Zalutumumab is a fully human, high-affinity antibody targeted at the Epidermal Growth Factor receptor (EGFr) and is in clinical development to treat head and neck cancer. EGFr is a receptor molecule found on the surface of many cancer cells. Activation of EGFr by the appropriate growth factor molecule promotes the growth of tumor cells.

Based on data from clinical cancer trials conducted by other biotechnology and pharmaceutical companies using both anti-EGFr antibodies and small molecule drugs, we believe that an antibody targeting EGFr may be an effective treatment for a variety of cancers, particularly when used in combination with chemotherapy or radiation.

Zalutumumab has been awarded Fast Track status from the US FDA covering head and neck cancer patients who have previously failed standard therapies.

Head and Neck Cancer

Head and neck cancers may affect the mouth, nasal cavities, sinuses, larynx and pharynx. Most are squamous carcinomas but others include lymphoepithelioma and lymphoma. Head and neck cancers account for 3% of all cancers in the US, with 40,000-60,000 cases diagnosed and 12,000 deaths annually. Worldwide incidence is about half a million with nearly 250,000 deaths.

Ongoing Clinical Studies

Phase I/II Radiotherapy Combination Study
Genmab initiated a Phase I/II study of zalutumumab in combination with radiotherapy for the treatment of advanced head and neck cancer in June 2008. The study will include a maximum of 36 patients who are ineligible for platinum based chemotherapy.

In the dose-escalation part of the study, 6 to 24 patients will be enrolled in cohorts of 3 patients per dose level of zalutumumab. The dose level for each successive cohort will be determined by the aggregate safety data observed in the prior cohorts. When the maximum tolerated dose of zalutumumab is established, an additional cohort of 12 patients will be enrolled and treated at this level.

Patients in the study will receive 8 weekly infusions of zalutumumab with the first cohort receiving an initial dose of 12 mg/kg of zalutumumab followed by 7 maintenance doses of 8 mg/kg of zalutumumab in addition to radiotherapy. Patients will be evaluated at 4 weeks following the last dose of zalutumumab and will be followed for a total of 2 years.

The objective of the study is to evaluate the safety of repeat dosing and establish the maximum tolerated dose of zalutumumab in combination with radiotherapy in patients with advanced head and neck cancer who are ineligible for platinum based chemotherapy. The primary endpoint of the study is adverse events.

Phase I/II Chemo-radiation Combination Study
Genmab is conducting a Phase I/II study of zalutumumab in combination with chemo-radiation as first line treatment of head and neck cancer. The study will include a total of 36 patients with advanced squamous cell carcinoma of the head and neck (SCCHN). The open label study consists of an initial dose-escalation part and a subsequent parallel group design. In the dose-escalation part of the study, three dose levels of zalutumumab will be tested in combination with conventional fractionated radiotherapy and cisplatin. Patients in the first treatment group will receive one initial dose of 8 mg/kg of zalutumumab followed by seven weekly maintenance doses of 4 mg/kg. The safety of this dose level will then be evaluated before dosing is continued at the next level. The planned dosing for the two other dose groups is an initial dose of 12 or 16 mg/kg followed by seven weekly maintenance doses of 8 or 12 mg/kg, respectively, but can be adjusted according to safety data from the first treatment group.

In the following parallel group design part of the study, zalutumumab will be tested in combination with cisplatin and three different regimens of accelerated radiotherapy.

All patients in the study will be evaluated four weeks after administration of the last dose of zalutumumab and will be followed for at least three years.

The objective of the study is to investigate the efficacy of zalutumumab in combination with chemo-radiation as first line treatment of patients with advanced SCCHN. The primary endpoint of the study is safety and patients will also be evaluated for efficacy.

Phase III Pivotal Study
Genmab is also conducting a Phase III pivotal study with zalutumumab to treat patients with head and neck cancer that is considered incurable with standard treatment. The pivotal study will include a maximum of 273 patients with SCCHN who are refractory to or intolerant of standard plantinum-based chemotherapy.

Patients in the study will be randomized into two treatment groups: zalutumumab in combination with best supportive care or best supportive care alone. Patients treated with zalutumumab in combination with best supportive care will receive an initial dose of 8mg/kg of zalutumumab, followed by weekly infusions of a maintenance dose until disease progression. The maintenance dose will be adjusted as necessary until the patient develops a dose limiting skin rash, up to a maximum dose of 16 mg/kg of zalutumumab. Disease status will be assessed every 8 weeks by CT scan or MRI according to RECIST criteria until disease progression and patients will be followed for survival.

The objective in the study is to evaluate the efficacy of zalutumumab in combination with best supportive care as compared to best supportive care alone in terms of overall survival. The primary endpoint in the study is overall survival from randomization until death.

Phase III Front Line Radiotherapy Combination Study
The Danish Head and Neck Cancer Group (DAHANCA) has initiated a Phase III study of zalutumumab to treat approximately 600 previously untreated head and neck cancer patients. Patients in the study will be randomized to treatment with radiotherapy or zalutumumab plus radiotherapy. All patients will receive treatment with accelarated radiotherapy plus nimorazole and may also receive cisplatin chemotherapy. Patients receiving zalutumumab will receive six weekly doses of 8 mg/kg of zalutumumab. Patients will be followed for at least 5 years and will be clinically evaluated at months 2, 5, 8 and 12 after completion of treatment. Evaluations will continue every 4 months in the second year and every 6 months the third and fourth years and once a year thereafter.

