Phase I study of chlorogenic acid injection for recurrent high-grade glioma with long-term follow-up
Open accessAbstract
Objective: This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid (CGA) in patients with recurrent high-grade glioma after standard of care treatments, through a first-in-human, open-label, dose-escalation phase I trial. Methods: A total of 26 eligible patients were enrolled, received intramuscular CGA injections at 5 dose levels, and were followed up for 5 years. CGA was well tolerated, and the maximum tolerated dose was 5.5 mg/kg. Results: The most common treatment-related adverse events occurred at the sites of injection. No grade 3 or 4 adverse events (e.g., drug allergy) were reported for these patients except for induration at the injection sites. A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma, with a t1/2 of 0.95–1.27 h on day 1 and 1.19–1.39 h on day 30, and no detectable CGA was observed on days 9, 11, 13, 23, 25, 27, and 29 before CGA administration. After the first treatment cycle, 52.2% of patients (12 of 23) achieved stable disease. Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients. Of the 18 patients with grade 3 glioma, the median overall survival was 9.5 months. Two patients remained alive at the cutoff day. Conclusions: This phase I study demonstrated that CGA has a favorable safety profile (with no severe toxicity), and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies, thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Xu, R., Qiumei, K., Ren, J., Li, Z., & Xiao-ping, X. (2013) · Journal of Analytical Methods in Chemistry · doi:10.1155/2013/951319 · Cited by 40 · see citing works
RetractedWen, P. Y., Macdonald, D. R., Reardon, D. A., Cloughesy, T. F., Sorensen, A. G., Galanis, E., DeGroot, J. F., Wick, W., Gilbert, M. R., Lassman, A. B., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.3541 · Cited by 3,814 · see citing works
Ohgaki, H. (2008) · Methods in molecular biology · doi:10.1007/978-1-60327-492-0_14 · Cited by 423 · see citing works
Galanis, E., Jaeckle, K. A., Maurer, M. J., Reid, J. M., Ames, M. M., Hardwick, J. S., Reilly, J. F., Loboda, A. P., Nebozhyn, M., Fantin, V. R., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.19.0694 · Cited by 360 · see citing works
Nonsurgical Treatment of Recurrent Glioblastoma
Gallego, O. S. (2015) · Current Oncology · doi:10.3747/co.22.2436 · Cited by 296 · see citing works
Rasmussen, B. K., Hansen, S., Laursen, R. J., Kosteljanetz, M., Schultz, H., Nørgård, B. M., Guldberg, R., & Gradel, K. O. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2607-5 · Cited by 280 · see citing works
Jin, U., Lee, J.-Y., Kang, S., Kim, J., Park, W., Kim, J.-G., Moon, S., & Kim, C. (2005) · Life Sciences · doi:10.1016/j.lfs.2005.02.028 · Cited by 221 · see citing works
Linde, M. E. V., Brahm, C. G., Hamer, P. C. D. W., Reijneveld, J. C., Bruynzeel, A. M. E., Vandertop, W. P., van de Ven, P. M., Wagemakers, M., van der Weide, H. L., Enting, R. H., et al. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2564-z · Cited by 198 · see citing works
Xue, N., Zhou, Q., Ji, M., Jin, J., Lai, F., Chen, J., Zhang, M., Jia, J., Yang, H., Zhang, J., et al. (2017) · Scientific Reports · doi:10.1038/srep39011 · Cited by 181 · see citing works
Self-citationEpidemiology, diagnosis, and optimal management of glioma in adolescents and young adults
Diwanji, T. P., Engelman, A., Snider, J. W., III, & Mohindra, P. (2017) · Adolescent Health Medicine and Therapeutics · doi:10.2147/ahmt.s53391 · Cited by 115 · see citing works
Rechallenge with temozolomide in patients with recurrent gliomas
Wick, A., Pascher, C., Wick, W., Jauch, T., Weller, M., Bogdahn, U., & Hau, P. (2009) · Journal of Neurology · doi:10.1007/s00415-009-5006-9 · Cited by 104 · see citing works
