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)

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发表日期：

2024年2月10日

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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

摘要

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.