Nanopharmaceutical May Offer Benefits in Combinations

In very early results from a phase Ib/IIa clinical trial, a combination of Cerulean Pharma's nanopharmaceutical CRLX101 and the antiangiogenesis drug bevacizumab (Avastin; Genentech) achieved a partial response in three of nine patients with renal cell carcinoma who had received prior antiangiogenesis treatment with limited success.

“This is early days, among only nine patients, but it's a dramatic finding in this setting,” said Scott Eliasof, PhD, vice president of the Cambridge, MA, firm, who presented the results at the International Conference on Molecular Targets and Cancer Therapeutics. The conference was held in Boston, MA, on October 19 through 23 and was sponsored by the American Association for Cancer Research, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer.

CRLX101 packages the cytotoxic alkaloid camptothecin in nanoparticles measuring 20 to 30 nanometers in diameter. Preclinical studies indicated that once it is taken up by tumor cells, the drug releases slowly and inhibits the enzyme topoisomerase-1, which in turn inhibits hypoxia-inducible factor 1α (HIF-1α), Eliasof said.

Angiogenesis inhibitors induce hypoxia, which then upregulates HIF-1α, a protein that has been linked to resistance to that class of drugs, Eliasof said. Cerulean's preclinical work demonstrated synergistic efficacy when CRLX101 was combined with various antiangiogenesis drugs. Additionally, synergistic effects were seen when the agent was used along with radiation, which also induces hypoxia.

Previous studies have implicated HIF-1α not just in tumor angiogenesis but also in invasion, metastasis, and cancer stem-cell formation, Eliasof noted, although he acknowledged that the potential benefits of inhibiting HIF-1α expression have not been validated clinically.

Results from the renal cell carcinoma trial so far suggest that CRLX101 has low toxicity, with far fewer high-grade adverse effects than are typically seen with the topoisomerase-1 inhibitors irinotecan and topotecan, which are often given to patients with kidney cancer.

In a separate imaging trial of the agent in patients with gastric cancer, CRLX101 accumulated more in tumor tissue than in nearby normal tissue, suggesting that more direct delivery to the tumor may be occurring in patients and thus helping to minimize toxicity, Eliasof said.

Cerulean's preclinical research also indicated that ovarian cancer cell lines may be particularly sensitive to HIF-1α inhibition, and the agent is being tested in early trials for ovarian cancer. A phase II trial of CRLX101 as a monotherapy for 29 patients with ovarian cancer has completed enrollment and produced three partial responses so far. Another phase II trial in patients with relapsed ovarian cancer, this one combining CRLX101 with bevacizumab, is scheduled to start by year's end.