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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open-label, International, Multi-Center, Phase I/II, Dose-escalation Trial Investigating the Safety of Zalutumumab, a Human Monoclonal Epidermal Growth Factor Receptor Antibody in Combination With Radiotherapy, in Patients With Stage III, IVa or IVb Locally Advanced Squamous Cell Carcinoma of the Head and Neck Ineligible for Platinum Based Chemotherapy

Conditions
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Head and Neck Cancer, Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Zalutumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Measurable disease defined as one or more target lesions according to RECIST based onCT scan or MRI and clinical evaluation Eligible for intended curative radiotherapy Patients considered ineligible for platinum based chemotherapy based on investigator's judgment Age > 18 years 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: Prior radiotherapy to the head and neck area Prior chemotherapy administered for cancer in the head and neck area Prior targeted therapy (e.g. EGFR antibodies or EGFR inhibitors) Received the following treatments within 4 weeks prior to Visit 2: Retinoic acid Other immunosuppressive drugs (e.g. drugs interfering with the functions of T cells, IL-2 or equivalent) Any non-marketed drug substance 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 Metastatic SCCHN disease Chronic or current infectious disease such as, but not limited to, chronic renal infection and tuberculosis 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 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 Known HIV positive Known active hepatitis B and/or hepatitis C Screening laboratory values: Neutrophils < 1.5 x 109/L Platelets < 100 x109/L Hemoglobin < 6 mmol/L Current participation in any other interventional clinical study Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency, or psychological disorder) Known or suspected hypersensitivity to components of the investigational medicinal Product Breast feeding women or women with a positive pregnancy test at screening blood Sample 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zalutumumab 4 mg/kg<br>Zalutumumab in combination with radiotherapy for 8 weeks. The treatment period of 8 weeks is followed by a 3 week follow-up period where all adverse events are collected and then additionally a 2 year follow-up period where only serious adverse events are collected. | Drug: Zalutumumab<br>* Eight weekly infusions<br>|
| Experimental: Zalutumumab 8 mg/kg<br>Zalutumumab in combination with radiotherapy for 8 weeks. The treatment period of 8 weeks is followed by a 3 week follow-up period where all adverse events are collected and then additionally a 2 year follow-up period where only serious adverse events are collected. | Drug: Zalutumumab<br>* Eight weekly infusions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | Number of participants with at least one adverse event. All adverse events are collected during 12 weeks and all serious adverse events are collected during 2 years. | From first dose date up to end of the safety follow up period (Up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Best Overall Tumour Response | The Best Overall Tumour Response defined as the best response recorded from the start of treatment until disease progression or recurrence per RECIST criteria. Complete response (CR) defined as the disappearance of all target lesions. Partial response (PR) defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Progressive disease (PD) defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one or more new lesions since the prior scan. Stable disease (SD) defined as responses not fulfilling CR, PR or PD. | Up to 2 years | 
| Number of Participants With Objective Response | Objective response is defined as CR or PR according to RECIST criteria. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. | Up to 2 years |