Phase IIa, Open-Label, Randomized, Pharmacokinetic Comparative, Cross-Over Study of Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

Though high-dose melphalan and autologous transplantation is a standard procedure in transplant eligible multiple myeloma patients, the use of melphalan in this setting is considered an off-label use. The marketed formulation of melphalan, Alkeran for Injection (Alkeran), has marginal solubility and limited chemical stability upon reconstitution. Alkeran uses propylene glycol as a co-solvent, which has been reported to cause complications including renal dysfunction, arrhythmias, and a sepsis-like syndrome. Propylene Glycol-Free Melphalan HCL for Injection (PG-free Melphalan) is a reformulation of Alkeran developed by CyDex Pharmaceuticals, Inc. (A Ligand Company). It incorporates Captisol®, a specially modified cyclodextrin, to replace the co-solvents and improve stability, potentially allowing for alternative dosing such as longer infusion times. In an interim analysis of this study, PG-free Melphalan, compared to Alkeran, appeared bioequivalent, yet was associated with marginally higher blood drug levels. This abstract summarizes the final findings from this study after enrollment of all planned patients.

This is a phase IIa, open-label, randomized, cross-over design bioequivalence study. In this study, the pharmacokinetics (PK) of PG-free Melphalan and Alkeran were assessed in the same MM patients undergoing transplantation. Patients received both drug products in alternating dosing day fashion and were their own control for PK comparison. The PK measures were determined using WinNonLin 6.1 and bioequivalence assessed per FDA guidance. Furthermore, the safety and tolerability of high-dose melphalan HCL and rates of myeloablation and subsequent engraftment were determined in all patients.

24 patients, 11 females and 13 males, were enrolled between 2/4/2010 and 05/16/2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. Median age of enrolled subjects was 58 years old (range: 48–65). All had ECOG performance status of 0–1. All patients achieved myeloablation followed by successful engraftment. Median time to myeloablation was 6 days post the start of preparative regimen (range 3–8 days). Median time to neutrophil engraftment was day +9.5 post transplant (range: 9–12). No additional toxicities were reported with PG-free Melphalan. The following events occurred more frequently (>2 difference) when Alkeran was given first (edema, fluid retention, headache, dysguesia, Pollakiuria, rash, bundle branch block,) and the following events occurred more frequently (>2 difference) when PG-free Melphalan was given first (dizziness). PK analysis showed PG-free Melphalan was bioequivalent with Alkeran (Table-1 ) and also revealed that Cmax and AUC were higher (∼10%) after PG-free Melphalan. Interestingly, plasma concentrations of PG-free Melphalan were higher than Alkeran for up to 3 hours post-administration.

PG-free Melphalan, administered as half of a high-dose conditioning regimen, resulted in successful myeloablation and subsequent engraftment with no immediate infusion-related toxicity and no additional overall transplant-related toxicity. PG-free Melphalan met the guidance requirements for bioequivalence with Alkeran while also demonstrating a marginally higher systemic drug exposure.

Estimated values are based on an ANOVA on the log transformed PK parameters with fixed effects of sequence, formulation, and period and patient nested within sequence as a random effect.

Off Label Use: I will discuss the use of high-dose melphalan for autologous transplantation. Pipkin:CyDex Pharmaceuticals, Inc (A Ligand Company): Employment.