Abstract CT230: A phase I first in human dose escalation trial of MNK-010 in subjects with advanced solid tumors
Authors: Rochon Louise S. , Devarakonda Krishna , Martinez Jose , Williams Kelly , Hamilton Erika P. , Shapiro Geoffrey , Sukari Ammar 
Published: August 2015

Abstract
Background: Taxanes possess broad activity and are widely used for a variety of tumor types. Currently available formulations are associated with dose limiting myelosuppression, neurotoxicity, fluid retention and other toxicities. MNK-010, a liposomal prodrug formulation of docetaxel, is designed to act as a drug depot with the slow conversion and release of docetaxel resulting in a relatively lower Cmax, and enhanced systemic exposure (AUC) over a prolonged period of time. It is anticipated that this unique PK profile would improve efficacy with a better safety profile compared to docetaxel.
Design: This study is a dose escalation first in human (FIH) study in subjects with advanced solid malignancies who have failed conventional therapy. MNK-010 is administered IV every 21 days for four cycles. The primary objectives are to evaluate the safety and tolerability and determine the MTD and DLT of MNK-010. The secondary objectives are to characterize the PK profile of docetaxel, the liposomal components (DSPE-PEG[2000]) and docetaxel prodrug (MP-3528) and preliminary anti-tumor activity of MNK-010.Twelve dose levels are planned: 3, 6, 12, 24, 48, 80, 120, 160, 190, 225, 270, and 320 mg/m2 Dosing at 160 mg/m2 is underway. The recommended phase II dose will be administered to 20 patients with metastatic SCCHN to further evaluate the safety, PK profile, and preliminary antitumor activity of MNK-010.
Results: 25 subjects have received at least one dose of MNK-010 for a total of 106 cycles administered. Efficacy results include six stable diseases (SDs) in tumor types including thymic cancer, NSCLC, prostate, ovarian, cervical and gastroesophageal cancer. Safety data shows that MNK-010 is well tolerated at doses up to 120 mg/m2. The major drug related adverse events reported are nausea, vomiting and fatigue.
The Clearance (CL), volume of distribution (Vss), half-life (t1/2), peak level (Cmax) and extent of exposure (AUC) values are comparable between DSPE(PEG-2000) and MP-3528. The CL (∼ 0.026 L/h/m2) and Vss (∼ 1.6 L/m2) of MNK-010 are very low, with the mean t1/2 being about 60h. Cmax and AUC demonstrate dose proportionality and linearity for MP-3528, DSPE(PEG-2000) and docetaxel. The dose normalized Cmax of docetaxel released from MNK-010 is about nine-fold lower relative to a comparable dose of Taxotere.
Conclusion: MNK-010 is well tolerated up to doses of 120 mg/m2. Stable diseases have been observed in several tumor types.
Citation Format: Louise S. Rochon, Krishna Devarakonda, Jose Martinez, Kelly Williams, Erika P. Hamilton, Geoffrey Shapiro, Ammar Sukari. A phase I first in human dose escalation trial of MNK-010 in subjects with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT230. doi:10.1158/1538-7445.AM2015-CT230