Earlier this week the first patient has been dosed in a Phase Ib/IIa study of CRLX101 (formerly called IT-101, Cerulean Pharma Inc.), dual inhibitor of topoisomerase 1 and hypoxia-inducible factor-1 alpha, in combination with bevacizumab (Avastin?, Genentech/Roche) in metastatic renal cell carcinoma (mRCC) patients. Cerulean also announced the completion of enrollment of its randomized Phase II study in advanced non-small cell lung cancer.

The trial drug couples camptothecin, a cytotoxic quinoline alkaloid, to a cyclodextrin based polymer that self-assembles into nanoparticles. The tumor-targeted nanopharmaceuticals are designed to concentrate in tumors and prolonging drug exposure at the site of action. Significant anti-tumor activity has been observed across a wide range of cancers in animal models.

Results from the Phase I clinical study of CRLX101 have shown that it has a favorable safety profile in patients with advanced cancer. Combining camptothecin?s potency and ?s nanopharmaceutical design features, we believe CRLX101 has the potential to kill tumor cells while minimizing the side effects typically associated with chemotherapy treatment. The trial drug provides clinical validation of Cerulean’s CDP technology by improving the tolerability of the parent drug camptothecin.

Completed enrollment
Having completed enrollment of a 150-patient randomized Phase II study in advanced non-small cell lung cancer, the company is beginning to capitalize on CRLX101 by expanding its development into additional tumor.

Trial design
The new Phase Ib/IIa trial is designed to evaluate the activity of CRLX101 in combination with bevacizumab in mRCC patients whose disease has progressed following treatment with at least one prior molecularly targeted therapy.

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This study, which incorporates a rapid dose escalation stage and a subsequent efficacy stage, is being conducted at the Abramson Cancer Center of the University of Pennsylvania and is led by principal investigator Stephen Keefe, M.D.

“We have observed that the unique intratumor pharmacokinetic properties of our nanopharmaceuticals can lead to novel pharmacodynamic effects,” noted Edward Garmey, M.D., chief medical officer of Cerulean. “We will be collaborating with Dr. Keefe and his colleagues to assess the impact of CRLX101 on HIF-1 alpha, an exciting oncology drug target that appears to be widely upregulated in hypoxic conditions and in RCC.”

Synergistic with bevacizumab?
“Reaching multiple tumor targets at once may be more efficient at shrinking patients’ tumors, and make them less likely to become resistant to the drugs. In this new trial for patients with RCC, we will learn if CRLX101 is synergistic with bevacizumab, the leading VEGF inhibitor,” Keefe said. “The rationale of combining the two drugs is that they should mechanistically reinforce each other. The benefit of this approach, attacking multiple targets at once, is not limited to RCC, however, and could be applicable in other cancers as well.”

Clinical trials:
NCT01625936 – CRLX101 Plus Bevacizumab in Advanced RCC
NCT00333502 – Study of CRLX101 (Formerly Named IT-101) in the Treatment of Advanced Solid Tumors
NCT01612546 – Cyclodextrin-Based Polymer-Camptothecin CRLX101 in Treating Patients With Advanced or Metastatic Stomach, Gastroesophageal, or Esophageal Cancer That Cannot be Removed by Surgery
NCT01380769 – A Phase 2 Study of CRLX101 in Patients With Advanced Non-Small Cell Lung Cancer

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