A Small Molecule to Activate Tumor Immunity after PLX403 in V600E BRAF Melanoma

描述（由申请人提供）：在美国，预计2012年约有76，250例新的黑色素瘤病例和9，180例黑色素瘤相关死亡。在目前可用的治疗选择下，转移性黑色素瘤患者面临着最多10个月存活和十分之一存活10年的机会的暗淡前景。手术和放射治疗是主要的治疗方法。基于达卡巴嗪的化疗在30年后仍然是主要的全身治疗，因为没有更好的治疗方法。目前使用的免疫疗法几乎没有改善。高剂量IL-2（Proleukin）和易普利姆玛（Yerlimumab）可以增加生存率，但仅在少数患者中，并且有严重毒性的风险。突变 BRAF癌基因存在于80%的黑素瘤中，并激活B-Raf丝氨酸/苏氨酸激酶以驱动不受控制的细胞生长。新型靶向药物vemurafenib（PLX 4032）可抑制由V600 E突变激活的B-Raf，该突变发生在黑色素瘤中85%的BRAF突变中。高反应率、良性和可管理的毒性以及BRAFV 600 E突变的伴随诊断的可用性提高了转移性黑色素瘤治愈的前景。这种希望已经被耐药性的发展和恶性疾病的复发所挫败，这些疾病在对PLX 4032的响应消退后仅数月就复发了。PLX 4032产生的缓解期为免疫治疗方法提供了一个机会窗口，该方法可能激活肿瘤免疫力以抑制PLX 4032耐药黑色素瘤的复发。Arisaph已经鉴定了脯氨酰肽酶家族的小分子抑制剂ARI-4175，其可以通过诱导免疫调节细胞因子和趋化因子来激活肿瘤免疫以杀死肿瘤。Arisaph选择ARI-417作为第二代候选药物，其活性高于相关化合物PT-100（talabostat），毒性低于PT-100。ARI-4175在小鼠中产生肿瘤的免疫排斥方面是显著有效的。因此，如果在PLX 4032产生的缓解期给予ARI-4175，ARI-4175可能会激活免疫反应，从而抑制疾病的复发。该假设将通过特定目的进行检验，即在Philip Hinds博士（Tufts Medical Center）建立的BRAFV 600 E阳性黑色素瘤模型中，证明ARI-4175在对PLX 4032产生初始应答后可抑制肿瘤进展。为了成为可行的候选药物，ARI-4175必须通过在小鼠BRAFV 600 E阳性黑素瘤中PLX 4032治疗后激活肿瘤免疫而产生比单独PLX 4032显著更大的抗肿瘤作用。如果ARI-4175符合STTR I期的可行性测试，则将提议进行IND使能研究并启动II期临床试验以研究安全性和有效性。

DESCRIPTION (provided by applicant): In the United States, around 76,250 new cases of melanoma and 9,180 melanoma-related deaths are predicted for 2012. With the therapeutic options currently available, metastatic melanoma patients face the bleak prospect of at best, 10 month's survival and a one-in-ten chance of surviving for 10 years. Surgery and radiation therapy are the mainstay of treatment. Dacarbazine-based chemotherapy remains after 30 years, for want of anything better, to be the main systemic therapy. As currently used, immunotherapy affords little improvement. High dose IL-2 (Proleukin) and ipilimumab (Yervoy) can increase survival, but only in a few patients, and at the risk of severe toxicity. Mutations in the BRAF oncogene occur in 80% of melanomas and activate the B-Raf serine/threonine kinase to drive uncontrolled cell growth. The new, targeted agent, vemurafenib (PLX4032), inhibits B-Raf activated by the V600E mutation occurring in 85% of BRAF mutations in melanoma. High response rates, benign and manageable toxicities, and the availability of a companion diagnostic for the BRAFV600E mutation raised the prospect of a cure in metastatic melanoma. This hope has been thwarted by the development of drug resistance and the recurrence of malignant disease only months after regression in response to PLX4032. The period of remission produced by PLX4032 provides a window of opportunity for immunotherapeutic approaches that might activate tumor immunity to suppress the recurrence of PLX4032-resistant melanoma. Arisaph has identified a small molecule inhibitor of the prolyl peptidase family, ARI-4175, that can activate tumor immunity to kill tumors via the induction of immunoregulatory cytokines and chemokines. Arisaph has selected ARI-417 as a second-generation drug candidate with greater activity and less toxicity than the related compound, PT-100 (talabostat). ARI-4175 is remarkably effective in producing immune rejection of tumors in mice. Therefore, if given during the period of remission produced by PLX4032, ARI-4175 might activate an immune response that can suppress reemergence of disease. This hypothesis will be tested with the Specific Aim of demonstrating that ARI-4175 can inhibit progression of tumors after the initial response to PLX4032 in a model of BRAFV600E-positive melanoma established by Dr. Philip Hinds (Tufts Medical Center). In order to be a viable drug candidate, ARI-4175 must produce a significantly greater antitumor effect than PLX4032 alone by the activation of tumor immunity after PLX4032 treatment in BRAFV600E-positive melanoma in mice. If ARI-4175 meets the test of feasibility in STTR Phase I, IND-enabling studies and initiation of clinical trials to investigae safety and efficacy will be proposed for Phase II.