A-007: Immune Modulation of HPV - Associated Neoplasia

描述（由申请人提供）：4，4 '-二羟基二苯甲酮-2，4-二硝基苯腙（A-007）最初开发为免疫缺陷相关癌性生长的免疫调节剂。在最近的一项研究中，A-007作为局部凝胶给药，用于治疗与人乳头瘤病毒（HPV）相关的肛门生殖器癌。 无局部或全身毒性，观察到极好的反应，CR为76%。所有宫颈或阴道肿瘤患者要么完全消除HPV感染，要么病毒类型从高危组降至低危组。免疫组织化学（IHC）和计算机建模研究支持动物数据和假设，即A-007与蛋白酪氨酸磷酸酶（PTP）T细胞膜受体CD 45相互作用，上调T细胞并改善局部免疫力。后者的变化覆盖了局部肿瘤性CIN转化。在本申请中提供了支持以评价A-007作为与HPV相关的宫颈上皮内瘤变（CIN）的疗法。文献表明，高达70%的CIN I疾病可以自发消失。因此，本研究旨在将CIN I随机分配至安慰剂组和A-007组。安慰剂组将允许活检后的任何免疫刺激和与宫颈操作相关的局部物理刺激。疾病的晚期- CIN II/III-将仅用A-007治疗;因为对于该疾病阶段没有其他药物治疗，手术将是下一个治疗选择。接受安慰剂治疗的CIN I患者在一个疗程后，如果疾病仍然存在，将选择接受A-007治疗。 这项II期研究的具体目的是局部治疗250例感染HPV的不同阶段的CIN，并评估A-007逆转CIN变化和消除HPV的能力。将密切监测局部免疫调节，并进行标准组织病理学和病毒评估。 本研究将在三家合格的临床中心进行。

DESCRIPTION (provided by applicant): 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) was originally developed as an immune modulator of immune deficiency associated cancerous growths. In a recent study, A-007 was administered as a topical gel to treat anogenital cancers associated with the human papillomavirus (HPV). There were no local or systemic toxicities and excellent responses were seen -76% CR. All patients with cervical or vaginal neoplasia either had complete elimination of HPV infections or the viral types reduced from high risk to low risk groups. Immunohistochemical (IHC) and computer modeling studies support animal data and the hypothesis that A-007 interacts with the protein tyrosine phosphatase (PTP) T-cell membrane receptor CD45 up-regulating T-cells and improving local immunity. The latter changes override the local neoplastic CIN transformations. Support is provided in the present application to evaluate A-007 as therapy for cervical intraepithelial neoplasia (CIN) associated with HPV. Literature indicates that up to 70% of the CIN I disease can spontaneously disappear. Thus, the present studies have been designed to randomize CIN I to a placebo vs. A-007. The placebo arm will allow for any immune stimulation that follows biopsies and local physical stimulation associated with manipulations of the cervix. The advanced stages of the disease - CIN II/Ill - will be treated only with A-007; since there are no other medical treatments for this stage of disease and surgery would be the next treatment of choice. The CIN I patients treated with placebos will be given the option to receive A-007 after one course, if disease remains. The specific objectives of this Phase II study will be to topically treat 250 with various stages of CIN infected with HPV and evaluate A-007's ability to reverse CIN changes and eliminate HPV. Local immune modulation will be closely monitored, and standard histopathology and viral assessments will be performed. The study will be performed at three qualified clinical centers.