Safety and Efficacy of Tag-7 Gene-modified Vaccine in Locally Advanced or Metastatic Malignant Melanoma or Kidney Cancer

Melanoma Clinical Trial

Official title:

An Open-label Study of the Safety and Efficacy of Tag-7 Gene-modified Tumor Cell-based Vaccine in Patients With Locally Advanced or Metastatic Malignant Melanoma or Renal Cell Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04180774
• Other study ID #: 07-???-?
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 31, 2001
• Est. completion date: December 31, 2018

Study information

• Verified date: November 2019
• Source: N.N. Petrov National Medical Research Center of Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study was designed to assess the safety and efficacy of inactivated tumor cells genetically modified with the TAG-7 gene as immunotherapy for cancer. Patients with melanoma or kidney cancer were included since they have immune-dependent tumors. Treatment was done in the adjuvant setting after complete cytoreduction of locally advanced or metastatic disease or in the therapeutic setting in patients where complete cytoreduction was impossible.

Description:

During the last decade, novel approaches for cancer treatment have been developed. Antitumor vaccines are one of the most promising approaches in tumor immunotherapy. Tumor cells possess low immunogenicity properties due to a number of the not completely understood mechanisms of resistance. One of the ways to overcome it is immune genes transfection. Genes encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and IL-12 have been used most commonly, both in preclinical studies and clinical trials. These cytokines are well known to participate in the systemic immune response. Several studies have shown that the professional antigen-presenting cells (APCs) of the host, rather than the vaccinating tumor cells themselves, are responsible for priming CD4+ and CD8+ T cells, both of which are required to generate systemic antitumor immunity. Recent findings indicate that the adaptive arm of immunity is governed by the innate immune mechanisms that control the co-stimulatory signaling of APCs. Recently, investigators identified a novel gene, tag7, also know as PGRP-S. The insect ortholog of the tag7/PGRP-S was shown to be involved in the innate immune response in Drosophila. In preclinical studies, tag7-modified mouse tumor cells induced a long-lasting T-cell dependent immune response in mice. The effectiveness of antitumor vaccination was demonstrated on different models of mouse tumors, particularly for melanoma cells (M3, B16, F10). Clinically important results of vaccine therapy were achieved in patients with melanoma and renal carcinoma in a number of studies. The results with this treatment are comparable to chemotherapy and immunotherapy. Investigators assume that one has to activate the innate component of immunity first, followed by the activation of the adaptive one, to make anticancer vaccines more effective. Thus, a phase I/II clinical trial has been performed to evaluate the feasibility and toxicity of treatment with autologous tumor cells modified with the tag7 gene, which has been shown to be involved in innate immunity mechanisms,

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: December 31, 2018
• Est. primary completion date: December 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed inform consent form.

2. Patients age = 18 years of age at the time of informed consent.

3. Ability to provide and understand written informed consent prior to any study procedures.

4. Histologically confirmed locally advanced or metastatic MM or RCC.

5. Tumor cell culture should be obtained and successfully transfected before inclusion.

6. No evaluable therapy with a proved survival advantage in the current patient setting.

7. The life expectancy of > 3 months as estimated by the investigator

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 -2 at Screening.

Exclusion Criteria:

1. Patient with any out-of-range laboratory values defined as:

• Serum creatinine > 1.5 × upper limit of normal (ULN) and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/minute

• Total bilirubin > 2.5 × ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN

• Alanine aminotransferase > 2.5 × ULN

• Aspartate aminotransferase > 2.5 × ULN

• Absolute neutrophil count < 1.5 × 109/L

• Platelet count < 100 × 109/L

• Hemoglobin < 80 g/L (blood transfusions permitted)

2. History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies

3. Any clinically significant unstable disease

4. Presence of symptomatic or untreated central nervous system (CNS) metastases

5. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug

6. Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated

7. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection

8. Malignant disease, other than that being treated in this study

9. Patients receiving systemic steroid therapy or any other systemic immunosuppressive medication at any dose level, as these may interfere with the mechanism of action of study treatment. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable

10. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)

Related Conditions & MeSH terms

• Carcinoma, Renal Cell
• Kidney Cancer
• Kidney Neoplasms
• Melanoma

Intervention

Biological:
• Tag-7 gene modified inactivated tumor cells
Patients received GMV once in three weeks subcutaneously in three points in the paravertebral region. One dose consisted of 10 million transfected and inactivated tumor cells. No dose reduction was allowed.

Locations

Country	Name	City	State
Russian Federation	N.N. Petrov Research Institute of Oncology Chemotherapy and Innovative Technologies Department	St. Petersburg

Sponsors (2)

Lead Sponsor	Collaborator
N.N. Petrov National Medical Research Center of Oncology	Institute of Gene Biology Russian Academy of Sciences

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events rate	CTC AE v.3 was used for safety assesment	From the fist injection to 3 month after the last injection
Secondary	Response rate	To assess the objective response rate (OR) RECIST v1.1 and irRC were used at the final assesment	every 8 weeks until disease progression or therapy completion, then every 3 month for 2 years, every 6 month for the next 2 years and annually thereafter
Secondary	Concentration of MICA in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Secondary	Concentration of TGF-ß1 in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Secondary	Concentration of IL-10 in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Secondary	Concentration of VEGF in patient's cultures supernatants	Factor production by culture of patient's tumor cells, used for vaccine preparation	Samples obtained before therapy start
Secondary	Number of T-cells in peripheral blood of patients	Absolute (10^9/L) of CD3+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of T-helper lympocytes in peripheral blood of patients	Absolute (10^9/L) concentration of CD4+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of Cytotoxic lymphocytes in peripheral blood of patients	Absolute (10^9/L) concentration of CD8+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of NK-lymphocytes in peripheral blood of patients	Absolute (10^9/L) concentration of CD16+CD56+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of CD38+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD38+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of HLA-DR+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of HLA-DR+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of CD71+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD71+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of B-lymphocytes cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD71+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Number of CD25+ cells in peripheral blood of patients	Absolute (10^9/L) concentration of CD25+ cells in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	IgA level	IgA (g/L) level in serum	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	IgG level	IgG (g/L) level in serum	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	IgM level	IgM (g/L) level in serum	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Spontaneous lymphocytes migration	Lymphocytes migration (U) without stimulation	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Kon-A stimulated migration	Lymphocyte migration after in vitro stimulation with Kon A (% inhibition of migration)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	PGA stimulated migration	Lymphocyte migration after in vitro stimulation with PGA (% inhibition of migration)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Ingestion rate of monocytes	Ingestion rate (%)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Ingestion rate of neutrophils	Ingestion rate (%)	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)
Secondary	Circulating immune complex level	Immune complexes (U) in peripheral blood	1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks)