Dose Escalation Study With 99mTC - or 186 Re-labelled Humanised Monoclonal Antibody (hMAb) BIWA 4 in Patients With Head and Neck Cancer

Study Overview
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Brief Summary
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The general aim of the present study was to assess the safety and tolerability of intravenously administered Technetium 99m (99mTc) and Rhenium-186 radionuclide (186 Re) -labelled hMAb BIWA 4, to confirm preferential accumulation in the tumour of 99mTc - labelled hMAb BIWA 4, to determine the maximum tolerated radiation dose of 186 Re-labelled hMAb BIWA 4 and to propose a safety dose for phase II development.

Official Title
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A Phase I Dose Escalation Study With 99mTC - or 186 Re-labelled Humanised Monoclonal Antibody BIWA 4, in Patients With Head and Neck Cancer

Conditions
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Head and Neck Neoplasms

Intervention / Treatment
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* Drug: 99mTc - labelled hMAb BIWA 4
* Drug: 186 Re - labelled hMAb BIWA 4
* Drug: unlabelled hMAb BIWA 4 - low dose
* Drug: unlabelled hMAb BIWA 4 - medium dose
* Drug: unlabelled hMAb BIWA 4 - high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histological confirmation of squamous cell carcinoma in the head and neck Patients destined for surgery by means of neck dissection (Part A) or : Patients with either local and/or regional recurrent disease for which curative treatment options were not available or distant metastases. The tumor deposits had to be measurable either clinically or by one or more radiological technique (s) (CT, MRI, bone scintigraphy). Because RIT was expected to be more effective in smaller size tumor deposits, patients with lesions measuring > 3 cm in greatest dimension were preferred (Part B) Patients over 18 years of age Patients younger than 80 years of age Patients who had given 'written informed consent' Patients with a life expectancy of at least 3 months Patients with a good performance status: Karnofsky > 60 Exclusion Criteria: Life-threatening infection, allergic diathesis, organ failure (bilirubin > 30µmol/l and/or creatinine > 150 µmol/l) or evidence of a recent myocardial infarction on ECG or unstable angina pectoris Pre-menopausal women (last menstruation <= 1 year prior to study start) Not surgically sterile (hysterectomy, tubal ligation) and Not practicing acceptable means of birth control, (nor not planned to be continued throughout the study). Acceptable methods of birth control include oral, implantable or injectable contraceptives Women with a positive serum pregnancy test at baseline Chemotherapy or radiotherapy within 4 weeks before inclusion in the study White blood cell count < 3000/mm³, granulocyte count < 1500/mm³ or platelet count < 100000/mm³ Hematological disorders, congestive heart failure, bronchial asthma, alimentary or contact allergy, severe atopy or allergy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: 99mTc - labelled hMAb BIWA 4 - low dose<br> | Drug: 99mTc - labelled hMAb BIWA 4<br> <br> Drug: unlabelled hMAb BIWA 4 - low dose<br> <br> |
| Experimental: 99mTc - labelled hMAb BIWA 4 - medium dose<br> | Drug: 99mTc - labelled hMAb BIWA 4<br> <br> Drug: unlabelled hMAb BIWA 4 - medium dose<br> <br> |
| Experimental: 99mTc - labelled hMAb BIWA 4 - high dose<br> | Drug: 99mTc - labelled hMAb BIWA 4<br> <br> Drug: unlabelled hMAb BIWA 4 - high dose<br> <br> |
| Experimental: 186 Re - labelled hMAb BIWA 4 - escalating dose<br> | Drug: 186 Re - labelled hMAb BIWA 4<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events |  | up to 10 weeks | 
| Presence of human-anti-human-antibody (HAHA) |  | after 144 hours post infusion | 
| Number of patients with clinically significant changes in vital signs |  | up to 6 weeks after infusion | 
| Biodistribution of 99mTC-labelled hMAb BIWA 4 in tumour and normal tissue samples - Biopsy (Part A) | uptake expressed as percentage of the injected dose per kg tissue (%ID/kg) | at 48 h after infusion | 
| Immunoscintigraphic imaging evaluation (Parts A + B) |  | up to 21 hours after infusion | 
| AUC0-∞ (Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | up to 336 hours after infusion | 
| Cmax (Maximum measured concentration of the analyte in plasma) |  | up to 336 hours after infusion | 
| tmax (Time from dosing to the maximum concentration of the analyte in plasma) |  | up to 336 hours after infusion | 
| t½ (Terminal half-life of the analyte in plasma) |  | up to 336 hours after infusion | 
| Vz (Apparent volume of distribution during the terminal phase) |  | up to 336 hours after infusion | 
| Vss (Apparent volume of distribution under steady-state conditions) |  | up to 336 hours after infusion | 
| CL (Total body clearance) |  | up to 336 hours after infusion | 
| MRT (Mean residence time) |  | up to 336 hours after infusion | 
| Cumulative urinary excretion of radioactivity over time |  | up to 96 hours after infusion | 
| Number of patients with abnormal changes in laboratory parameters |  | up to 6 weeks after infusion | 
| Occurence of dose limiting toxicities (DLT) |  | up to 144 hours post infusion | 
| Uptake of 99mTC-labelled hMAb BIWA 4 in tumour and normal tissue samples (Part A) | Assessment of biodistribution by radioimmunoscintigraphy expressed as low, medium or high | up to 6 weeks after infusion | 
| Actual organ uptake of 99mTC-labelled hMAb BIWA 4 | expressed as % I.D. (injected dose) | at 21 h after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumour response according to response criteria of the World Health Organisation (WHO) | assessed by Computer Tomography (CT) and/or by Magnet resonance imaging (MRI) and/or bone scintigraphy and/or by physical examination | up to 144 hours after infusion | 
| Maximum tolerated radiation dose of 186Re-labelled hMAb BIWA 4 |  | up to 144 hours after infusion |