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

Abstract

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.

• Authors: S Kaye, S Aamdal, R Jones, G Freyer, E Pujade-Lauraine, E G E de Vries, J Barriuso, S Sandhu, D S-W Tan, V Hartog, B Kuenen, R Ruijter, G B Kristensen, M Nyakas, S Barrett, W Burke, D Pietersma, M Stuart, U Emeribe, E Boven
• Journal: British journal of cancer (Br J Cancer) Vol. 106 Issue 11 Pg. 1728-34 (May 22 2012) ISSN: 1532-1827 [Electronic] England
• PMID: 22531637 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Cancer Research UK

Chemical References

• Benzodioxoles
• Quinazolines
• saracatinib
• Carboplatin
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzodioxoles (administration & dosage, adverse effects)
• Carboplatin (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Paclitaxel (administration & dosage, adverse effects)
• Quinazolines (administration & dosage, adverse effects)