A Phase I/IB, Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics and Efficacy of Pembrolizumab in Combination With Vorinostat in Patients With Advanced Prostate, Renal or Urothelial Carcinoma

IF 3.1 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2025-03-27 DOI:10.1002/cam4.70725

Roberto Pili, David I. Quinn, Nabil Adra, Theodore Logan, Sean Colligan, Heather N. Burney, Noah M. Hahn

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Abstract

Background

Immunosuppressive factors such as regulatory T cells and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial (UC), renal (RCC) and prostate (PCA) carcinoma.

Methods

The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and 1 week OFF) and a fixed dose of pembrolizumab (200 mg IV every 21 days). Patients (pts) were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve UC and RCC), Cohort B (previously treated, anti-PD1/PD-L1 resistant UC and RCC pts), and Cohort C (PCA pts).

Results

Dose levels 1 and 2 were completed without DLTs. We have enrolled 44 pts. (36 evaluable) in the dose expansion cohorts, and the most common resolved grade 3/4 toxicities were diarrhea, hypophosphatemia, acute kidney injury, anemia, and hypothyroidism. For Cohort A (13 pts), B (11 pts), and C (12 pts) the objective response rate was 8%, 0%, and 17%, and the median progression-free survival was 2.9, 3.5, and 3.5 months, respectively. Four partial responses were observed, and two PCA pts. had a complete biochemical response with undetectable PSA. Persistent lower levels of peripheral CD11⁺, CD14⁺ HLA-DR⁻ monocytic MDSCs were associated with clinical benefit.

Conclusion

The combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint-resistant UC/RCC pts. and immune checkpoint-naïve PCA pts.

Trial Registration: NCT02619253

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一项I/IB期、开放标签、剂量发现研究评估派姆单抗联合伏立诺他治疗晚期前列腺癌、肾癌或尿路上皮癌患者的安全性、药效学和疗效

免疫抑制因子如调节性T细胞和髓源性抑制细胞（MDSCs）限制了免疫治疗的效果。组蛋白去乙酰化酶（HDAC）抑制剂已被证明具有免疫调节作用。因此，我们对转移性尿路上皮癌（UC）、肾癌（RCC）和前列腺癌（PCA）患者进行了一项使用HDAC抑制剂vorinostat和PD-1抑制剂pembrolizumab的Ib期临床研究。方法I期部分包括两个剂量水平的伏立诺他（100和200 mg， PO每日2周ON和1周OFF）和固定剂量的派姆单抗（200 mg IV每21天）。患者（pts）被分配到三个队列：队列A（先前治疗过，抗pd1 /PD-L1 naïve UC和RCC），队列B（先前治疗过，抗pd1 /PD-L1耐药UC和RCC患者）和队列C （PCA患者）。结果1、2个剂量水平均未出现dlt。我们招收了44名学生。（36例可评估），最常见的3/4级缓解毒性是腹泻、低磷血症、急性肾损伤、贫血和甲状腺功能减退。队列A（13名患者）、B（11名患者）和C（12名患者）的客观缓解率分别为8%、0%和17%，中位无进展生存期分别为2.9个月、3.5个月和3.5个月。观察到四个部分反应，两个PCA患者。有完全的生化反应，PSA检测不到。持续降低外周血CD11+、CD14+ HLA-DR -单核细胞MDSCs水平与临床获益相关。结论伏立诺他联合派姆单抗耐受性相对较好，可能对免疫检查点耐药的UC/RCC患者有效。免疫checkpoint-naïve PCA患者。试验注册：NCT02619253

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.