Falchook Gerald, Infante Jeffrey, Arkenau Hendrik-Tobias, Patel Manish R, Dean Emma, Borazanci Erkut, Brenner Andrew, Cook Natalie, Lopez Juanita, Pant Shubham, Frankel Arthur, Schmid Peter, Moore Kathleen, McCulloch William, Grimmer Katharine, O'Farrell Marie, Kemble George, Burris Howard
Sarah Cannon Research Institute at HealthONE, 1800 Williams St Ste 300, Denver, CO, 80218, United States.
Tennessee Oncology, 250 25th Ave N #100, Nashville, TN 37203, United States.
EClinicalMedicine. 2021 Mar 30;34:100797. doi: 10.1016/j.eclinm.2021.100797. eCollection 2021 Apr.
We conducted a first-in-human dose-escalation study with the oral FASN inhibitor TVB-2640 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as monotherapy and with a taxane.
This completed open-label outpatient study was conducted at 11 sites in the United States and United Kingdom. Patients with previously-treated advanced metastatic solid tumors and adequate performance status and organ function were eligible. TVB-2640 was administered orally daily until PD. Dose escalation initially followed an accelerated titration design that switched to a standard 3 + 3 design after Grade 2 toxicity occurred. Disease-specific cohorts were enrolled at the MTD. Statistical analyses were primarily descriptive. Safety analyses were performed on patients who received at least 1 dose of study drug. (Clinicaltrials.gov identifier NCT02223247).
The study was conducted from 21 November 2013 to 07 February 2017. Overall, 136 patients received TVB-2640, 76 as monotherapy (weight-based doses of 60 mg/m to 240 mg/m and flat doses of 200 and 250 mg) and 60 in combination, (weight-based doses of 60 mg/m to 100 mg/m and flat dose of 200 mg) (55 paclitaxel, 5 docetaxel). DLTs with TVB-2640 were reversible skin and ocular effects. The MTD/RP2D was 100 mg/m. The most common TEAEs (n,%) with TVB-2640 monotherapy were alopecia (46; 61%), PPE syndrome (35; 46%), fatigue (28; 37%), decreased appetite (20; 26%), and dry skin (17; 22%), and with TVB-2640+paclitaxel were fatigue (29 ; 53%), alopecia (25; 46%), PPE syndrome (25; 46%), nausea (22; 40%), and peripheral neuropathy (20; 36%). One fatal case of drug-related pneumonitis occurred with TVB-2640+paclitaxel; no other treatment-related deaths occurred. Target engagement (FASN inhibition) and inhibition of lipogenesis were demonstrated with TVB-2640. The disease control rate (DCR) with TVB-2640 monotherapy was 42%; no patient treated with monotherapy had a complete or partial response (CR or PR). In combination with paclitaxel, the PR rate was 11% and the DCR was 70%. Responses were seen across multiple tumor types, including in patients with KRAS NSCLC, ovarian, and breast cancer.
TVB-2640 demonstrated potent FASN inhibition and a predictable and manageable safety profile, primarily characterized by non-serious, reversible adverse events affecting skin and eyes. Further investigation of TVB-2640 in patients with solid tumors, particularly in KRAS lung, ovarian, and breast cancer, is warranted.
This trial was funded by 3-V Biosciences, Inc. (now known as Sagimet Biosciences Inc.).
我们开展了一项口服脂肪酸合酶（FASN）抑制剂TVB - 2640的首次人体剂量递增研究，以确定最大耐受剂量（MTD）和推荐的2期剂量（RP2D），分别作为单一疗法以及与紫杉烷联合使用时的剂量。
这项已完成的开放标签门诊研究在美国和英国的11个地点进行。既往接受过治疗的晚期转移性实体瘤患者，且体能状态和器官功能良好者符合入组条件。TVB - 2640每日口服给药，直至疾病进展（PD）。剂量递增最初采用加速滴定设计，在出现2级毒性后改为标准的3 + 3设计。在MTD剂量水平纳入特定疾病队列。统计分析主要为描述性分析。对接受至少1剂研究药物的患者进行安全性分析。（Clinicaltrials.gov标识符NCT02223247）。
该研究于2013年11月21日至2017年2月7日进行。总体而言，136例患者接受了TVB - 2640治疗，其中76例接受单一疗法（基于体重的剂量为60mg/m²至240mg/m²，固定剂量为200mg和250mg），60例接受联合治疗（基于体重的剂量为60mg/m²至100mg/m²，固定剂量为200mg）（55例联合紫杉醇，5例联合多西他赛）。TVB - 2640引起的剂量限制性毒性（DLT）为可逆性皮肤和眼部效应。MTD/RP2D为100mg/m²。TVB - 2640单一疗法最常见的治疗期间出现的不良事件（TEAE）（n，%）为脱发（46；61%）、掌跖红细胞感觉障碍（PPE）综合征（35；46%）、疲劳（28；37%）、食欲减退（20；26%）和皮肤干燥（17；22%），TVB - 2640与紫杉醇联合治疗时为疲劳（29；53%）、脱发（25；46%）、PPE综合征（25；46%）、恶心（22；40%）和周围神经病变（20；36%）。TVB - 2640与紫杉醇联合治疗时发生1例与药物相关的致命性肺炎；未发生其他与治疗相关的死亡。TVB - 2640证实有靶点作用（FASN抑制）和脂肪生成抑制作用。TVB - 2640单一疗法的疾病控制率（DCR）为42%；接受单一疗法治疗的患者无完全缓解（CR）或部分缓解（PR）。与紫杉醇联合治疗时，PR率为11%，DCR为70%。在多种肿瘤类型中均观察到缓解，包括KRAS非小细胞肺癌（NSCLC）、卵巢癌和乳腺癌患者。
TVB - 2640显示出强效的FASN抑制作用以及可预测和可管理的安全性特征，主要表现为影响皮肤和眼睛的非严重、可逆性不良事件。有必要对TVB - 2640在实体瘤患者中，特别是KRAS肺癌、卵巢癌和乳腺癌患者中进行进一步研究。
本试验由3 - V生物科学公司（现称为Sagimet生物科学公司）资助。
