Abstract：
BACKGROUND: This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma.
METHODS: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients.
RESULTS: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study.
CONCLUSIONS: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.
METHODS: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients.
RESULTS: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study.
CONCLUSIONS: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.
摘要：
背景：这是一个单臂，巴伐利亚北欧（BN）-Brachyury疫苗加放疗（RT）的2期临床试验，旨在确定客观反应率（ORR），无进展生存期（PFS），以及脊索瘤联合用药的安全性。
方法：对29例晚期脊索瘤成年患者进行了两次皮下引发疫苗剂量的改良安卡拉-巴伐利亚北欧牛痘（MVA-BN）-Brachyury和一次疫苗剂量的鸡痘病毒（FPV）-Brachyury在RT之前。RT之后,每4周给予FPV-Brachyury加强疫苗接种，共4剂，然后每12周（第110周）。对于每个靶标,需要在一个部分中>8Gy的最小RT剂量。通过改良的实体瘤反应评估标准1.1（mRECIST）评估反应，只有辐射损伤被认为是目标，并通过标准RECIST1.1在一部分患者中进行。
结果：26名可评估患者中有2名经历了持久的部分反应（PR）（ORR为7.7％；90％置信区间[CI]，2.6-20.8])由mRECIST1.1。共有21例患者(80.8%;90%CI,65.4-90.3)病情稳定,根据mRECIST1.1,3例患者(11.5%;90%CI,4.7-25.6)的病情进展为最佳缓解。研究期间未达到PFS中位数。
结论：该试验证实了BN-Brachyury和RT的安全性。尽管该研究未达到29名患者的四个反应的预定研究目标，我们确实观察到两个PR和大于2年的PFS.对于一项基于疫苗的脊索瘤研究，一种反应率很低的超罕见疾病，可能需要随机研究或新的试验设计来确认活性.
方法：对29例晚期脊索瘤成年患者进行了两次皮下引发疫苗剂量的改良安卡拉-巴伐利亚北欧牛痘（MVA-BN）-Brachyury和一次疫苗剂量的鸡痘病毒（FPV）-Brachyury在RT之前。RT之后,每4周给予FPV-Brachyury加强疫苗接种，共4剂，然后每12周（第110周）。对于每个靶标,需要在一个部分中>8Gy的最小RT剂量。通过改良的实体瘤反应评估标准1.1（mRECIST）评估反应，只有辐射损伤被认为是目标，并通过标准RECIST1.1在一部分患者中进行。
结果：26名可评估患者中有2名经历了持久的部分反应（PR）（ORR为7.7％；90％置信区间[CI]，2.6-20.8])由mRECIST1.1。共有21例患者(80.8%;90%CI,65.4-90.3)病情稳定,根据mRECIST1.1,3例患者(11.5%;90%CI,4.7-25.6)的病情进展为最佳缓解。研究期间未达到PFS中位数。
结论：该试验证实了BN-Brachyury和RT的安全性。尽管该研究未达到29名患者的四个反应的预定研究目标，我们确实观察到两个PR和大于2年的PFS.对于一项基于疫苗的脊索瘤研究，一种反应率很低的超罕见疾病，可能需要随机研究或新的试验设计来确认活性.
