First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers.

Abstract

BACKGROUND:

With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors.

METHODS:

Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.i.d. The primary endpoint was safety, and the secondary endpoints included time-to-progression (TTP), overall survival (OS) and the clinical benefit rate (CBR). Icaritin treatment induced immune biomarkers and immune-modulating activities in myeloid cells were also explored.

RESULTS:

No drug-related adverse events ≥ Grade 3 were observed in all 20 enrolled HCC patients. Among the 15 evaluable patients, 7 (46.7%) achieved clinical benefit, representing one partial response (PR, 6.7%) and 6 stable disease (SD, 40%). The median TTP was 141 days (range: 20-343 days), and the median OS was 192 days (range: 33-1036 days). Durable survival was observed in PR/SD patients with a median OS of 488 days (range: 72-773). TTP was significantly associated with the dynamic changes of peripheral neutrophils (p = 0.0067) and lymphocytes (p = 0.0337). Icaritin treatment induced changes in immune biomarkers-and immune-suppressive myeloid cells were observed.

CONCLUSIONS:

Icaritin demonstrated safety profiles and preliminary durable survival benefits in advanced HCC patients, which were correlated with its immune-modulation activities and immune biomarkers. These results suggested the potential of icaritin as a novel oral immunotherapy for advanced HCC in addition to antibody-based PD-1/PD-L1 blockade therapies.

TRIAL REGISTRATION:

Clinicaltrial.gov identifier. NCT02496949 (retrospectively registered, July 14, 2015).

• Authors: Ying Fan, Shu Li, Xiaoyan Ding, Jian Yue, Jun Jiang, Hong Zhao, Rui Hao, Weiliang Qiu, Kezhen Liu, Ying Li, Shengdian Wang, Limin Zheng, Bin Ye, Kun Meng, Binghe Xu
• Journal: BMC cancer (BMC Cancer) Vol. 19 Issue 1 Pg. 279 (Mar 28 2019) ISSN: 1471-2407 [Electronic] England
• PMID: 30922248 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Biomarkers, Tumor
• Flavonoids
• icaritin

Topics

• Administration, Oral
• Adult
• Aged
• Biomarkers, Tumor (immunology)
• Carcinoma, Hepatocellular (drug therapy, immunology)
• Drug Administration Schedule
• Female
• Flavonoids (administration & dosage, adverse effects, pharmacology)
• Humans
• Liver Neoplasms (drug therapy, immunology)
• Lymphocytes (drug effects)
• Male
• Middle Aged
• Neutrophils (drug effects)
• Survival Analysis
• Treatment Outcome