Phase 1b Dose Escalation and Dose Expansion Trial of DV281 in Combination With an Approved Anti-PD-1 Inhibitor in Subjects With Advanced Non-Small Cell Lung Cancer

This open-label, multicenter, dose-escalation and expansion trial is designed to evaluate the safety and preliminary efficacy of inhaled DV281 in combination with nivolumabfor the treatment of NSCLC and to select a recommended phase 2 dose (RP2D).

开始日期2017-09-20

申办/合作机构

Dynavax Technologies Corp.

100 项与 DV-281 相关的临床结果

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100 项与 DV-281 相关的转化医学

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100 项与 DV-281 相关的专利（医药）

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项与 DV-281 相关的文献（医药）

2021-08-15·Clinical Cancer Research1区 · 医学

A Phase Ib Open-Label, Multicenter Study of Inhaled DV281, a TLR9 Agonist, in Combination with Nivolumab in Patients with Advanced or Metastatic Non–small Cell Lung Cancer

1区 · 医学

Article

作者: Spira, Alexander I. ; Coffman, Robert L. ; Leach, Joseph ; Janatpour, Mary J. ; Garon, Edward B. ; Cummings, Amy L. ; Bazhenova, Lyudmila ; Candia, Albert ; Johnson, Melissa ; Janssen, Robert ; Chow, Laura Q.M. ; Gamelin, Erick

AbstractPurpose:Although PD-(L)1 inhibitors have shown efficacy in advanced/metastatic non–small cell lung cancer (NSCLC), many patients do not respond to this treatment and more effective combinations with acceptable toxicities are needed. To assess the potential benefit of combining localized innate immune stimulation with checkpoint blockade, the TLR9 agonist DV281 was combined with nivolumab in a phase Ib study.Patients and Methods:Patients after one or two prior lines of systemic therapy were enrolled in a dose-escalation study with a 3+3 design. DV281 was administered via inhalation in five dose cohorts at 1 to 25 mg; nivolumab 240 mg was administered intravenously every 2 weeks. Safety, tolerability, pharmacodynamics, and response to treatment were assessed.Results:Twenty-six patients with advanced NSCLC enrolled. Baseline programmed death ligand 1 (PD-L1) expression was present in 16 patients (61.5%); 21 (80.7%) had received previous anti–PD-1/PD-L1. Thirteen patients (50%) had stable disease, nine (34.6%) had progressive disease, and four (15.4%) were not evaluable. Median duration of disease control was 124 days. Adverse events were seen in 16 patients (61.5%), mostly grade 1/2 chills, fatigue, flu-like symptoms, diarrhea, and rash; there was only one grade 3 adverse event (dyspnea). Pharmacodynamic assessment, measured by IFN- inducible gene expression, showed target engagement in all dose cohorts. Systemic pharmacodynamic responses plateaued in the 2 highest dose cohorts.Conclusions:DV281 with nivolumab was well tolerated with target engagement observed at every dose. Pharmacodynamic advantages at doses above 10 mg were unclear. The long duration of disease control in 50% of patients suggests clinically relevant activity in this population of heavily pretreated patients.

2019-01-01·International Immunopharmacology2区 · 医学

Preclinical development of the TLR9 agonist DV281 as an inhaled aerosolized immunotherapeutic for lung cancer: Pharmacological profile in mice, non-human primates, and human primary cells

2区 · 医学

Article

作者: Kell, Sariah A ; Traquina, Paula ; Renn, Alex ; Campbell, John D ; Coffman, Robert L ; Kachura, Melissa A

CpG-motif-containing oligodeoxynucleotides (CpG-ODN) activate innate immunity through Toll-Like Receptor (TLR) 9 signaling and generate local immune responses when delivered directly to the lung. Herein we describe pharmacological studies in mice, cynomolgus monkeys, and in human primary cells which support the development of DV281, a C-class CpG-ODN, as an inhaled aerosolized immunotherapeutic for lung cancer to be combined with an inhibitor of the anti-programmed cell death protein 1 (PD‑1) immune checkpoint. In vitro, DV281 potently induced Interferon (IFN)‑α from monkey and human peripheral blood mononuclear cells (PBMCs), stimulated interleukin‑6 production and proliferation in human B cells, and induced TLR9-dependent cytokine responses from mouse splenocytes. Intranasal delivery of DV281 to mice led to substantial but transient cytokine and chemokine responses in the lung. Lung responses to repeated intranasal DV281 were partially to fully reversible 2 weeks after the final dose and were absent in TLR9-deficient mice. Single escalating doses of aerosolized DV281 in monkeys induced dose-dependent induction of IFN-regulated genes in bronchoalveolar lavage cells and blood. In a repeat-dose safety study in monkeys, inhaled DV281 was well-tolerated, and findings were mechanism of action-related and non-adverse. Co-culture of human PBMC with DV281 and anti-PD‑1 antibody did not augment cytokine or cellular proliferation responses compared to DV281 alone, indicating that the combination did not lead to dysregulated cytokine responses. These studies support clinical development of inhaled aerosolized DV281 as a combination therapy with anti-PD‑1 antibody for lung cancer immunotherapy.

100 项与 DV-281 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床2期	-	Dynavax Technologies Corp.	-
晚期非小细胞肺癌	药物发现	美国	Dynavax Technologies Corp.	2017-09-20

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03326752 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	非小细胞肺癌二线	26	Nivolumab+DV281	(壓襯選壓襯構範積廠艱) = 鹹襯鬱衊壓鬱艱壓膚餘夢窪範鹽鏇鬱餘壓鏇顧 (餘範壓廠鬱簾膚簾餘窪 ) 更多	积极	2021-08-15