Safety Study of EF-022 ( Modified Vitamin D Binding Protein Macrophage Activator) in Subjects With Advanced Solid Tumors

Solid Tumors Clinical Trial

Official title: A PHASE I, OPEN LABEL, DOSE-ESCALATION TRIAL EVALUATING THE SAFETY AND TOLERABILITY OF EF-022 (MODIFIED VITAMIN D BINDING PROTEIN MACROPHAGE ACTIVATOR) IN SUBJECTS WITH ADVANCED SOLID MALIGNANCIES

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Solid Tumors

• NCT number: NCT02052492
• Study type: Interventional
• Source: Efranat Ltd.
• Status: Completed
• Phase: Phase 1
• Start date: May 2014
• Completion date: May 2017