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CRLX101 plus bevacizumab demonstrated activity against HIF-1 alpha
CRLX101 combined with antiangiogenic therapy inhibited the upregulation of hypoxia-inducible factor 1 alpha, according to findings presented at the International Conference on Molecular Targets and Cancer Therapeutics.
The combination also slowed tumor growth in renal cell carcinoma and ovarian cancer, results showed.
CRLX101 (Cerulean Pharma Inc) is a nanopharmaceutical containing camptothecin, a topoisomerase-1 inhibitor that did not succeed on its own in clinical trial, according to Scott Eliasof, PhD, vice president of Cerulean Pharma Inc.
Researchers evaluated CRLX101’s effect on hypoxia-inducible factor 1 alpha (HIF-1 alpha), which plays a role in the upregulation of survival pathways through angiogenesis, drug resistance, radiation therapy resistance, cancer stem cells and metastasis.
“We reasoned that if we could combined an HIF-1 alpha inhibitor — ie, CRXL101 — with an antiangiogenic agent or with radiation, then we can overcome this sort of mechanism of resistance that’s caused when the hypoxia draws HIF-1 alpha up and then turns on all these cancer cell survival pathways,” Eliasof said during a press conference.
A single dose of CRLX101 inhibited up to 50% to 77% of HIF-1 alpha tumor expression in mice, with the strongest benefit demonstrated in ovarian tumors. Further analysis indicated this effect lasted for up to a week.
“The durability of this effect is quite important for HIF-1 alpha since it is very tightly regulated because it’s such an important transcription factor, and this kind of durable inhibition is simply not possible with either topotecan or irinotecan, the two approved topoisomerase-1 inhibitors,” Eliasof said. “This is why CRLX101 is really differentiated from the existing topoisomerase-1 inhibitors.”
Analysis of ovarian xenograft models indicated that 5 mg/kg CRLX101 three times weekly plus an antiangiogenic drug inhibited HIF-1 alpha more than bevacizumab (Avastin, Genentech), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer HealthCare) or ziv-aflibercept (Zaltrap, Sanofi Aventis) alone.
Researchers at the University of Pennsylvania Abramson Cancer Center evaluated CRLX101 plus bevacizumab in nine patients with renal cell carcinoma, which is associated with high levels of HIF-1 alpha.
Three patients (33%) demonstrated RECIST criteria for partial response with CRLX101 plus bevacizumab, compared with the 2% partial response rate reported in prior studies of bevacizumab alone. The three patients who demonstrated partial response, as well as a fourth who achieved stable disease, achieved longer PFS with this drug combination than with any other prior treatment regimen.
Researchers noted fewer adverse events of all grades in patients with renal cell carcinoma who received CRLX101 compared with published data on irinotecan and topotecan.
Further trials evaluating the novel agent in patients with small–cell lung cancer, ovarian cancer and neoadjuvant rectal cancer are underway, Eliasof said.
For more information:
Eliasof S. Abstract #PR09/B1. Presented at: International Conference on Molecular Targets and Cancer Therapeutics; Oct. 19-23; Boston, Mass.
Disclosure: Eliasof reports employment with and stock ownership in Cerulean Pharma Inc.