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

NCT02052492 | Completed Phase 1

• 1 other identifier: PR-001
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

Brief 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. 1.To determine the safety and tolerability of EF-022 and to define the maximal tolerated dose (MTD) for potential administration.
2. 2.To identify the Dose Limiting Toxicity (DLT) of EF-022.
3. 3.To determine the 'Recommended Phase 2 Dose' (RP2D) based on MTD data, immunological and pharmacodynamics markers
4. 4.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.
5. 5.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.
6. 6.To assess the change in serum levels of protein biomarkers in the blood.
7. 7.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.

Conditions

Solid Tumors

Outcome Measures

Primary Outcomes (2)

• Number of Adverse Events that meets the DLT definition

  During first course of treatment (up to 4 weeks)

• Percentage of participants with Adverse Events grade 3-4

  During two courses of treatment (up to 8 weeks)

Study Arms (4)

Cohort A: EF-022 100 ng once weekly

EXPERIMENTAL

Intra-Muscular injections of EF-022 100 ng once weekly for a period of 8 weeks

Drug: EF-022 (Modified Vitamin D Binding Protein Macrophage Activator)

Cohort B: EF-022 500 ng once weekly

EXPERIMENTAL

Intra-Muscular injections of EF-022 500 ng once weekly for a period of 8 weeks

Drug: EF-022 (Modified Vitamin D Binding Protein Macrophage Activator)

Cohort C: EF-022 1000 ng once weekly

EXPERIMENTAL

Intra-Muscular injections of EF-022 1000 ng once weekly for a period of 8 weeks

Drug: EF-022 (Modified Vitamin D Binding Protein Macrophage Activator)

Expanded Cohort

EXPERIMENTAL

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). 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.

Drug: EF-022 (Modified Vitamin D Binding Protein Macrophage Activator)

Interventions

EF-022 (Modified Vitamin D Binding Protein Macrophage Activator) DRUG

Cohort A: EF-022 100 ng once weekly; Cohort B: EF-022 500 ng once weekly; Cohort C: EF-022 1000 ng once weekly; Expanded Cohort

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients diagnosed with inoperable, recurrent or metastatic tumor, deemed incurable, and who have either failed to respond to standard therapy or for whom no standard therapy is available or refuse to receive standard therapies or in case of SCC, the investigator decides that delay of the standard therapy does not have any risk for the patient.
• Histologically or cytological-confirmed diagnosis of solid tumor on file. For the expanded cohort only the following immunological tumors will be recruited: epithelial ovarian cancer, cervical carcinoma, head \& neck cancer, melanoma, kidney cancer (RCC), gastric cancer, lung cancer (SCLC or NSCLC), sarcoma, bladder cancer or squamous cell carcinoma (SCC) of the skin.
• Measurable disease (i.e., present with at least one measurable lesion per modified RECIST, version 1.1).
• Age: 18-80 years.
• BMI: 18-36.
• ECOG Performance Status 0 or 1.
• Estimated life expectancy of at least 4 months.
• Off prior chemotherapy, radiation therapy with curative intent, hormonal therapy, immunotherapy, biological therapies (excluded checkpoint inhibitors and Erbitux), immunosuppressive therapy \[e.g., cyclosporine, humera, prograf, etc.\] or immunomodulators \[e.g., thalidomide, revlimid, etc.\] for at least 4 weeks. Hormonal treatment is not allowed ONLY if given as an anti-cancer therapy. In any case the sponsor should be consulted prior to final decision.
• Prior treatment with checkpoint inhibitors (such as anti PD-1, anti PDL-1), and/or Erbitux, and/or palliative irradiation, does not require any wash out period before commencement of study drug treatment.
• Patients who were receiving mitomycin C, nitrosoureas, or carboplatin must be 6 weeks from the last administration of chemotherapy.
• Patients must have adequate organ and marrow function within 7 days of first dosing. Hematology re-test results must keep meeting eligibility criteria on Day 1 of treatment prior to dosing.
• All prior anti-cancer treatment-related toxicities (except alopecia and certain laboratory values) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events at the time of start of treatment. Stable grade 2 peripheral neuropathy secondary to neurotoxicity and/or chronic stable grade 2 radiotherapy related toxicity from prior therapies may be considered on a case by case basis.
• No extensive radiotherapy (e.g., whole-pelvis, greater than 50% of neuroaxis, whole abdomen, whole body) within 12 months prior to start of study treatment.
• No bone marrow transplantation within 3 years prior to start of study treatment.
• Women and man of child bearing potential practicing an acceptable method of birth control during the study and at least 3 months after completion.

You may not qualify if:

• Current evidence of active and uncontrolled infection.
• Known Cirrhosis.
• Treatment refractory hypertension (blood pressure of systolic\> 150 mmHg and/or diastolic \> 95 mm Hg) which cannot be controlled by anti-hypertensive therapy;
• A history or evidence of current Class IV congestive heart failure.
• Current left ventricular ejection fraction \< 50%
• A history of acute coronary syndromes, coronary angioplasty.
• Use of nonsteroidal anti-inflammatory drugs - including Aspirin - and/or any steroids within 7 days prior to start of study treatment (excluding eye drops and ointments). Those medications must be stopped or replaced by another equivalent permitted medication at least 7 days prior to Day 1. Those medications will be allowed within 7 days prior to start of treatment only if required as premedication prior to CT scan for patients who are allergic to the contrast media.
• Patient has a known hypersensitivity to the components of study drug, its analogs, or drugs of similar chemical or biologic composition.
• Patients with known brain metastases.
• Patient has known psychiatric or substance abuse disorders that is uncontrolled and would interfere with cooperation with the requirements of the trial.
• Patient is Human Immunodeficiency virus (HIV)-positive.
• Evidence of active bleeding or bleeding diathesis, including blood or platelet transfusion within 14 days of the commencement of study treatment.
• Patients with known chronic active hepatitis, hepatitis B virus (HBV) or hepatitis C virus (HCV) carriers.
• Any known autoimmune disorders other than hypothyroidism or B12 deficiency.
• Female subjects who are pregnant or nursing.

Sponsors & Collaborators

• Efranat Ltd.: lead

Study Sites (2)

Rambam MC

Haifa, 31096, Israel

Location

Sheba Medical Center

Ramat Gan, 52621, Israel

Location

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2014
• First Posted: February 3, 2014
• Study Start: May 1, 2014
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: June 20, 2017

Record last verified: 2017-06

Locations

IL (2)