Phase III Randomized Blinded Trial of Sorafenib vs Placebo in Desmoid Tumor A091105/116279 12/2013

索拉非尼治疗硬纤维瘤的三期双盲、随机、安慰剂对照试验 侵袭性纤维瘤病(DT/DF)(NSC#091105，IND116279,2013年12月2日) 硬纤维样瘤(DT/DF)是一种纤维母细胞起源的肉瘤，困扰儿童、青少年和成人。 发病年龄中位数为30岁1。硬纤维瘤可发生在任何解剖位置 威胁到重要的器官和四肢，通常会因器官衰竭而导致严重的发病率，致残 手术(和截肢)，肢体功能丧失，疼痛和死亡2，3。 DT/DF的治疗。手术与高复发率有关(~40%)4，5。在晚期疾病中， 全身疗法的范围从抗雌激素到细胞毒化疗，应答率各不相同 然而，没有系统的治疗方法被证明可以改善这个孤儿的存活率或生活质量。 疾病6.Dt/df通过EXPRESS c-kit和PDGFR和伊马替尼的II期研究显示令人失望 部分应答率(PR)为6%14.据此推断，本申请的首席调查员(Mr Gounder)治疗了一名指标性患者：一名37岁的女性，她表现出一个巨大的不可切除的，内含 胸椎韧带样瘤伴索拉非尼。索拉非尼是一种多靶点的BRAF、PDGFR和 VEGFR并通过同情使用、扩展访问计划提供。索拉非尼目前的FDA 肾脏、肝脏和甲状腺的孤儿适应症 癌症。在表现时，患者的韧带样变 肿瘤移位了她的纵隔，表现为 心肺衰竭的高风险和 猝死(图1)。这位病人是 依赖氧气，不能走动 超过30英尺。在实施以下管理 索拉菲尼，这位年轻的女士成为 在4周内脱离氧气，开始 走动，3个月内回到 工作。近4年后，她仍在服用索拉非尼。 这种部分反应和显著的临床益处促使申请者和MSKCC的同事们 评估索拉非尼在另外26名患者中的单一机构经验。我们报告了25%的部分 70%的患者有反应(30%的大小，持续4年)和症状改善。我们报道了 病情稳定但报告症状有主观改善的患者表明 MRI T2信号强度降低。这项提议的中心假设是索拉非尼将导致 改善无进展存活率、客观反应以及症状和功能的改善。这是一个 全国性，第三阶段，随机、双盲、安慰剂对照的DT患者索拉非尼试验。病人在 安慰剂将在进展中交叉使用。这项研究将招募75名患者来检测9个月的PFS差异 在服用索拉非尼组(15个月)和安慰剂组(6个月)之间，风险比为0.4。 样本大小在单侧显着性水平为0.025的情况下将具有90%的功率来检测这种差异。应该 这项研究达到了这个主要终点，这将是第一次在这个孤儿中确定活性物质的第三阶段试验 并将提供FDA新适应症所需的关键数据。 关于索拉非尼在DT中的使用，许多问题仍未得到回答。其中包括：1) 索拉非尼治疗DT的作用机制，2)缺乏预测反应的生物标志物，3)DT的意义 MRI T2信号的降低，以及这是否代表了评估药物疗效和 4)量化服用索拉非尼对生活质量的益处，如果是的话，开发一种有效的工具来 比较这种药物和未来药物的有效性。为了回答生物学问题，我们将在全基因组范围内进行 治疗前和治疗中肿瘤活检组织的特征(基因、甲基化、微RNA和蛋白质) 验证我们最近确定的潜在反应生物标记物的靶点。一旦独立验证 我们希望开发一种配套的诊断测试，为这种药物选择合适的患者。改进，改进 目前的成像方式(即RECIST)在这种疾病中，我们正在研究MRI信号特征以 量化和标准化T2信号的变化，作为一种准确的工具来衡量未来药物在这方面的疗效 疾病。最后，我们正在开发和验证新的生活质量和患者报告结果工具 疾病获取的临床益处没有充分反映在肿瘤的维度变化中。通过坚持 达到最高的监管标准(随机、盲目、安慰剂)，这一新的QOL/PRO工具为 一种衡量这种疾病药物疗效的创新终点。这项第三阶段研究试图回答 以前瞻性和统计稳健的方式提出重要问题。这些相关的研究构成了基础 为这笔RFA-FD-13-001赠款申请的资金。

A Phase III, Double Blind, Randomized, Placebo-Controlled Trial of Sorafenib in Desmoid Tumors or Aggressive Fibromatosis (DT/DF) (NSC# 091105, IND116279, 12/2/2013) Desmoid tumor (DT/DF) is a sarcoma of fibroblastic origin that afflicts children, adolescents and adults and has a median age of onset of 30 years1. Desmoid tumors can occur in any anatomic location and threatens vital organs and limbs which often results in significant morbidity from organ failure, mutilating surgeries (and amputations), loss of limb function, pain and death2,3. There is no standard of care for the treatment of DT/DF. Surgery is associated with high rates of recurrences (~40%)4,5. In advanced disease, systemic therapies range from anti-estrogens to cytotoxic chemotherapies with variable response rates however no systemic therapies have been demonstrated to improve survival or quality of life in this orphan disease6. DT/DF over express c-KIT and PDGFR and a Phase II study of imatinib showed a disappointing partial response (PR) rate of 6%14. Extrapolating this, the principal investigator of this application (Mrinal Gounder) treated an index patient: a 37 year old woman who presented with a large unresectable, intra- thoracic desmoids tumor with sorafenib. Sorafenib is a multi-target kinase inhibitor of BRAF, PDGFR and VEGFR and available through a compassionate use, expanded access program. Sorafenib has a current FDA orphan indication for renal, liver and thyroid cancers. At presentation the patient's desmoid tumor shifted her mediastinum and presented a high risk for cardiopulmonary