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A Phase IIa, Non-Randomized, Open-Label Dose Expansion Trial of Isunakinra in Combination with Pembrolizumab in Patients with Metastatic or Unresectable, Locally Advanced Colorectal Cancer

This study will enroll patients with colorectal cancer that is locally advanced or metastatic. The tumor must be microsatellite stable (MSS), have a tumor mutational burden that is high (TMB-H) and be kras mutated. Patients must have been treated with available approved treatments already. In this study the investoigators are testing a new type of immunotherapy aclled isunakinra to be added to already approved immunotherapy (PD-1/PD-L1 inhibitor) in an attempt to get this otherwise effective treatment to work on this treatment resistant type of tumor.

开始日期2024-12-15

申办/合作机构

Buzzard Pharmaceuticals AB

NCT04121442 / Completed临床1/2期

Phase I/IIa, Non-Randomised, Open-Label Dose Escalation and Expansion Trial With Isunakinra Alone and in Combination With a PD-1/PD-L1 Inhibitor in Patients With Metastatic or Unresectable, Locally Advanced Malignant Solid Tumors

Isunakinra - a potent Interleukin-1 receptor inhibitor - will be given to patients with solid tumors to determine safety and tolerability of three different doses. Isunakinra will then be combined with a PD-(L)1 inhibitor. Pharmacokinetics and Pharmacodynamic effects of monotherapy treatment as well as the combination will be evaluated.

开始日期2020-09-01

申办/合作机构

Buzzard Pharmaceuticals AB

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2

项与 Buzzard Pharmaceuticals AB 相关的文献（医药）

2023-06-01·Journal of Clinical Oncology

A phase I study of isunakinra, an IL-1 alfa/beta inhibitor, in combination with nivolumab for patients with solid tumors refractory to standard therapies.

作者: Becerra, Carlos Roberto ; Kowalski, Jan ; Paulson, Andrew Scott ; Olivecrona, Hans ; de Chateau, Maarten

e14580 Background: Interleukin-1 is a master cytokine produced by macrophages (IL-1 β) and released upon cell death (IL-1 α). IL-1 upregulates other cytokines in the tumor microenvironment (i.e. IL-6 and IL-8), drives chronic non-resolving inflammation in the tumor, induces cancer cell invasion and metastasis (EMT), has profound effects on immune cells and cancer associated fibroblasts and can attract granulocytic myeloid suppressor cells to the tumor (PMN-MDSC), that in turn inhibit cytotoxic T cell responses. Isunakinra is a small recombinant protein resembling IL-1Ra, with an inhibitory potency 10-20 times higher, that binds to the IL1-R1 and blocks activation of the receptor by both IL-1α and IL-1β. We conducted a phase I dose escalation study with isunakinra as monotherapy and in combination with a PD-1 inhibitor in patients with locally advanced or metastatic solid tumors that had exhausted all treatment options. Methods: Enrolled patients with refractory metastatic solid tumor, ECOG 0-2, on a 3 + 3 dose-escalation trial at three dose levels of isunakinra (15, 25 or 50 mg). Isunakinra was self-administered once daily SC for three weeks followed by 4 additional weeks in combination with nivolumab Q4W at 480 mg, flat dose to complete the DLT period of 7 weeks. Thereafter, isunakinra/nivolumab was continued until week 28. Primary endpoints: DLTs, safety, and pharmacokinetics. Secondary endpoints: tumor and immune monitoring. Results: Enrolled fifteen patients with metastatic or unresectable locally advanced solid tumors (colorectal, pancreatic, triple-negative BC, anal, prostatic, CCA, and appendix) that had received 2-5 prior lines of therapy. Seven SAE occurred in three rapidly deteriorating subjects, all disease related hospitalizations, leading to study withdrawal during the DLT period. No DLTs, irAE or predefined laboratory deviations occurred in any subject. The highest dose, 50 mg, was selected as RP2D. Twelve subjects completed visit week 8, six of them week 12, and four completed the trial. One patient with metastatic colon cancer (MSS, KRAS mut, high TMB) was granted extended treatment for PR and continued response at end of study. Isunakinra exposure totaled 1575 daily doses, 81% during combination with nivolumab, t 1/2 5 hours with no accumulation over time. At 50mg of isunakinra, plasma levels where well above 100 ng/mL, a target for complete IL-1 inhibition. Conclusions: Isunakinra is safe and well-tolerated in combination with standard dose nivolumab. Ongoing expansion cohorts and future studies will explore the safety and efficacy of isunakinra in specific tumors and with other immunotherapy combinations. Clinical trial information: NCT04121442 .

Cancers

Non-Oncogene Addiction of KRAS-Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ

Article

作者: Hatz, Rudolph A. ; de Château, Maarten ; Giopanou, Ioanna ; Yull, Fiona E. ; Pepe, Mario A. A. ; Petrera, Agnese ; Arendt, Kristina A. M. ; Jenne, Dieter E. ; Lindner, Michael ; Behr, Juergen ; Bouloukou, Eleni ; Hauck, Stefanie M. ; Giotopoulou, Georgia A. ; Skiadas, Georgios ; Vreka, Malamati ; Ntaliarda, Giannoula ; Lilis, Ioannis ; Savai, Rajkumar ; Koch, Ina ; Spella, Magda ; Weiss, Stefanie A. I. ; Stathopoulos, Georgios T. ; Lamort, Anne-Sophie ; Brunn, David ; Marazioti, Antonia ; Blackwell, Timothy S.

Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.

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