EZN-2208 (Pegylated SN-38) in Combination With Bevacizumab in Refractory Solid Tumors
Condition: Neoplasms
Study type: Interventional
Phase: Phase 1

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.
    

Detailed 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.
    

Intervention name(s): EZN-2208; Bevacizumab
Intervention type(s): Drug; Drug
Intervention MeSH terms: Bevacizumab
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Bevacizumab; Camptothecin; EZN-2208; Anti-Angiogenesis; Advanced Cancer; Cancer; Solid Tumor