History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhoea
19. Symptomatic peritoneal carcinosis
20. Severe, non-healing wounds, ulcers or bone fractures
21. Patients with act. infect requiring syst. therapy
22. Known history of testing positive for HIV or known acquired immunodeficiency syndr.
23. 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).
24. Requirement for immunisation with live vaccine under the study treatm.
25. Haemorrhagic diathesis or known thrombophilia
26.Known complete DPD deficiency (spec. screen accor to the recommend of the SmPC in effect for 5-FU; pat. with a known compl DPD deficiency must be excluded; (further see Protocol)
27. Known glucuronidation deficiency (Gilbert's syndrome) (spec screen not required)
28. Treatm with sorivudine or brivudine within 28 days before study enrollm or requirement for concom antiviral treatm with
sorivudine or brivudin
29. History of a second primary malignancy dur. the past 5 years before incl. in the study or during participat in the study, with the
except of a basal cell or squamous cell carcinom of the skin or cervical carcinom in situ, if these were treated curatively.
30. Known history of alcohol or drug abuse
31. Any other severe acute or chronic concom. disease or medical condition incl psychiatric conditions (incl recent i.e. within the past year or active suicidal ideation or behaviour) or labor. abnorm that may incr. the risk associated with study participation or study treatm. administr or may interfere with the interpret of study results and, in the judgm of the invest, would make the pat inappropriate for entry into this study.
32. Absent or restricted legal capacity |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression-free survival (PFS) according to RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Restaging according to RECIST 1.1 will be performed every eight weeks |
|
| E.5.2 | Secondary end point(s) |
• Objective response rate (ORR) according to RECIST v1.1 and irRECIST
• Progression-free survival (PFS) according to irRECIST
• Progression-free survival rate after 12 months of treatment (PFSR@12) according to RECIST v1.1 and irRECIST
• Overall survival (OS)
• Duration of treatment
• Type, frequency and severity of adverse events (severity according to NCI CTCAE version 5.0) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Restaging according to RECIST 1.1 will be performed every eight weeks
• OS will be evaluated in a continously manner, after study Treatment every 3 month until death or end of study
• Evaluated when end of treatment is reached
• Safety and tolerability will be evaluated in a continously manner
|
|
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Yes |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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