A Phase IIa, Open-Label, Randomized, Pharmacokinetic Comparative, Cross-Over Studyof Melphalan HCl for Injection (propylene glycol-free) and Alkeran for Injection for Myeloablative Conditioning In Multiple Myeloma Patients Undergoing Autologous Transplantation.

Abstract 4525

High dose therapy and autologous transplantation is considered a standard of care procedure in symptomatic, transplant eligible multiple myeloma patients. The chemotherapy of choice in this situation is high dose melphalan. The later has marginal solubility and limited chemical stability upon reconstitution and dilution. The marginal stability of this compound has limited the use of regimens utilizing higher absolute dosages and/or longer infusions (> 60 minutes) that could potentially lead to improved outcomes. Accordingly, co-solvents are used in the marketed formulation, which are believed to contribute to the side effects of the therapy. A co-solvent used in Alkeran for Injection is propylene glycol, which has been reported to cause renal dysfunction, arrhythmias, hyperosmolality, increased anion gap metabolic acidosis, and sepsis-like syndrome. On the other hand, Melphalan HCl for Injection (Propylene Glycol-Free), a reformulation of Alkeran for Injection, incorporates the Captisol® brand of β-cyclodextrin sulfobutyl ethers, sodium salts (also known as [SBE]7m-β-CD) into a freeze-dried product developed by CyDex Pharmaceuticals, Inc. (CyDex). Captisol improves stability allowing for potentially longer infusion times. Study Design/Goals: In this phase IIa, open-label, randomized, cross-over design, the PK of Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection are assessed in the same MM patients undergoing transplantation. Furthermore, the rates of myeloablation and subsequent engraftment are determined, and any difference in expected safety and tolerability due to high-dose Melphalan HCl for Injection (Propylene Glycol-Free) is assessed in transplanted patients. Results: Seven patients of the planned 24 patients have already enrolled in the study at the University of Kansas Medical Center. All patients achieved myeloablation followed by successful engraftment. Median time to myeloablation, defined as number of days from the start of chemotherapy until absolute neutrophil count dropped below 500/Ul, was 6.4 days (range 5–7 days). Median time to neutrophil engraftment, defined as first day of three consecutive days where ANC was higher than 500/Ul following their nadir, was day +9. Beside expected grade 2–3 toxicities related to high dose melphalan, no additional toxicities were reported. In specific, no renal insufficiency was noted. Preliminary PK analysis has been performed on five patients. Preliminiary parameter estimates (Mean± SEM) are presented in the Table. The mean bioavailability was 113%. The mean half-lifes for the Melphalan HCl for Injection (Propylene Glycol-Free) and Alkeran for Injection were 70 and 75 min. Following Melphalan HCL for Injection (PropyleneGlycol-Free) and Alkeran for Injection, the distribution volumes were 0.23 and 0.35 L/kg and clearances were 0.29 and 0.34 L/hr per kg, respectively. Conclusion: Melphalan HCl for Injection (Propylene Glycol-Free), administered as half of a high-dose conditioning regimen, appears to result in successful myeloablation and subsequent engraftment at no extra-toxicity, and trending toward higher bio-availability compared to Alkeran. Future studies that are designed to expose patients exclusively to the propylene glycol-free formulation will delineate potential safety and efficacy advantages over the current therapy.