Bandyopadhyay, G. K., Biswas, T., Roy, K. C., Mandal, S., Mandal, C., Pal, B. C., Bhattacharya, S., Rakshit, S., Bhattacharya, D. K., Chaudhuri, U., et al. (2004) · Blood · doi:10.1182/blood-2003-11-4065 · Cited by 104 · see citing works
Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway
Park, J. J., Hwang, S. J., Park, J., et al. (2015) · Cellular Oncology · doi:10.1007/s13402-014-0216-2 · Cited by 98 · see citing works
Li, S., Chang, C., Fu-Ying, M. A., et al. (2009) · Biomedical and Environmental Sciences · doi:10.1016/s0895-3988(09)60034-9 · Cited by 94 · see citing works
Self-citationUhm, J. H. (2010) · Yearbook of Neurology and Neurosurgery · doi:10.1016/s0513-5117(10)79301-7 · Cited by 78 · see citing works
Wu, J., Chen, H., Li, H., Tang, Y., Yang, L., Cao, S.-S., & Qin, D.-L. (2016) · Molecules · doi:10.3390/molecules21030260 · Cited by 76 · see citing works
Wu, H., Luo, J., Yin, Y., et al. (2004) · PubMed · Cited by 37 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nguyen, V., Taine, E. G., Meng, D., Cui, T., & Tan, W. (2024) · Nutrients · doi:10.3390/nu16070924 · Cited by 385 · see citing works
“…ratio of Bax/Bcl-2 [276,277]; blockages of (1) p-STAT-5 and p-CrkL [283,287], (2) the NF-kb pathway [276], (3) the STAT3/Snail pathway [294,295], (4) the PI3K/Akt/mTORpathway[301],and EMT [276] CGA Cancer management in patients (Section 7.12) Patients with recurrent high-grade glioma [302] n.a. CGA”
BackgroundInfluentialTarget fishing and mechanistic insights of the natural anticancer drug candidate chlorogenic acid
Wang, Q., Du, T., Zhang, Z., Zhang, Q., Zhang, J., Li, W., Jiang, J., Chen, X., & Hu, H. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.07.005 · Cited by 45 · see citing works
“…few years, with the great improvement in the industrial scale of preparation and purification of CGA from raw plant extracts, CGA has become a novel agent, which has not only been tested in preclinical models but also in clinical trials for solid tumors in China (phase I, NCT02728349, Apr. 2016) 6 .”
Self-citationChlorogenic Acid’s Role in Metabolic Health: Mechanisms and Therapeutic Potential
Zalewska, K., Kulawik, M., Gierszewska, J., Gramala, Z., Kalus, O., Karpiński, M., Maćkowiak, J., Staniewski, A., Szymańska, Z., Zalewska, B., et al. (2025) · Nutrients · doi:10.3390/nu17203303 · Cited by 39 · see citing works
“These microbial metabolites can display different levels of bioactivity and bioavailability compared to the parent compound, and in some cases, they may mediate part of CGA’s antioxidant, vasoprotective, or anti-inflammatory effects observed in vivo [175–177].”
Lin, C.-H., Jiang, W., Itokazu, N., & Huang, G. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117982 · Cited by 32 · see citing works
Harnessing phytochemicals: Innovative strategies to enhance cancer immunotherapy
Zhu, Q., Zhang, R., Zhao, Z., Xie, T., & Sui, X. (2025) · Drug Resistance Updates · doi:10.1016/j.drup.2025.101206 · Cited by 28 · see citing works
Yuan, Q., Liu, C., Zhang, Z., Chen, F., Xiao, Q., Zhang, L., Pan, X., He, F., & Xiao, M. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1613048 · Cited by 27 · see citing works
Self-citationLi, R., Zhan, Y., Ding, X., Cui, J.-J., Han, Y.-X., Zhang, J.-L., Zhang, J., Li, W.-B., Wang, L.-L., & Jiang, J.-D. (2024) · International Journal on Biological Sciences · doi:10.7150/ijbs.83599 · Cited by 27 · see citing works
“Our Phase I clinical trial (using the intramuscular injection formula) showed that CGA was very well tolerated and demonstrated a significant overall survival benefit for the patients with recurrent high-grade glioma [27].”
