CetuGEX™: Dose Escalation Study

• To evaluate the safety and tolerability profile of CetuGEX™ at various dose levels [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
• To define the recommended phase II dose and regimen [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]

• To make a preliminary evaluation of anti-tumour activity of CetuGEX™ in the selected patient population(s) [ Time Frame: throughout the study ] [ Designated as safety issue: No ]
• To make a preliminary evaluation of anti-tumour activity of CetuGEX™ in the selected patient püopulation(s) [ Time Frame: throughout study ] [ Designated as safety issue: No ]

• To determine the pharmacokinetics of CetuGEX™ in patients after single and multiple dose applications [ Designated as safety issue: No ]
• To make a preliminary evaluation of anti-tumour activity of CetuGEX™ in the selected patient population(s) [ Designated as safety issue: No ]

This is a prospective, open label, multicenter study evaluating the safety, tolerability and pharmacokinetics of CetuGEX™ after intravenous administration in patients with EGFR positive, locally advanced and/or metastatic solid cancers. The effect of CetuGEX™ on the development of anti-drug antibodies and on tumour response will also be evaluated.

• Experimental: CetuGEX™, 3-weekly
  application q3w
  Intervention: Drug: CetuGEX™
• Experimental: CetuGEX™ 2-weekly
  application q2w
  Intervention: Drug: CetuGEX™

Inclusion Criteria:

1. Male or female and age ≥ 18 yrs
2. Histologically confirmed EGFR positive locally advanced and/or metastatic solid organ tumour
3. Measurable or non-measurable tumour
4. Failure of standard therapy or non-availability of standard therapy (Patients must have received at least 1 line of chemotherapy and further standard therapy is not an option at study entry)
5. All anti-tumour therapies must be completed 4 weeks before start of study treatment; treatment with Cetuximab must be completed at least 6 weeks prior to study start
6. ECOG Performance Status ≤1 and estimated life expectancy of ≥ 3 months

7. Adequate organ function:

   • Bone marrow function: hemoglobin ≥ 100 g/L; white blood cell count (WBC) ≥ 3.0 x 10^9/L; absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥ 100 x 10^9/L
   • Hepatic: aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 2.5 times upper limit of normal (ULN) (≤ 5 x ULN if hepatic metastases present); bilirubin ≤ 1.5 x ULN; alkaline phosphatase ≤ 5.0 x upper limit of normal (ULN)
   • Renal: creatinine < 1.5 x ULN
8. Patients of both genders with procreative potential must use effective contraception while enrolled in the study and for at least 4 weeks after the last study drug infusion

9. Written informed consent must be obtained prior to conducting any study-specific procedures

   For Expansion Phase only:

10. No prior treatment with Cetuximab allowed

Exclusion Criteria:

1. Chemotherapy, radiation, other anti-cancer therapies including any investigational agents at the study enrolment within 4 weeks prior to study enrolment
2. Concurrent anti-tumour therapy or concurrent immunotherapy
3. Concurrent systemic steroids except topical (inhaled, topical, nasal) or replacement therapy for the last 28 days.
4. Major surgery within 4 weeks prior entering the study and/or incomplete recovery from surgery or planned major surgery
5. Primary or secondary immune deficiency
6. Clinically active infections > CTCAE grade 2
7. Prior allergic reaction to a monoclonal antibody (e.g. Trastuzumab, Cetuximab or Bevazicumab).
8. Active hepatitis B assessed by serology, hepatitis C by histology; human immunodeficiency virus (HIV) seropositivity
9. Any concurrent malignancy other than basal cell carcinoma or carcinoma in situ of the cervix. Patients with a previous malignancy but without evidence of disease for ≥ 3 years will be allowed to enter the study.
10. Uncontrolled medical condition considered as high risk for the treatment with an investigational drug including unstable diabetes mellitus, vena-cava-syndrome, chronic symptomatic respiratory disease.
11. Clinical signs of brain metastasis or leptomeningeal involvement
12. Symptomatic congestive heart failure (New York Heart Association [NYHA] 3 or 4); unstable angina pectoris within 6 months prior to enrollment; significant cardiac arrhythmia, or history of stroke or transient ischemic attack within 1 year.
13. Active drug abuse or chronic alcoholism
14. Pregnancy or Breastfeeding