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Phase I Therapy Study with ¹⁸⁶Re-labeled Humanized Monoclonal Antibody BIWA 4 (Bivatuzumab) in Patients with Head and Neck Squamous Cell Carcinoma¹

Departments of Otolaryngology/Head and Neck Surgery [P. K. E. B., D. R. C., R. d. B., G. B. S., G. A. M. S. v. D.] and Nuclear Medicine [J. C. R.], VU University Medical Center, 1081 HV Amsterdam, the Netherlands; Departments of Nuclear Medicine [E. J. P., W. J. G. O.] and Otolaryngology/Head and Neck Surgery [H. A. M. M.], UMC Nijmegen, 6500 HB Nijmegen, the Netherlands; Boehringer Ingelheim bv, 1802 KA Alkmaar, the Netherlands [M. H. v. S.]; and Boehringer Ingelheim Pharma KG, 88397 Biberach an der Riss, Germany [G. S.]

Purpose: In previous studies, we have shown the potential of radioimmunotherapy (RIT) with ¹⁸⁶Re-labeled chimeric monoclonal antibody (MAb) U36 for treatment of head and neck cancer. A limitation of this anti-CD44v6 MAb, however, appeared to be its immunogenicity, resulting in human antichimeric antibodies in 40% of the patients. Aiming for a less immunogenic anti-CD44v6 MAb, the humanized MAb BIWA 4 (bivatuzumab) was introduced. In the present Phase I RIT study, we determined the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity, and therapeutic potential of ¹⁸⁶Re-labeled BIWA 4 in patients with squamous cell carcinoma of the head and neck.

Experimental Design: Twenty patients with inoperable recurrent and/or metastatic head and neck squamous cell carcinoma received a single dose of ¹⁸⁶Re-labeled BIWA 4 in radiation dose-escalation steps of 20, 30, 40, 50, and 60 mCi/m². Three patients received a second dose at least 3 months after the initial dose. After each administration, whole-body images as well as planar and tomographic images of the head and neck region were obtained, and the pharmacokinetics and the development of human antihuman antibody responses were determined. Radiation absorbed doses were calculated for whole body, red marrow, organs, and tumor.

Results: First and second administrations were all well tolerated, and targeting of tumor lesions proved to be excellent. The only significant manifestations of toxicity were dose-limiting myelotoxicity consisting of thrombo- and leukocytopenia and, to a lesser extent, oral mucositis (grade 2). Grade 4 myelotoxicity was seen in two patients treated with 60 mCi/m². The MTD was established at 50 mCi/m², at which level dose-limiting myelotoxicity was seen in one of six patients. Stable disease, varying between 6 and 21 weeks, was observed in three of six patients treated at the MTD level. The median tumor dose, recalculated to MTD level, was 12.4 Gy. The absorbed dose in red marrow was 1.82 ± 0.11 cGy/mCi for males and 2.35 ± 0.10 for females. Two patients experienced a human antihuman antibody response. Pharmacokinetics showed consistency across patients and within the three patients receiving ¹⁸⁶Re-BIWA 4 on two occasions.

Conclusions: This study shows that ¹⁸⁶Re-labeled BIWA 4 can safely be administered, also in a repeated way. The MTD was established at 50 mCi/m². In comparison with the previously described anti-CD44v6 MAb U36, the humanized MAb BIWA 4 seems to be less immunogenic. The fact that antitumor effects were seen in incurable patients with bulky disease justifies the evaluation of RIT with ¹⁸⁶Re-labeled BIWA 4 in an adjuvant setting.

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