Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

• Published in: British journal of cancer Vol. 106; no. 11; pp. 1728 - 1734
• Main Authors: Kaye, S, Aamdal, S, Jones, R, Freyer, G, Pujade-Lauraine, E, de Vries, E G E, Barriuso, J, Sandhu, S, Tan, D S-W, Hartog, V, Kuenen, B, Ruijter, R, Kristensen, G B, Nyakas, M, Barrett, S, Burke, W, Pietersma, D, Stuart, M, Emeribe, U, Boven, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.05.2012; Nature Publishing Group
• Subjects: 631/67/1059; 692/699/67; 692/700/565/1436/1437; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzodioxoles - administration & dosage; Benzodioxoles - adverse effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Carboplatin - administration & dosage; Carboplatin - adverse effects; Chemotherapy; Clinical Study; Cytotoxicity; Dose-Response Relationship, Drug; Drug Resistance; Epidemiology; Female; Hospitals; Humans; Kinases; Male; Medical research; Medical sciences; Metastasis; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Oncology; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Quinazolines - administration & dosage; Quinazolines - adverse effects; Tumors; United Kingdom > UK; Norway; Netherlands; paclitaxel; saracatinib; Src; carboplatin; combination chemotherapy; Antineoplastic agent; Human; Solid tumor; Drug combination; Enzyme; Transferases; Malignant tumor; Cancerology; Taxane derivatives; C-Onc gene; Paclitaxel; Carboplatin; Phase I trial; Combined treatment; Antimitotic; Protein-tyrosine kinase; Protooncogene; Cancer; Platinum II Complexes; Saracatinib
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.158

Background: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. Methods: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m −2 q3w, paclitaxel 80 mg m −2 every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m −2 q3w. The primary endpoint was safety/tolerability. Results: A total of 116 patients received saracatinib 125 ( N =20), 175 ( N =44), 225 ( N =40), 250 ( N =9), or 300 mg ( N =3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ⩾3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; ⩾225 mg, 33%), and grade ⩾3 neutropenia occurred more commonly at doses ⩾225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w. Conclusion: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.