ORAL D-METHIONINE (MRX-1024) SIGNIFICANTLY PROTECTS AGAINST CISPLATIN-INDUCED HEARING LOSS: A PHASE II STUDY IN HUMANS

Campbell KCM (1), Nayar R (2), Borgonha S (2), Hughes L (1), Rehemtulla A (3) , Ross B (3), Sunkara P (3).

(1) Southern Illinois University School of Medicine, Springfield, IL, USA; (2)  St. John’s National Academy of Sciences, Bangalore, India; (3) Molecular Therapeutics, Ann Arbor, Michigan, USA.

Background: D-methionine (D-met) protects against cisplatin-, aminoglycoside- and noise-induced hearing loss in multiple animal studies. Further, D-met protects against radiation induced oral mucositis. We are currently preparing for clinical trials for D- met protection against noise-induced and aminoglycoside-induced hearing loss. Phase II clinical trials results for D-met protection from radiation-induced oral mucositis are currently being prepared for publication.

Aims: This study represents the first clinical trials results for D-met protection from cisplatin-induced ototoxicity in humans. The purpose is to determine if hearing thresholds can be protected without antitumor interference or significant side effects.

Methods: In this double blind randomized pilot study, 14 adult patients received 100mg/kg dose of an oral orange flavored suspension of D-met (MRX-1024) and 13 subjects received flavor matched placebo in equivalent volume prior to each dose of cisplatin. Mean cumulative cisplatin dosing was 263.57 (SD 74.79) in the experimental group and 253.85 (SD 56.94) in the control group. Primary tumor sites ranged from genitourinary tract to head and neck cancers. Six patients in the experimental group and four patients in the placebo group also received radiation to the head and/or neck area for primary tumors in that region. Auditory thresholds were tested bilaterally at 8, 10, 11.2 and 12.5 kHz with a GSI 61 audiometer using a modified Hughson-Westlake technique.

Results: Significant hearing threshold protection was obtained for the frequencies of 10 kHz and above.  No difference in tumor regression was noted between groups.

Conclusions: We are encouraged that significant otoprotection was observed even with a small group of patients receiving fairly low cumulative cisplatin dosing.  Larger scale clinical trials are being planned.

Email: kcampbell@siumed.edu