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A Randomized, Double-Blinded, Placebo-Controlled Phase II Trial of Recombinant Human Leukemia Inhibitory Factor (rhuLIF, Emfilermin, AM424) to Prevent Chemotherapy-Induced Peripheral Neuropathy

¹ Austin Health, Heidelberg, Victoria, Australia; ² Royal Melbourne Hospital and ³ Cancer Trials Australia, Inc., Parkville, Victoria, Australia; ⁴ Royal Women's Hospital, Carlton, Victoria, Australia; ⁵ Albert Einstein College of Medicine, New York, New York; ⁶ Western Hospital, Footscray, Victoria, Australia; ⁷ Burnside Hospital, Toorak Gardens, South Australia, Australia; ⁸ Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; and ⁹ Amrad Operations Pty Ltd., Richmond, Victoria, Australia

Requests for reprints: Ian D. Davis, Austin Health Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-5726; Fax: 61-3-9457-6698; E-mail: Ian.Davis{at}ludwig.edu.au.

Purpose: To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m² over 3 hours).

Experimental Design: Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 µg/kg), high-dose rhuLIF (4 µg/kg), or placebo.

Results: Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 µg/kg), 39 received high dose rhuLIF (4 µg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables.

Conclusions: rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.

Key Words: rhuLIF • emfilermin • Phase I - III Clinical Trials • Cytokines • Toxicities • Biochemical modulators of the therapeutic index • Long-term toxicities

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