Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours.

Abstract

BACKGROUND:

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine.

METHODS:

This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule.

RESULTS:

The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non-hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease.

CONCLUSION:

The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates.

• Authors: H A Tawbi, L Villaruz, A Tarhini, S Moschos, M Sulecki, F Viverette, J Shipe-Spotloe, R Radkowski, J M Kirkwood
• Journal: British journal of cancer (Br J Cancer) Vol. 105 Issue 6 Pg. 773-7 (Sep 06 2011) ISSN: 1532-1827 [Electronic] England
• PMID: 21811257 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Purines
• Dacarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• lomeguatrib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Dacarbazine (administration & dosage)
• Drug Administration Schedule
• Female
• Humans
• Male
• Melanoma (drug therapy)
• Middle Aged
• Neoplasms (drug therapy)
• O(6)-Methylguanine-DNA Methyltransferase (antagonists & inhibitors)
• Purines (administration & dosage)