PankoMab-GEX™: Phase 1 Dose Escalation Study

Prospective, open label, dose escalating, multicenter, phase I study measuring the safety, tolerability, and pharmacokinetics of PankoMab-GEX™ after intravenous administration in patients with locally advanced or metastatic solid cancers refractory to standard treatment. The effect of PankoMab-GEX™ on the development of antibodies and tumor response was also evaluated.

Male or female patients of age 18 years or older with a histologically-confirmed, tumor-associated mucin 1 (TA-MUC1) positive, measurable or non-measurable solid tumor who had failed standard therapy and for whom no standard therapy was available.

Open-label, non-randomized, inter-patient dose escalation, multi-center study in a 3 + 3 design.

Patients received PankoMab-GEX™ treatment until disease progression or until the treatment was no longer tolerated.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female and age ≥ 18 yrs
2. Histologically-confirmed TA-MUC1 positive measurable or non-measurable solid tumors according to RECIST criteria who failed standard therapy and for whom no further standard therapy is available (TA-MUC1 positivity assessed by PankoMab-GEX™ staining in immunohistology of the tumor).
3. Failure of standard therapy or non-availability of standard therapy

   * Patients must have received at least 1 standard chemotherapy during the course of the tumor disease
   * All therapies must be completed 6 weeks (therapeutic monoclonal antibodies) or 4 weeks (all other anti-cancer agents) before start of study treatment and patients must have recovered from all prior therapy toxicities to at least CTCAE grade 1
4. Performance status: Eastern Cooperative Oncology Group (ECOG) 0-1 and estimated life expectancy of \> 3 months
5. Adequate organ function as assessed by the following laboratory parameters within 14 days prior to study drug application:

   * Bone marrow function: hemoglobin ≥ 100 g/L; white blood cell count (WBC) ≥ 3.0 x 10\^9/L; absolute neutrophil count (ANC) ≥ 1.5x 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 times upper limit of normal (ULN)
   * Renal: Calculated creatinine clearance \> 80 ml/min using the Modification of Diet in Renal Disease (MDRD) formula according to Levey 2005: Glomerular filtration rate (GFR) (ml/min/1.73 m²) = 186 x (serum creatinine /0,95)\^-1.154 x (age)\^-0.203 x (0.742 females) x (1.21 in black patients)
6. Patients of both genders with procreative potential must use effective contraception while enrolled in the study and for at least 6 weeks after the last study drug infusion
7. Written informed consent must be obtained prior to conducting any study-specific procedures

Exclusion Criteria:

1. Antibody-based immunotherapy within 6 weeks and chemotherapy, radiation or other anti-cancer therapies within 4 weeks prior to study enrolment
2. Any investigational agents at the study enrolment
3. Concurrent anti-tumor therapy or concurrent immunotherapy
4. Concurrent systemic steroids except topical (inhaled, topical, nasal), replacement therapy for the last 28 days. Steroids at low and stable dose (up to 20 mg prednisone) given for chronic disease are also permitted
5. History of allergic reactions to previous antibody therapy
6. Major surgery within 4 weeks prior entering the study and/or incomplete recovery from surgery or planned major surgery
7. Documented history of active autoimmune disorders requiring systemic immunosuppressive therapy such as sarcoidosis, lupus erythematosus, rheumatoid arthritis, glomerulonephritis or systemic vasculitis (except autoimmune thyroiditis with only thyroid hormone replacement and stable disease \>1 year)
8. Primary or secondary immune deficiency
9. Clinically active infections \> CTCAE grade 2
10. Prior allergic reaction to a monoclonal antibody (e.g. Trastuzumab, Cetuximab or Bevacizumab).
11. Active hepatitis B or C; human immunodeficiency virus (HIV) seropositivity
12. 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.
13. 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.
14. Brain metastasis or leptomeningeal involvement
15. Symptomatic congestive heart failure (New York Heart Association \[NYHA\] 3 or 4); unstable angina pectoris within 6 months prior to enrollment; significant cardiac arrhythmia, history of stroke or transient ischemic attack within 1 year or left ventricular ejection fraction (LVEF) below the institutional range of normal on a baseline multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
16. History of seizures, encephalitis or multiple sclerosis
17. History of deep vein thrombosis and/or thromboembolic events within the past 6 months before entering the study and/or requiring anticoagulation therapy
18. Evidence or history of bleeding diathesis or coagulopathy
19. Active drug abuse or chronic alcoholism
20. Pregnancy or breastfeeding