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.

中文翻译：

---

DKN-01 作为单一疗法或与多西他赛联合治疗转移性去势抵抗性前列腺癌 (mCRPC) 的 1/2 期多中心试验

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) 中表达上调。 DKN-01 是一种中和 DKK1 的 IgG4，可在临床前 DKK1 表达模型中延迟 PCa 生长。这些数据为在转移性去势抵抗性 PCa (mCRPC) 患者中测试 DKN-01 的临床试验提供了理论基础。

方法

这是一项由研究者发起的平行臂 1/2 期临床试验，测试 DKN-01 单独使用（单一疗法）或与多西他赛 75 mg/m ²联合使用（联合疗法），用于治疗使用≥1种 AR 信号抑制剂进展的 mCRPC 男性。 DKK1 状态通过 RNA 原位表达来确定。 1 期剂量递增队列的主要终点是确定推荐的 2 期剂量 (RP2D)。 2 期扩展队列的主要终点是根据 iRECIST 标准，联合治疗患者的客观缓解率。

结果

18 名患者参加了这项研究——其中 10 名患者属于单一疗法队列，8 名患者属于联合疗法队列。未观察到 DLT，并将 DKN-01 600 mg 确定为 RP2D。在单一疗法队列中，七分之二 (29%) 的可评估患者中出现了疾病稳定的最佳总体反应。在联合队列中，七名可评估患者中有五名 (71%) 出现部分缓解 (PR)。在联合队列中观察到的中位 rPFS 为 5.7 个月。在联合队列中，肿瘤 DKK1 表达 H 评分中位数为 0.75，并且 DKK1 H 评分≥1 与 H 评分 = 0 的患者之间观察到的 rPFS 相似。

结论

DKN-01 600 mg 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。在联合队列中观察到抗肿瘤活性，但反应持续时间有限。大多数 mCRPC 中的 DKK1 表达较低，并且与 DKN-01 加多西紫杉醇的抗肿瘤活性没有明显相关性。