Zalutumumab in Combination With Radiotherapy in Head and Neck Cancer Patients Ineligible for Platinum Based Chemotherapy

The purpose of this study is to investigate the safety of zalutumumab in combination with radiotherapy as the treatment of patients with head and neck cancer who are not eligible for platinum based chemotherapy.

This is an open label, multi-center, phase I/II dose-escalation clinical trial investigating the safety of zalutumumab in combination with radiotherapy. The safety of zalutumumab doses in combination with radiotherapy (RT) will be investigated using 3 patient cohorts in a dose-escalation / de-escalation design based on Dose Limiting Toxicity (DLT). The dose-escalation starts at 8 mg/kg zalutumumab in combination with RT. Initially, three patients will be treated at a dose level and observed for DLTs. If none of the three patients experience a DLT, then the next cohort of three patients is treated at the next higher dose of zalutumumab. If one of three patients treated at a dose level experience a DLT, then three more patients are treated at the same dose level. If two or more of the three patients experience DLTs, then the next cohort of three patients should be treated at the next lower dose of zalutumumab, unless at least six patients on that dose have already been dosed. Furthermore, if 1 or fewer DLTs are observed among six patients at a given dose level, then the next cohort of three patients is treated at the next higher dose of zalutumumab. The maximum tolerated dose will be decided by Genmab based on the recommendations made by the IDMC on the basis of their review of the aggregated safety data.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically or cytologically confirmed diagnosis of locally advanced squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx stage III, IVa or IVb
2. Measurable disease defined as one or more target lesions according to RECIST based onCT scan or MRI and clinical evaluation
3. Eligible for intended curative radiotherapy
4. Patients considered ineligible for platinum based chemotherapy based on investigator's judgment
5. Age \> 18 years
6. Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity is carried out

Exclusion Criteria:

1. Prior radiotherapy to the head and neck area
2. Prior chemotherapy administered for cancer in the head and neck area
3. Prior targeted therapy (e.g. EGFR antibodies or EGFR inhibitors)
4. Received the following treatments within 4 weeks prior to Visit 2:

   1. Retinoic acid
   2. Other immunosuppressive drugs (e.g. drugs interfering with the functions of T cells, IL-2 or equivalent)
   3. Any non-marketed drug substance
5. Past or current malignancy other than SCCHN, except for:

   * Cervical carcinoma Stage 1B or less
   * Non-invasive basal cell skin carcinoma
   * Squamous cell skin carcinoma
   * Stage 1 or 2 treated prostate cancer with PSA in the normal range for \>2 years post treatment
   * Malignant melanoma with a complete response duration of \> 10 years
   * Other cancer diagnoses with a complete response duration of \> 5 years
6. Metastatic SCCHN disease
7. Chronic or current infectious disease such as, but not limited to, chronic renal infection and tuberculosis
8. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months before Visit 1, congestive heart failure, and arrhythmia requiring anti-arrhythmic therapy, with the exception of extra systoles or minor conduction abnormalities
9. Significant concurrent, uncontrolled medical condition including, but not limited to,hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease considered to preclude trial treatment and/or compliance according to the Investigator's opinion, or any other condition preventing therapy according to the Investigator's opinion
10. Known HIV positive
11. Known active hepatitis B and/or hepatitis C
12. Screening laboratory values:

    * Neutrophils \< 1.5 x 109/L
    * Platelets \< 100 x109/L
    * Hemoglobin \< 6 mmol/L
13. Current participation in any other interventional clinical study
14. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency, or psychological disorder)
15. Known or suspected hypersensitivity to components of the investigational medicinal Product
16. Breast feeding women or women with a positive pregnancy test at screening blood Sample
17. Males not willing to use adequate contraception during study and for 12 months after last dose of zalutumumab or women of childbearing potential not willing to use adequate contraception as hormonal birth control or intrauterine device during study and for 12 months after last dose of zalutumumab