Early Clinical Testing for Melanin Targeting Radio-therapeutic agent in melanoma

描述（由申请人提供）： 该快速通道I/II期SBIR提案的最终目标是对新型药物碘氟苯甲酰胺I-131进行临床评估，以评估其作为转移性黑色素瘤分子靶向放射治疗的潜力。在表达黑色素的细胞培养物中的初步结果表明与黑色素癌的高选择性结合。小鼠肿瘤模型中的器官分布研究显示，肿瘤中蓄积较高，并通过肾脏和肝胆系统快速消除。在该系列中的类似化合物的早期人体测试也证明了转移性黑色素瘤患者的肿瘤中的高摄取和保留。然而，对这种早期铅化合物的工艺开发研究表明，它太不稳定，无法扩大到高放射性浓度。Ioflubenzamide I-131是一种放射性碘化苯甲酰胺分子，与表达黑色素的黑色素瘤具有极高的选择性结合，非靶器官蓄积较低。分子靶点特异性、高肿瘤蓄积和保留是有效治疗黑素瘤转移的药剂的理想性质。初步临床前疗效研究证明，在SK-Mel-3人黑色素瘤异种移植小鼠模型（约100 mCi/m2作为人剂量当量）中，碘氟苯甲酰胺I-131治疗两次（0.68 mCi）后肿瘤完全缓解。本提案的前六个月阶段将重点关注生成支持向FDA提交探索性IND申请所需的CMC文件。该提案的第二阶段将在FDA接受该方案后启动。这一为期18个月的II期部分将侧重于在12例（男性和女性）确诊为转移性恶性黑色素瘤的受试者中执行和完成临床成像研究，以确定安全性和器官剂量测定。要求快速通道考虑的理由是建立主要证据并为治疗递增研究选择治疗起始剂量。该提案的创新是转移性黑色素瘤潜在治愈性治疗的令人兴奋的承诺。在SBIR计划成功完成后，Molecular Insight将制定一项临床方案，以确定行业赞助的NDA的剂量和疗效。公共卫生相关性：在美国，恶性黑色素瘤的发病率上升速度比任何其他类型的癌症都要快。能够用破坏细胞的放射性同位素标记并专门靶向黑色素瘤组织的放射性药物将提供特异性用于治疗转移性疾病的药物。I-131标记的恶性黑色素瘤分子靶向放射治疗剂的成功开发将把这种治疗技术引入到目前无法治愈的疾病中，并引起治疗放射学领域的相当大的关注。Molecular Insights希望在确诊黑色素阳性转移性黑色素瘤的受试者中测试一种新的分子靶向药物：碘氟苯甲酰胺I-131，以确定其作为全身放疗药物的潜力。恶性黑色素瘤发病率的上升、转移的早期和广泛发生以及当前疗法的不良反应率，产生了有效治疗转移性黑色素瘤患者的基本需求和宝贵的商业机会。

DESCRIPTION (provided by applicant): The ultimate goal of this Fast Track Phase I/II SBIR proposal is to perform the clinical assessment of a novel pharmaceutical agent, ioflubenzamide I-131, to evaluate its potential as a molecular targeting radio-therapeutic treatment for metastatic melanoma. Preliminary results in melanin expressing cell cultures, demonstrate high and selective binding to melanoma cancers. Organ distribution studies in mouse tumor models showed high accumulation in tumors and rapid elimination through the renal and hepatobillary systems. Early human testing, of a similar compound in this series, also demonstrated high uptake and retention in tumors of metastatic melanoma patients. However, process development studies of this earlier lead compound indicated it was too unstable to scale up to high radioactive concentrations. Ioflubenzamide I-131 is a radio-iodinated benzamide molecule with extremely high selective binding to melanin expressing melanomas and low non-target organ accumulation. The molecular target specificity, high tumor accumulation and retention are ideal properties for an agent to effectively treat melanoma metastasis. Preliminary preclinical efficacy studies demonstrated complete tumor remission after two treatments (0.68 mCi) with ioflubenzamide I-131 in a SK-Mel-3 human melanoma xenograft mouse model (about 100 mCi/m2 as a human dose equivalent). The first six month phase of this proposal will focus on generating CMC documentation necessary to support an exploratory IND application to the FDA. The second phase of the proposal will be initiated after the protocol has been accepted by the FDA. This 18 month phase 2 portion will focus on executing and completing a clinical imaging study in 12 (male and female) subjects with confirmed metastatic malignant melanoma to determine safety and organ dosimetry. The justification for requesting Fast Track consideration is to establish the proof-of-principal and select a therapeutic starting dose for a therapy escalation study. The innovation in this proposal is the exciting promise for a potential curative treatment of metastatic melanoma. Following successful completion of the SBIR program, Molecular Insight will develop a clinic protocol to determine dosage and efficacy for an industry sponsored NDA to the FDA. PUBLIC HEALTH RELEVANCE: The incidence of malignant melanoma is rising faster than that of any other types of cancer in the United States. A radiopharmaceutical, capable of being labeled with cell destroying radioisotopes and exclusively targeted to melanoma tissue, would provide a drug specific for the treatment of metastatic disease. The successful development of an I-131 labeled molecular targeting radiotherapeutic agent for malignant melanoma would introduce this therapeutic technique to a now incurable disease and bring considerable attention to the field of therapeutic radiology. Molecular Insights desires to test a new molecular targeting agent: ioflubenzamide I-131 in subjects with confirmed melanin positive metastatic melanomas, to determine its potential as a systemic radiotherapy agent. The rising incidence of malignant melanomas, the early and wide-spread occurrence of metastases, and the poor response rates for current therapies, creates an essential need and valuable commercial opportunity to effectively treat patients with metastatic melanomas.