The objective of the study is to determine the efficacy of zalutumumab in combination with radiotherapy in treating patients with squamous cell carcinoma of the head and neck. The primary endpoint is loco-regional control and secondary endpoints are overall survival, disease free survival and acute and late side effects.

Previous Clinical Studies

Phase I/II Results
Genmab has conducted an open label Phase I/II clinical trial using zalutumumab to treat patients suffering from confirmed recurrent SCCHN who had previously failed standard therapies. Twenty-four patients were included in the initial trial, which was expanded to include three additional patients. Patients were divided into six dose groups and received intravenous infusions of zalutumumab at doses of 0.15, 0.5, 1, 2, 4, or 8 mg/kg. Twenty patients received all five infusions. The primary and secondary endpoints of the study were safety and efficacy of zalutumumab.

Clinical and metabolic response was demonstrated by two types of scanning. Assessed by FDG-PET, which visualizes tumor metabolism, 7 of 18 evaluable patients achieved partial metabolic response (PMR) and 4 had stable metabolic disease (SMD) one week after their fifth and last infusion. In the two highest dose groups, 9 out of 11 patients obtained PMR or SMD.

Clinical response evaluated by computerized tomography (CT scan) supported the positive FDG-PET results. Two of 19 evaluable patients achieved partial response (PR) and 9 patients had stable disease (SD) according to RECIST criteria. The partial response was maintained at week 12 by one of the two patients. The other patient's disease progressed five weeks after the last treatment, but following additional zalutumumab treatment at 8 mg/kg on a compassionate use basis, the patient re-obtained the partial response. In the two highest dose groups 7 out of 10 patients obtained PR or SD.

Results from the trial indicate that zalutumumab was well tolerated by head and neck cancer patients. Furthermore, no patients experienced Dose Limiting Toxicity when treated with the highest dose of 8 mg/kg. The most frequent adverse event was acneiform rash demonstrating biological activity of zalutumumab in 56% of the patients. The occurrence increased with dose, with 10 of 11 patients in the 4 and 8 mg/kg dose groups experiencing rash. Other adverse events included rigors, fatigue, pyrexia, nausea, flushing and increased sweating. One case of grade 3 rash was reported. One patient reported a serious adverse event considered related to treatment with zalutumumab, grade 2 pyrexia, which developed during the first infusion. The patient recovered and completed the study. Click here to view a poster of the preliminary study results presented in 2005.

Genmab worked with the Danish Head and Neck Cancer Group (DAHANCA), an organization which is in contact with all patients suffering from head and neck cancer in Denmark, to identify potential trial participants for the Phase I/II study.

Pre-clinical Studies

Zalutumumab has been shown to effectively stop tumor growth in laboratory tests, and in animal disease models, induce regression of established tumors that overexpress EGFr. In these animal studies, HuMax-EGFr eradicated tumors at very low and infrequent doses, especially when compared to other antibodies directed to EGFr. In addition, pre-clinical studies have shown that zalutumumab appears to be more effective against variations of the EGF receptor than other EGFr directed treatments.

Further pre-clinical studies have provided new insights into the novel mechanisms of action of zalutumumab. By using Protein Tomography™, a relatively new technology which uses an electron microscope to view the three dimensional structure of proteins on the surface of cells, zalutumumab was shown to lock the EGF receptor in an inactive conformation which prevents receptor activation and the binding of growth factors. Furthermore, zalutumumab was shown to inhibit EGF receptor signaling by preventing receptor dimerization, the pairing of two receptor molecules which starts the signaling cascade. All of these mechanisms have the potential to interfere with cancer cell growth.

In a novel cancer cell laboratory model, zalutumumab effectively inhibited the growth of tumor cells that express both mutated or normal EGF receptors. This inhibition occurred through different mechanisms of action including direct inhibition of cancer cell growth and an immune cell-mediated killing activity known as antibody dependent cell-mediated cytotoxicity (ADCC).

Genmab scientists also used the model to test the effects of tyrosine kinase inhibitors (TKI) such as the marketed products Iressa and Tarceva on EGFr-expressing tumor cells. Tumor cells expressing various mutated EGFr varied strongly in their sensitivity to TKI therapy, whereas no differences in efficacy where observed for zalutumumab. These data indicate that zalutumumab may have more potential in the treatment of some types of cancer, such as lung cancer, than TKI.

New insights have shown that zalutumumab locks epidermal growth factor receptor (EGFr) molecules into a very compact, inactive conformation. The flexibility of the EGFr is central to its role in signaling and binding of zalutumumab results in effective inhibition of cancer cell growth.

Selected Scientific References:

Bleeker WK, Lammerts van Bueren JJ, van Ojik HH, Gerritsen AF, Pluyter M, Houtkamp M, Halk E, Goldstein J, Schuurman J, van Dijk MA, van de Winkel JG, Parren PW. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol. 2004 Oct 1;173(7):4699-707.

Sridhar, S. S., Seymour, L., and Shepherd, F. A. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol. 2003; 4: 397-406.

Arteaga, C. L. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res. 2003; 284: 122-130.

Mendelsohn, J. and Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000; 19: 6550-6565.

Salomon, DS, Brandt, R, Ciardiello, F, and Normanno, N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995; 19: 182-232.

Gullick, W. J. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull. 1991; 47: 87-98.

Cowley GP, Smith, JA and Gusterson, BA. Increased EGF receptors on human squamous carcinoma cell lines. Br. J. Cancer. 1986; 53 (2): 223-9.