MethodSelf-citationScuto, M. C., Lombardo, C. M. G., Sasso, B. L., Fatta, E. D., Ferri, R., & Salinaro, A. T. (2025) · Toxics · doi:10.3390/toxics13060438 · Cited by 17 · see citing works
Polyphenols: Potential Applications in Cancer Therapy
Oriol-Caballo, M., Moreno-Murciano, M., López-Blanch, R., Estrela, J., & Obrador, E. (2025) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.70011 · Cited by 14 · see citing works
Zhang, H., Wang, Y., Yuan, X., Zou, Y., & Xiong, H. (2024) · Oncology and Translational Medicine · doi:10.1097/ot9.0000000000000028 · Cited by 11 · see citing works
Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems
Loeffler, D. A. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240212 · Cited by 12 · see citing works
Wang, J., Li, S., Chen, Y., Chen, J., Wang, C., Kang, Z., Huang, M., Cai, Z., Fan, Y., Lan, Y., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1494806 · Cited by 8 · see citing works
“According to the research results on the ef fi cacy and safety of CHA in treating high-grade gliomas (CTR20160113), CHA has good safety and provides preliminary clinical bene fi ts for high-grade glioma patients who relapse after receiving standard therapy (20).”
Self-citationRepurposing Clemastine to Target Glioblastoma Cell Stemness
Sun, M. A., Yang, R. R., Liu, H., Wang, W., Song, X., Hu, B., Reynolds, N., Roso, K., Chen, L. H., Greer, P. K., et al. (2023) · Cancers · doi:10.3390/cancers15184619 · Cited by 9 · see citing works
Sarker, S., & Newland, B. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.125935 · Cited by 7 · see citing works
“One phase I clinical trial used chlorogenic acid as a monotherapy in patients with different grades of glioma, achieving a median survival of only 11.3 months for all patients and 9.5 months for high grade glioma (Kang et al., 2023).”
InfluentialRe‐Innovation in Clinical Trial Designs Based on Precision Therapy
Li, S., Wang, J., Kang, Z., Kang, X., Chen, F., & Li, W. (2025) · Cancer Innovation · doi:10.1002/cai2.70028 · Cited by 7 · see citing works
“Notably, in glioblastoma patients, CHA treatment demonstrated a median OS of 11.3 months ‐ a significant improvement over standard therapy (5.7 – 7.5 months) [28].”
InfluentialSelf-citationVladimir‐Knežević, S., Štefan, M. B., Blažeković, B., Jelić, D., Petković, T., Mandić, M., Šprajc, E., & Lovković, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115512 · Cited by 6 · see citing works
“A phase I trial of chlorogenic acid injection demonstrated clinical benefits for patients with high-grade glioma, who had relapsed after previous standard therapies, and a favorable safety profile up to a dose of 5.5 mg/kg [76].”
BackgroundInfluentialBéjaoui, A., M’Rabet, Y., & Boulila, A. (2024) · Chemistry Africa · doi:10.1007/s42250-024-00985-4 · Cited by 6 · see citing works
Healthy and Unhealthy Plant-Based Diets and Glioma in the Chinese Population
Zhang, W., Yue, P., Kang, X., Wang, C., Chen, F., He, Y., & Li, W. (2023) · Brain Sciences · doi:10.3390/brainsci13101401 · Cited by 5 · see citing works
Self-citationDrug clinical trials on high-grade gliomas: challenges and hopes
Huang, M., Li, S., Li, P., et al. (2024) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2023.0364 · Cited by 5 · see citing works
“This completed trial has established the safety profile of CGA and its potential OS benefit 23 .”
BackgroundSelf-citationIsemura, M., Hayakawa, S., Ohishi, T., Miyoshi, N., Fukutomi, R., & Nakamura, Y. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47110898 · Cited by 3 · see citing works
“Kang et al. [110] conducted a phase I trial for CGA in injectable form in patients with recurrent high-grade glioma.”
Velázquez-Enríquez, J. M., Mendoza-Crisostomo, R. C., Reyes-Jiménez, E., et al. (2024) · Future Pharmacology · doi:10.3390/futurepharmacol4040042 · Cited by 1 · see citing works
Rao, X., Chen, Z., Qi, X., Sun, L., Wang, J., Guan, M., An, B., Wang, S., Lin, J., & Lin, L. (2026) · Phytotherapy Research · doi:10.1002/ptr.70175 · Cited by 2 · see citing works
Alenezi, H., Albrahim, J. S., El‐Gendi, H., Saleh, A. K., El‐Maradny, Y. A., & El‐Fakharany, E. M. (2026) · International Journal of Polymer Science · doi:10.1155/ijps/1309512 · Cited by 1 · see citing works
Progress in Pharmacological Activities and Biosynthetic Pathways of Chlorogenic Acid
Huang, W., Guo, Z., Cui, J., & Zhao, Y. (2026) · Natural Product Communications · doi:10.1177/1934578x251413503 · Cited by 1 · see citing works
“39,40 To address these limitations, researchers have endeavored to develop strategies to prolong the half-life and enhance the ef fi cacy of CGA.”
