EZN-2208 (Pegylated SN-38) in Combination With Bevacizumab in Refractory Solid Tumors

Neoplasms Clinical Trial

Official title: Pilot Study of Weekly EZN-2208 (Pegylated SN-38) in Combination With Bevacizumab in Refractory Solid Tumors

Status Completed

Clinical Trial Summary

Background:

• The anticancer drug bevacizumab works by reducing the formation of new blood vessels in tumors, which can slow or stop the growth of cancer cells and supporting blood vessels. The experimental drug EZN-2208 works by limiting how well cancer cells can divide. Drugs similar to EZN-2208 also work by turning off the production of the HIF protein, which otherwise can help cancer cells to grow even when blood supply is limited. Researchers are interested in determining if EZN-2208 turns off HIF in patient tumors, and whether combining it with bevacizumab is an effective treatment for cancers that have not responded to standard treatment.

Objectives:

• To assess the safety and effectiveness of the combination of EZN-2208 and bevacizumab for solid tumors that have not responded to standard treatment.

Eligibility:

• Individuals at least 18 years of age who have solid tumors that have not responded to standard treatment.

Design:

• Participants will be screened with a full physical examination and medical history, blood and urine samples, and tumor imaging studies.

• Participants will receive EZN-2208 and bevacizumab intravenously on an outpatient basis in 4-week cycles (with the exception of the first cycle, which will be 5 weeks).

• Cycle 1: Participants will receive EZN-2208 once a week for 3 weeks in a row (days 1, 8, and 15), followed by 1 week without the drug. Participants will receive bevacizumab 1 week before EZN-2208 (day - 7) and then 3 weeks later (day 15).

• Subsequent cycles: Participants will receive EZN-2208 once a week for 3 weeks in a row (days 1, 8, and 15), followed by 1 week without the drug. Participants will receive bevacizumab every 2 weeks (days 1 and 15).

• Participants will have clinic visits with physical examinations and blood tests in the first 3 weeks of each cycle. Clinic visits may also include tumor imaging studies and tumor biopsies as directed by the study researchers.

• Participants will continue to take the study drugs for as long as the tumor shrinks or does not grow, and as long as they do not experience intolerable or unsafe side effects from the drugs.

Clinical Trial Description

Background

One reason postulated for the limited efficacy of anti-angiogenic or anti-VEGF agents such as bevacizumab is that they cause intra-tumoral hypoxia, resulting in the induction and up-regulation of hypoxia-inducible factors (HIF) such as HIF-1Alpha. These in turn play a central role in tumor progression by acting as master regulators of how cancer cells adapt to hypoxic conditions. HIF-1Alpha therefore represents an attractive target in oncology.

Camptothecin analogues (including SN-38, topotecan, and irinotecan) have been shown to consistently reduce the translation, expression, and transcriptional activity of HIF-1Alpha in vitro and in vivo, and therefore have the potential to inhibit the HIF-1? induction that occurs with anti-angiogenic agents.

The central rationale of this study is that HIF-1alpha induction by bevacizumab will be offset by weekly administration of EZN-2208 (PEGylated SN-38), and that this will result in synergistic anti-tumor effects.

Objectives

Determine the modulation of HIF-1alpha protein (by ELISA) in solid tumors after treatment with EZN-2208 and bevacizumab.

Determine the safety and tolerability of the combination of EZN-2208 and bevacizumab with EZN-2208 administered weekly times 3 (Days 1, 8, and 15) and bevacizumab administered every 2 weeks in 28-day cycles.

Perform correlative studies to assess changes in angiogenesis in tumor tissue.

Evaluate antitumor responses as determined by RECIST.

Eligibility

Adults with histologically documented solid tumors, whose disease has progressed following standard therapy or who have no acceptable standard treatment.

Performance status ECOG 0-2; adequate organ function; life expectancy at least 3 months; no major surgery, radiation or chemotherapy within 4 weeks prior to study enrollment; recovered from toxicities of prior therapies to at least eligibility levels.

Willingness to undergo tumor biopsies for research purposes.

Study Design

This is a single-arm pilot study.

Patients will receive EZN-2208 IV on Day 1, 8, and 15 of a 28-day cycle at a dose of 9 mg/m(2); bevacizumab will be administered IV every 2 weeks at a dose of 5 mg/kg.

For cycle 1: Bevacizumab will be administered on Day -7 (i.e., 1 week prior to EZN-2208) and Day 15.

For subsequent cycles: Bevacizumab will be administered on Day 1 and 15. ;

Related Conditions & MeSH terms

• Neoplasms

• NCT number: NCT01251926
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: November 15, 2010
• Completion date: April 23, 2014