Entry Detail
| General information | |
| Database: | DB00698 |
| Objective: | JNJ26483327 is an oral, potent, multitargeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)1, 2 and 4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. Thisphase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ26483327. |
| Authors: | Konings IR, et al |
| Title: | Phase I and pharmacological study of the broadspectrum tyrosine kinase inhibitor JNJ26483327 in patients with advanced solid tumours. |
| Journal: | Br J Cancer. |
| Year: | 2010 |
| PMID: | 20823884 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | JNJ26483327 |
| Target: | Epidermal growth factor receptor Protooncogene tyrosineprotein kinase Fyn Lyn tyrosine kinase Receptor proteintyrosine kinase erbB2 Vascular endothelial growth factor receptor 3 Protooncogene tyrosineprotein kinase LCK Protooncogene tyrosineprotein kinase Yes Receptor proteintyrosine kinase erbB4 |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Phase I and pharmacological study |
| Key Patients Feature: | Patients with a histologically or cytologically confirmed diagnosisof advanced solid malignancy for whom no standard optionsexisted or who were no longer responding to established treatments were eligible. Additional eligibility criteria included ageX18 years; ECOG performance p2; life expectancy 43 months;adequate bone marrow function, without the support of cytokinesand/or erythropoietin (white blood cell (WBC) count 43.0 109per l, absolute neutrophil count 41.5 109 per l, platelet count4100 109 per l, haemoglobin 410.0 g dl - 1), hepatic function(total bilirubin level p1.5 times institutional upper limit of normal(iULN), serum alanine transferase and aspartate aminotransferasep2.5 times iULN or p5 times iULN in case of liver metastases)and renal function (serum creatinine o1.5 times iULN); nochemotherapy, radiotherapy or immunotherapy within 28 days;no history of uncontrolled heart disease or arterial hypertension(systolic blood pressure X160 mm Hg and/or diastolic bloodpressure X100 mm Hg despite appropriate medication). Specificexclusion criteria included a history of pulmonary fibrosis, knowncentral nervous system metastases, impairment of gastrointestinalabsorption status and inability to swallow. Left ventricular ejectionfraction (LVEF) based on MUGA scan was required to be 450%. |
| Biomarker: | Pharmacodynamic effects were assessed in paired skin biopsies and blood. |
| Biomark Analysis: | Pharmacodynamic analysis did not show a substantial effect on expression of Ki67, p27(kip1), phosphorylated mitogenactivated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR2, VEGFC and VEGFD remained unchanged. |
| Control Group Info: | single arm |
| Treatment Info: | patients with advanced cancers received JNJ26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. |
| Primary End Point: | safety, maximum tolerated dose (MTD) and doselimiting toxicity (DLT), pharmacokinetic profile, pharmacodynamic activity. |
| Secondary End Point: | NA |
| Patients Number: | 19 |
| Trial Results | |
| DLT_MTD: | At 2100 mg, two episodes of DLT, consisting of grade 3 anorexiaand of a combination of grade 3 anorexia and fatigue, wereobserved in one patient each. the MTD was set at 1500 mg BID Nausea, diarrhoea, vomiting, anorexia, fatigue and skin rash were principal toxicities of JNJ26483327 |
| Objective Response Rate: | Stable disease was noted in six patients (32%). |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | 1500 mg BID, with targetinhibitionrelated toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of doselimiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively |
| Conclusions: | JNJ26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID. |