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Pelitinib

Pelitinib is a 3-cyanoquinoline pan-ErbB tyrosine kinase inhibitor with potential antineoplastic activity. EKB-569 irreversibly binds covalently to epidermal growth factor receptors (EGFR) ErbB-1, -2 and -4, thereby inhibiting receptor phosphorylation and signal transduction and resulting in apoptosis and suppression of proliferation in tumor cells that overexpress these receptors. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Current developer:    Wyeth Inc.

Phase I study of pelitinib with temsirolimus : Scientists from Mayo Clinic reported undertook a phase I trial of temsirolimus (T, an mTOR inhibitor) and EKB-569 (E, an EGFR inhibitor) to determine the safety and tolerability. Methods The primary aim was to determine the maximally tolerated dose (MTD) of this combination in adults with solid tumors. Following the dose-escalation phase, (Cohort A), two subsequent cohorts were used to assess any pharmacokinetic (PK) interaction between the agents. Results Forty eight patients were enrolled. The MTD of this combination was E, 35 mg daily and T, 30 mg on days 1-3 and 15-17 using a 28-day cycle. The most common toxicities were nausea, diarrhea, fatigue, anorexia, stomatitis, rash, anemia, neutropenia, thrombocytopenia, and hypertriglyceridemia. Sixteen patients (36%) had at least one grade 3 toxicity. The most frequent grade 3/4 toxicities were diarrhea, dehydration, and nausea and vomiting (19% each). No grade 5 events were seen. Four patients had a partial response and 15 had stable disease. Clinical benefit was seen across a range of tumor types and in all cohorts. PK analysis revealed no significant interaction between E and T. Conclusions This combination of agents is associated with tolerable toxicities at doses that induced responses. PK studies revealed no interaction between the drugs. Further investigations of this targeting strategy may be attractive in renal cell carcinoma, non-small cell lung cancer, alveolar sarcoma, and carcinoid tumor. (source: Invest New Drugs. 2011 Sep 1. [Epub ahead of print])

Phase I study of Pelitinib: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037). CONCLUSION:  In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction. (Source: Clin Cancer Res. 2008 Sep 1;14(17):5602-9).

1: Aravindan N, Thomas CR Jr, Aravindan S, Mohan AS, Veeraraghavan J, Natarajan M. Irreversible EGFR Inhibitor EKB-569 Targets Low-LET γ-Radiation-Triggered Rel Orchestration and Potentiates Cell Death in Squamous Cell Carcinoma. PLoS One. 2011;6(12):e29705. Epub 2011 Dec 29. PubMed PMID: 22242139; PubMed Central PMCID: PMC3248439.

2: Kim H, Lim HY. Novel EGFR-TK inhibitor EKB-569 inhibits hepatocellular carcinoma cell proliferation by AKT and MAPK pathways. J Korean Med Sci. 2011 Dec;26(12):1563-8. Epub 2011 Nov 29. PubMed PMID: 22147992; PubMed Central PMCID: PMC3230015.

3: Bryce AH, Rao R, Sarkaria J, Reid JM, Qi Y, Qin R, James CD, Jenkins RB, Boni J, Erlichman C, Haluska P. Phase I study of temsirolimus in combination with EKB-569 in patients with advanced solid tumors. Invest New Drugs. 2011 Sep 1. [Epub ahead of print] PubMed PMID: 21881915.

4: Laheru D, Croghan G, Bukowski R, Rudek M, Messersmith W, Erlichman C, Pelley R, Jimeno A, Donehower R, Boni J, Abbas R, Martins P, Zacharchuk C, Hidalgo M. A phase I study of EKB-569 in combination with capecitabine in patients with advanced colorectal cancer. Clin Cancer Res. 2008 Sep 1;14(17):5602-9. PubMed PMID: 18765554; PubMed Central PMCID: PMC3086427.

5: Folprecht G, Tabernero J, Köhne CH, Zacharchuk C, Paz-Ares L, Rojo F, Quinn S, Casado E, Salazar R, Abbas R, Lejeune C, Marimón I, Andreu J, Ubbelohde U, Cortes-Funes H, Baselga J. Phase I pharmacokinetic/pharmacodynamic study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) in first-line treatment of patients with metastatic colorectal cancer. Clin Cancer Res. 2008 Jan 1;14(1):215-23. PubMed PMID: 18172273.

6: Erlichman C, Hidalgo M, Boni JP, Martins P, Quinn SE, Zacharchuk C, Amorusi P, Adjei AA, Rowinsky EK. Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol. 2006 May 20;24(15):2252-60. PubMed PMID: 16710023.

7: Baselga J. Is there a role for the irreversible epidermal growth factor receptor inhibitor EKB-569 in the treatment of cancer? A mutation-driven question. J Clin Oncol. 2006 May 20;24(15):2225-6. PubMed PMID: 16710019.

8: Yoshimura N, Kudoh S, Kimura T, Mitsuoka S, Matsuura K, Hirata K, Matsui K, Negoro S, Nakagawa K, Fukuoka M. EKB-569, a new irreversible epidermal growth factor receptor tyrosine kinase inhibitor, with clinical activity in patients with non-small cell lung cancer with acquired resistance to gefitinib. Lung Cancer. 2006 Mar;51(3):363-8. Epub 2005 Dec 20. PubMed PMID: 16364494.

9: Nunes M, Shi C, Greenberger LM. Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther. 2004 Jan;3(1):21-7. PubMed PMID: 14749472.