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Oncology Times:
doi: 10.1097/01.COT.0000431570.53347.49
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Targeted, Controlled Nanoparticles Being Used to Deliver Docetaxel: Benefits Over Liposomal-Encapsulated Nanoparticle-Based Albumin Targeted Drugs

Carlson, Robert H.

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WASHINGTON—An anticancer agent developed with polymeric nanotechnology has advanced into the clinic, targeting the prostate-specific membrane antigen (PSMA) to achieve responses in refractory cervical, hepatobiliary, non-small cell, and prostate cancers in a Phase I trial reported here at the American Association for Cancer Research Annual Meeting (Abstract LB-203). Phase II trials are now under way.

Figure. Docetaxel...
Figure. Docetaxel...
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Polymeric nanoparticles differ from liposomal encapsulated nanoparticle-based albumin targeted drugs in improved tolerability and increased concentration in tumors of the active drug, noted Daniel Von Hoff, MD, presenting the results of the study of the agent called BIND-014 during a Clinical Pharmacology of Novel Agents in Solid Tumors session. And, since the polymeric-encapsulated docetaxel showed activity in patients refractory to docetaxel, the agent could prove effective in cancers that are notoriously resistant to taxanes.

BIND-014's target, PSMA, is a tumor antigen expressed on prostate cancer cells and on the neovasculature of most non-prostate solid tumors, explained Von Hoff, Physician-in-Chief at Translational Genomics Research Institute (TGen) and Director of TGen Clinical Research, who has also led recent research on nanoparticle albumin bound (nab) paclitaxel (Abraxane) in pancreatic cancer, Phase III results of which were reported at the Gastrointestinal Cancers Symposium (OT, 2/25/13 issue).

BIND Biosciences of Cambridge, Mass., sponsored the trial reported at AACR, and he disclosed that he was a consultant prior to the study and that his institution received clinical trial grant and research support from the company.

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Responses in Heavily Pretreated Patients

BIND-014 was well tolerated, with predictable and manageable toxicity, he said. Four of 28 patients in the trial had tumors that responded to the agent, including a complete response in a patient with cervical cancer, and partial responses in patients with prostate, ampullary, and non-small cell lung cancers. Five others with prostate, hepatobiliary, pancreatic, head and neck, and anal cancers had stable disease for 12 weeks or longer.

The Phase I study has two arms: BIND-014 given weekly, and given once every 21 days. The data Von Hoff presented here were for the 21-day schedule because the weekly study is ongoing, he said. There was no exclusion for patients who received prior taxanes.

The study patients received BIND-014 at doses ranging from 3.5 to 75 mg/m2. The patients' median age was 62, and they had a median of two lines of chemotherapy, ranging from none to eight.

Dose-limiting toxicities reported were Grade 3 fatigue in one patient and Grade 4 neutropenia lasting five days in another—both treated at the 75 mg/m2 dose. There was one death, due to sepsis in a patient with hepatobiliary cancer.

The researchers determined the maximum tolerated dose on this schedule and in this patient population to be 60 mg/m2 by 60-minute infusion every 21 days.

The most common drug-related toxicities were neutropenia, alopecia, anemia, diarrhea, dehydration, fatigue, and vomiting. All observed toxicities were docetaxel-associated, Von Hoff said, although several common docetaxel toxicities were mild or absent, including nail changes, neuropathy, and mucositis.

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Controllable, Tunable

To make BIND-014, docetaxel is dissolved and encapsulated in a hydrophobic biodegradable polymeric core, surrounded by a hydrophilic corona to protect it from immune recognition, he explained. Targeted polymeric nanoparticles are sometimes referred to as “controllable and tunable” because they are designed to traffic a greater percentage of the administered drug directly to tumor cells.

He said that in preclinical studies BIND-014's pharmacological properties are substantially different from those of docetaxel, including enhanced tumor accumulation and tumor growth suppression.

Figure. DANIEL VON H...
Figure. DANIEL VON H...
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In addition, the pharmacokinetics of BIND-014 differ from those of docetaxel in that there is prolonged circulation of the nanoparticles in the vascular compartment. “Docetaxel is obviously a clinically active agent in many solid tumor types, but it still has bothersome toxicities, such as polysorbate 80-associated edema, which is cumulative and requires fairly hefty doses of dexamethasone, especially in people with diabetes,” Von Hoff noted.

Researchers are working on two pharmacodynamic markers for BIND-014: PSMA scans of tumors for pre- and post-treatment analysis; and a method to determine the concentration of docetaxel in a patient's tumor delivered as part of BIND-014 to compare with the concentration of solvent-based docetaxel.

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Discussant: New Cytotoxics Needed

In her remarks as Discussant for the study, E. Gabriela Chiorean, MD, Associate Member in the Clinical Research Division of Fred Hutchinson Cancer Research Center and Associate Professor of Medicine in the GI Oncology and Phase I Programs at the University of Washington, said, “In an era that is very much dominated by molecularly targeted therapies, we do need better cytotoxics.”

She noted that more than 150 drugs have been in development that have attempted to use nanotechnology but few have hit the market. The best known is Doxil, the liposomal-encapsulated form of doxorubicin. Polymeric compounds such as BIND-014 have an advantage over liposomal drugs as they can carry a higher therapeutic load, and have slower clearance giving the anticancer agent more time to penetrate the tumor. Polymers can be amenable to targeted ligands conjugated on their surface against cell surface antigens, to reach the tumors more effectively, she said. “In animal models, we really see the targeted ligand add to the efficacy in terms of tumor growth inhibition.

“But, is BIND-014 better than docetaxel?,” Chiorean asked, listing other questions that might help answer that: The maximum tolerated dose in this study was lower than that of docetaxel with no dose-limiting toxicities at that dose, but might the maximum tolerated dose be higher if growth factor support with G-CSF was allowed? Alternatively, can drug delivery be increased so a lower dose might be sufficient as well as well tolerated?

And could it be possible that, with the lower clearance of BIND-014, the drug might accumulate with repeat dosing?

Chiorean noted that very high drug concentrations of BIND-014 are sustained for more than 24 hours, and ultimately that may matter more than the half-life of the drug. “We do want a drug that is better tolerated than docetaxel, at least as effective as docetaxel in first line, and effective in taxane-resistant tumors,” she said. ”And we would love another success in pancreatic cancer.”

Figure. E. GABRIELA ...
Figure. E. GABRIELA ...
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© 2013 Lippincott Williams & Wilkins, Inc.

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