David R Wise, Russell K Pachynski, Samuel R Denmeade, Rahul R Aggarwal, Jiehui Deng, Victor Adorno Febles, Arjun V Balar, Minas P Economides, Cynthia Loomis, Shanmugapriya Selvaraj, Michael Haas, Michael H Kagey, Walter Newman, Jason Baum, Andrea B Troxel, Sarah Griglun, Dayna Leis, Nina Yang, Viktoriya Aranchiy, Sabrina Machado, Erika Waalkes, Gabrielle Gargano, Nadia Soamchand, Amrutesh Puranik, Pratip Chattopadhyay, Ezeddin Fedal, Fang-Ming Deng, Qinghu Ren, Luis Chiriboga, Jonathan Melamed, Cynthia A Sirard, Kwok-Kin Wong
{"title":"DKN-01单药或与多西他赛联合治疗转移性耐受性前列腺癌（mCRPC）的1/2期多中心试验。","authors":"David R Wise, Russell K Pachynski, Samuel R Denmeade, Rahul R Aggarwal, Jiehui Deng, Victor Adorno Febles, Arjun V Balar, Minas P Economides, Cynthia Loomis, Shanmugapriya Selvaraj, Michael Haas, Michael H Kagey, Walter Newman, Jason Baum, Andrea B Troxel, Sarah Griglun, Dayna Leis, Nina Yang, Viktoriya Aranchiy, Sabrina Machado, Erika Waalkes, Gabrielle Gargano, Nadia Soamchand, Amrutesh Puranik, Pratip Chattopadhyay, Ezeddin Fedal, Fang-Ming Deng, Qinghu Ren, Luis Chiriboga, Jonathan Melamed, Cynthia A Sirard, Kwok-Kin Wong","doi":"10.1038/s41391-024-00798-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC).</p><p><strong>Methods: </strong>This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m<sup>2</sup> (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination.</p><p><strong>Results: </strong>18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0.</p><p><strong>Conclusion: </strong>DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. 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引用次数: 0
摘要
背景：Dickkopf相关蛋白1（DKK1）是一种Wingless相关整合位点（Wnt）信号调节剂，在雄激素受体表达较低的前列腺癌（PCa）中上调。DKN-01是一种能中和DKK1的IgG4，它能延缓临床前DKK1表达模型中PCa的生长。这些数据为在转移性耐受阉割 PCa（mCRPC）患者中测试 DKN-01 的临床试验提供了依据：这是一项由研究者发起的并行臂1/2期临床试验，测试DKN-01单药（单药治疗）或与多西他赛75 mg/m2联用（联用）治疗使用≥1种AR信号抑制剂后病情进展的男性mCRPC患者。DKK1状态通过RNA原位表达确定。1期剂量升级队列的主要终点是确定2期推荐剂量（RP2D）。2期扩大队列的主要终点是根据iRECIST标准确定接受联合疗法治疗的患者的客观反应率：研究共招募了18名患者，其中10名患者接受了单药治疗，8名患者接受了联合用药治疗。未观察到 DLT，DKN-01 600 mg 被确定为 RP2D。在单药治疗组中，7 名可评估患者中有 2 名（29%）出现了疾病稳定的最佳总体反应。在联合用药队列中，七名可评估患者中有五名（71%）出现了部分应答（PR）。联合用药队列的中位 RPFS 为 5.7 个月。在联合用药队列中，肿瘤 DKK1 表达 H 评分中位数为 0.75，DKK1 H 评分≥1 与 H 评分=0.结论相似：DKN-01 600毫克的耐受性良好。作为mCRPC的单一疗法，DKK1阻断具有适度的抗肿瘤活性。在联合用药队列中观察到了抗肿瘤活性，但反应持续时间有限。大多数mCRPC的DKK1表达量较低，与DKN-01加多西他赛的抗肿瘤活性并无明显关联。
A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).
Background: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC).
Methods: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination.
Results: 18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0.
Conclusion: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
期刊介绍：
Prostate Cancer and Prostatic Diseases covers all aspects of prostatic diseases, in particular prostate cancer, the subject of intensive basic and clinical research world-wide. The journal also reports on exciting new developments being made in diagnosis, surgery, radiotherapy, drug discovery and medical management.
Prostate Cancer and Prostatic Diseases is of interest to surgeons, oncologists and clinicians treating patients and to those involved in research into diseases of the prostate. The journal covers the three main areas - prostate cancer, male LUTS and prostatitis.
Prostate Cancer and Prostatic Diseases publishes original research articles, reviews, topical comment and critical appraisals of scientific meetings and the latest books. The journal also contains a calendar of forthcoming scientific meetings. The Editors and a distinguished Editorial Board ensure that submitted articles receive fast and efficient attention and are refereed to the highest possible scientific standard. A fast track system is available for topical articles of particular significance.
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