Microfluidic Construction of Glioma Micromodels on Hydrogel Microspheres for Drug Testing
Zhang, Y., Wu, Z., Li, J., Chen, S., Xu, T., Chen, S., Wang, X., Guo, Y., Zhang, Y., & Lin, J. (2026) · Engineering · doi:10.1016/j.eng.2026.01.010 · Cited by 1 · see citing works
Shen, X., Wang, Y., Lin, Y., et al. (2026) · Pharmaceuticals · doi:10.3390/ph19050782 · Cited by 1 · see citing works
Self-citationAghedi, M., Larijani, A., Bagheri, A. B., Rafiemanesh, H., Saraee, E., Mardi, S., & Shirani, M. (2025) · Neurosurgical Review · doi:10.1007/s10143-025-03632-9 · Cited by 1 · see citing works
Chemical modifications on biomacromolecules in cells: new exploration of drug design
Wang, X., & Jiang, J. (2025) · Scientia Sinica Chimica · doi:10.1360/ssc-2025-0180
Self-citationGhilane, F., Omari, N. E., Goh, K. W., Bourais, I., Bakri, Y., Btaouri, H. E., & Bouyahya, A. (2025) · Journal of Functional Foods · doi:10.1016/j.jff.2025.106991
Falsitta, L. V., & Pikula, A. (2026) · American Journal of Lifestyle Medicine · doi:10.1177/15598276261434176
“68,69 Despite robust dietary characterization and statistical controls, both studies were entirely observational and lacked neuroimaging data assessing tumor progression, structure, or metabolic changes in relation to diet.”
Qin, L., Cai, J., Lu, P., Chen, Y., Lu, H., Hou, R., Li, X., Pan, Y., Zhao, J., 黄艳军, et al. (2026) · Model Organisms Research · doi:10.1016/j.mores.2026.100003
Li, R. X., Hu, C., Zhou, P., Si, G., Cui, J., He, Y., Han, Y., Zhang, J., Li, W., Wang, L., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08538-8
“Recently, a Phase II clinical trial of CGA for recurrent high-grade glioma (NCT03758014) was completed, with Phase I results showing significant improvements in overall survival and a good safety profile [20].”
Self-citationRen, J., Yang, Y., Li, G., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1865654
The role of the gut-brain axis and polyphenolic compounds in glioblastoma
Agnihotram, B., Mutiu, I. N., Chiou, H., McGowen, K., & Mazewski, C. (2026) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2026.110484
Piermartiri, T., da Matta, A. C. A., Pinto, J. V. K., Tasca, C. I., & Nedel, C. B. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1984427
- Authors
- Kang, Z., Li, S., Kang, X., Deng, J., Yang, H., Chen, F., Jiang, J., Zhang, J., & Li, W.
- Affiliations
- Capital Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Zhang, Jie
- Li, Wenbin
- Venue
- Cancer Biology & Medicine
- Publisher
- China Anti-cancer Association
- Published
- 2023-06-22
- Volume
- 20
- Issue
- 6
- Pages
- 465-476
- ISSN
- 2095-3941 (ISSN-L)
- PMC
- PMC10291982
- OpenAlex
- W4381683394
- Semantic Scholar
- 55d801a15d44288de1c7eebf321b87ba9c6fe62d
- Cited by
- 37
- References
- 17
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 7 · 2023: 4
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Cancer Biology and Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- chlorogenic acid, recurrent high-grade glioma, intramuscular injection, dose escalation, pharmacokinetics, maximum tolerated dose, safety profile, overall survival, long-term follow-up, stable disease
- MeSH terms
- Temozolomide, Brain Neoplasms, Chlorogenic Acid, Dacarbazine, Follow-Up Studies, Glioma, Humans
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