collapse and sudden death (Figure 1). The patient was oxygen dependent and unable to ambulate more than 30 feet. Following administration of sorafenib, this young woman became independent of oxygen within 4 weeks, began to ambulate and within 3 months returned to work. She remains on sorafenib almost 4 years later. This partial response and dramatic clinical benefit prompted the applicant and colleagues at MSKCC to evaluate the single institution experience of sorafenib in 26 additional patients. We reported a 25% partial response (< 30% by size, durable for >4 yrs) and improvement of symptoms in 70% of patients. We reported that patients who had stable disease but reported subjective improvement in symptoms demonstrated decrease in the MRI T2 signal intensity. The central hypothesis of this proposal is that sorafenib will lead to improved progression free survival, objective responses and improvement in symptoms and function. This is a national, Phase III, randomized, double-blind, placebo-controlled trial of sorafenib in DT patients. Patients on placebo will cross over at progression. The study will enroll 75 patients to detect a PFS difference of 9 months between the sorafenib arm (15 months) and placebo arm (6 months) which represents a hazard ratio of 0.4. The sample size will have 90% power at a 1-sided significance level of 0.025 to detect this difference. Should the study meet this primary endpoint, it will be the first Phase III trial to identify an active agent in this orphan disease and will provide pivotal data needed for a new indication by FDA. Many questions remain unanswered regarding the use of sorafenib in DT. These include: 1) mechanism of action of sorafenib in DT, 2) the lack of a predictive biomarker of response, 3) the significance of decrease in MRI T2 signal and whether this represents a better imaging modality to assess drug efficacy and 4) to quantitate the magnitude of benefit in quality of life with sorafenib and if so, to develop a validated tool to compare effectiveness of this and future drugs. To answer biological questions, we will conduct genome-wide characterization (gene, methylation, microRNA and protein) of pre- and on-treatment tumor biopsies to validate targets we have recently identified as potential biomarkers of response. Once independently validated we hope to develop a companion diagnostic test to select appropriate patients for this drug. To improve upon current imaging modalities (i.e RECIST) in this disease, we are investigating MRI signal characteristics to quantitate and standardize changes in T2 signal as an accurate tool to measure efficacy of future drugs in this disease. Lastly, we are developing and validating new quality of life and patient reported outcome tools in this disease to capture clinical benefit that is not adequately reflected in tumor dimensional changes. By adhering to the highest regulatory standards (randomized, blinded, placebo), this new QOL/PRO tool sets the stage for an innovative endpoint to measure drug efficacy in this disease. This Phase III study attempts to answer important questions in a prospective and statistically robust manner. These correlative studies form the basis of the funding requested for this RFA-FD-13-001grant.