Safety Study of EF-022 ( Modified Vitamin D Binding Protein Macrophage Activator) in Subjects With Advanced Solid Tumors
Condition: Solid Tumors
Study type: Interventional
Phase: Phase 1

Summary: 
      Activated macrophages, present in excess during natural inflammatory responses, bear the
      potential to kill and eradicate cancer cells. Macrophage activation has been demonstrated to
      require the serum-borne vitamin D binding protein (known as Gc protein), as well as B and T
      lymphocytes. However, in various cancer patients the Gc protein is deglycosylated by serum
      α-N-acetyl galactosaminidase (Nagalase) secreted from cancer cells. This deglycosylated Gc
      protein, lacking the N-acetylgalactosamine monosaccharide, cannot be converted to its form of
      Macrophage Activating Factor, leading to immunosuppression rather than Macrophage activation
      against cancer cells.

      Efranat has developed cancer immunotherapy based on Macrophage Activating Factor produced
      from natural Gc protein extracted from FDA approved healthy human plasma.

      In this phase I study, the treatment is given as Intramuscular, once-weekly injection of
      EF-022, for two courses, while each course is comprised of 4 injections.

      The investigational treatment is expected to enhance immune response, thereby, improve
      patient's well being, quality of life and disease control.

      Primary objectives:

        1. To determine the safety and tolerability of EF-022 and to define the maximal tolerated
           dose (MTD) for potential administration.

        2. To identify the Dose Limiting Toxicity (DLT) of EF-022.

      Secondary objectives:

        1. To determine the 'Recommended Phase 2 Dose' (RP2D) based on MTD data, immunological and
           pharmacodynamics markers

        2. To explore preliminary efficacy of EF-022 in advanced solid tumors according to the
           'Response Evaluation Criteria in the modified Solid Tumors' (RECIST 1.1) and blood
           levels of tumor-related markers known to reflect tumor burden.

      Exploratory objectives:

        1. To assess levels of immune-related factors in peripheral blood (determined by FACS
           analysis), reflecting induced immunological activities, including but not limited to,
           natural killer (NK), monocytes (M1 and M2) and T cell subpopulations (effector vs
           regulatory, CD4+ and CD8+ cells), B cells (CD20), myeloid and dendritic cells etc.

        2. To assess the change in serum levels of protein biomarkers in the blood.

        3. To immunohistochemically assess and compare tumor derived tissue samples Pre and post
           treatment. To analyze the infiltration of different population of cells into the tumor
           bed.
    

Detailed description: 
      Part 1:

      Eligible subjects will be assigned, successively in order of accrual, to one of the three
      cohorts, to receive intramuscular (IM) injections of EF-022, once weekly for two courses of
      treatment. Each course will consist of 4 injections with one week intervals (total: 8 weeks
      of treatment).

      Dose escalation will only proceed in the absence of dose-limiting toxicity (DLT) during
      course 1. For this purpose, each cohort will only begin its first course of EF-022 when the
      cohort preceding it has successfully completed its first 4-week treatment course without any
      signs of DLT. During this first course, should 1/3 patients experience DLT, dose escalation
      for the next cohort will not be authorized; the next cohort will receive the same dose as the
      one preceding it. If 2 patients or more of all patients treated with a given dose develop
      DLT, dose escalation will be halted and no more patients will be treated at the DLT dose. The
      value of MTD will be defined as the EF-022 dose below the dose at which DLT was seen for at
      least 2 subjects. Upon determination of the MTD, an additional cohort will be opened
      (confirmatory cohort) and treated with two courses of that dose.

      Part 2:

      During the expanded cohort, 24 Patients will be allocated to receive either 100ng, 500ng or
      1000ng weekly treatment as detailed below: The first 18 patients will be assigned to
      alternating doses of either 100ng or 500ng in a sequential manner (each patient will be
      assigned to a single dose), with the caveat that given indications should be assigned
      equally, as much as possible, between these two doses.

      Interim analysis will be performed once the 12th patient reaches Day 57 and the CT results as
      well as PD analysis are available for at least 12 patients, while at least 18 patients have
      begun study treatment. A decision regarding adding a 1000ng dose cohort vs. continuing with
      the 100ng and 500ng doses will be based on a discussion of the interim analysis results.

      Each patient will receive 2 courses of treatment, i.e. weekly injections for a total period
      of 8 weeks, followed by a follow-up period of up to 12 months from the start of treatment
      (Day 1).

      Continuation of treatment after the second course will be at the discretion of the
      investigator. Patients who will continue extended treatment post course 2 will keep the
      weekly injection dosage mode and continue therapy until disease progression, development of
      unacceptable toxicities, non-compliance, inter-current illness that prevents treatment
      continuation, withdrawal of consent, or change in subject condition that renders the subject
      unacceptable for further treatment.

      All study patients who completed at least two courses of treatment will be followed up until
      12 months from day 1 of treatment.
    

Intervention name(s): EF-022 (Modified Vitamin D Binding Protein Macrophage Activator)
Intervention type(s): Drug
Intervention MeSH terms: Vitamin D
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment