AVETUX is a single arm multicentric phase II investigator initiated trial conducted by the
Arbeitsgemeinschaft Internistische Onkologie (AIO) in 11 German sites in patients with
previously untreated RAS/BRAF wildtype mCRC independent of MSI status.
The primary clinical objective is to determine the efficacy of a standard 1st line regimen
(FOLFOX and cetuximab) in patients with RAS/v-Raf murine sarcoma viral oncogene homolog B
(BRAF) wildtype, Microsatellite Instability (MSI) or icrosatellite Stability (MSS) MCRC with
avelumab in terms of progression free survival rate after 12 months (acc. to Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1).
The main secondary objective is to determine safety and tolerability, according to NCI Common
Terminology Criteria for Adverse Events (CTCAE v4.03) and to the obtained data on vital
signs, clinical parameters (oxygen saturation) and feasibility of the regimen. Further
secondary objectives are to determine the efficacy of the experimental regimen in terms of
objective response rate (acc. to RECIST v1.1 and irRECIST), and overall survival, to
correlate clonal dynamics (RAS/EGFR subclones) with immune response signature to determine
control of mutant subclones by the combination of anti-Epidermal growth factor receptor
(EGFR) with anti-PD-L1and PD-L1 staining (and MSI status) with efficacy.
Inclusion Criteria:
1. Patients with histologically confirmed, previously untreated RAS and BRAF wildtype,
MSI or MSS metastatic colorectal cancer (primary tumor may be present)
2. Patients with at least one measurable lesion acc. to RECIST v1.1
3. ECOG Performance status ≤ 1
4. Life expectancy > 3 months
5. Age ≥ 18 years.
6. Haematologic function as follows: ANC ≥ 1.5 x 10^9/L, platelets ≥ 100 x10^9/L,
hemoglobin ≥ 9 g/dL or 5.59 mmol/L
7. Adequate liver function as measured by serum transaminases (AST & ALT) ≤ 2.5 x ULN (in
case of liver metastases < 5 x ULN) and total bilirubin ≤ 1.5 x ULN. Patients with
known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
8. Adequate renal function: serum creatinine ≤ 1.5 x ULN
9. Negative serum pregnancy test at screening for women of childbearing potential. 10.
Highly effective contraception for both male and female subjects if the risk of
conception exists. (Note: The effects of the trial drug on the developing human fetus
are unknown; thus, women of childbearing potential and men able to father a child must
agree to use 2 highly effective contraception, defined as methods with a failure rate
of less than 1 % per year. Highly effective contraception is required at least 28 days
prior, throughout and for at least 90 days after avelumab treatment and 6 month after
standard chemotherapy.
11. At least 6 months after completion of adjuvant chemotherapy. 12. Written informed
consent 13. Ability to comply with the protocol for the duration of the study, including
hospital/office visits for treatment and scheduled follow-up visits and examinations
Exclusion Criteria:
1. Malignancies other than disease under study within 5 years prior to inclusion, with
the exception of those with a negligible risk of metastasis or death (e.g., expected
5-year OS > 90%) treated with expected curative outcome (such as adequately treated
carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized
prostate cancer treated surgically with curative intent, ductal carcinoma in situ
treated surgically with curative intent)
2. All subjects with known brain metastases, except those meeting the following criteria:
1. Brain metastases that have been treated locally and are clinically stable for at
least 2 weeks prior to enrolment
2. No ongoing neurological symptoms that are related to the brain localization of
the disease (sequelae that are a consequence of the treatment of the brain
metastases are acceptable)
3. Subjects must be either off steroids or on a stable or decreasing dose of <10mg
daily prednisone (or equivalent)
3. Prior organ transplantation, including allogeneic stem-cell transplantation
4. Significant acute or chronic infections including, among others:
1. Known history of testing positive test for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)
2. Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV
antibody tested positive)
5. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent (Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
disease not requiring immunosuppressive treatment are eligible)
6. Concomitant treatment with corticosteroids or other immunosuppressants, besides
treatment of brain metastases as mentioned in criteria 2 or:
1. Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at
doses ≤ 10 mg or 10 mg equivalent prednisone per day
2. Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE
v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
features of partially controlled asthma)
8. Pregnancy or lactation
9. Known alcohol or drug abuse 10. Clinically significant (i.e., active) cardiovascular
disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial
infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure
(≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia
requiring medication.
11. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however,
alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk
based on investigator's judgment are acceptable.
12. All other significant diseases (for example, inflammatory bowel disease, uncontrolled
asthma, colitis and pneumonitis), which, in the opinion of the Investigator, might impair
the subject's tolerance of trial treatment 13. Any psychiatric condition that would
prohibit the understanding or rendering of informed consent 14. Vaccination within 4 weeks
of the first dose of avelumab and while on trial is prohibited except for administration of
inactivated vaccines 15. Any approved anticancer therapy, including chemotherapy, hormonal
therapy or radiotherapy, within 4 weeks prior to initiation of study treatment 16. Major
surgical procedure within 28 days prior to treatment or anticipation of need for a major
surgical procedure during the course of the study