New Directions for Clinical Trials of Targeted Alpha Therapy for Metastatic Melanoma

Barry   J.   Allen; Chand      Raja; Syed   M.A.   Rizvi; Peter      Graham; John   H.   Kearsley

Abstract

This paper reviews the journey taken by the Centre for Experimental Radiation Oncology from bench to bedside in the development of targeted alpha therapy (TAT) for metastatic melanoma. The alpha-immunoconjugate (AIC) 213Bi-cDTPA-9.2.27 (AIC) has been prepared and investigated for stability, labelling yield, toxicity, cytotoxicity and preclinical and clinical response. Preclinical studies gave high labelling efficiency and high cytotoxicity, translating to clinical trials where the conjugate was found to be very effective in regressing tumours while sparing the normal tissues. These trials provided significant information regarding pharmacokinetics, antigen expression and tumour response. Intralesional TAT (16 patients) was found to be non-toxic up to 1350 μCi and locally efficacious at doses of 600 μCi. In a systemic trial, 38 patients received activities up to 27 mCi (1000 MBq), for which there was no evidence of adverse events at any level. However efficacy was indicated as one patient showed a near complete response, 9% of patients had partial responses and 30% had stable disease for at least 8 weeks. These responses were dose independent, implying that other parameters such as antigen expression and vascular permeability of tumour capillaries play a role, and were explained by the development of tumour anti-vascular alpha therapy (TAVAT). The above clinical trials paved way for a phase 1 bridging study to optimise key parameters so as to establish a dose response relationship, to be followed by a phase 2 trial.

Keywords: Metastatic melanoma, targeted alpha therapy, phase 1 clinical trial

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