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Stimotimagene copolymerplasmid will be administered intratumoral once in a dose of 20 mkg of DNA per 1 cm3 of tumor (for cohort 1) and 40 mkg of DNA per 1 cm3 of tumor (for cohort 2).

Ganciclovir (Cimeven®) will be administrated intravenous twice a day at 12-hour intervals for 15 days.

Stimotimagene copolymerplasmid will be administered intratumorally twice with 5-day interval in the optimal dose selected at previous stage of the trial.

Ganciclovir (Cimeven®) will be administrated intravenous twice a day at 12-hour intervals for 15 days.

Stimotimagene copolymerplasmid will be administered intratumorally three times with 5-day interval in the optimal dose selected at first stage of the trial.

Ganciclovir (Cimeven®) will be administrated intravenous twice a day at 12-hour intervals for 15 days.

Intratumoral administration of gene therapy drug Stimotimagene copolymerplasmid

Intratumoral administration of Stimotimagene copolymerplasmid

Intravenous administration of prodrug Ganciclovir (Cymeven®)

Intravenous administration of Ganciclovir (Cymeven®)

Max Koksharov

Ludmila Zhukova

Igor Samoylenko

Lev Ashrafian

Aleksander Fedenko

The purpose of this study is to evaluate the safety and tolerability of different doses and administration regimens of Stimotimagene copolymerplasmid in patients with histologically confirmed diagnosis of solid tumor and/or its metastases.

Stimotimagene copolymerplasmid is an anti-tumor gene therapy drug, contains super-coiled plasmid DNA encapsulated in polycationic envelope (PPT: polyethyleneimine (PEI) - polyethylene glycol (PEG) - TAT peptide). The plasmid encodes two therapeutic genes: herpes simplex virus thymidine kinase (HSVtk) and human granulocyte-macrophage colony-stimulating factor (hGM-CSF). HSVtk converts the prodrug ganciclovir to a toxin in cells that have been transfected by Stimotimagene copolymerplasmid, GM-CSF stimulates proliferation and differentiation of antigen-presenting cells.

Stimotimagene copolymerplasmid therapy is two-staged: (1) intratumoral injection of Stimotimagene copolymerplasmid, (2) intravenous administration of ganciclovir (Cimeven®) This is the first-in-human study of Stimotimagene copolymerplasmid which will be conducted in three arms. In this study dose escalation (Arm1) and number of drug administrations (Arms 2 and 3) will be explored. All study parts will investigate the safety, tolerability and pharmacokinetic profile of Stimotimagene copolymerplasmid.

Safety, Tolerability and Pharmacokinetics Investigation of Stimotimagene Copolymerplasmid

An Open Multicenter Study of the Safety, Tolerability, and Pharmacokinetics of Different Doses of Stimotimagene Copolymerplasmid at Patients With Advanced-stage Solid Tumors With Cymeven® (Ganciclovir) Infusions

Assessment of presence/absence of dose-limiting toxicities (DLTs)

Assessment of frequency and severity of adverse events (CTCAE classification)

Assessment of number of cases of early termination of participation in the study due to the development of Serious Adverse Events and Other Adverse Events associated with the study therapy)

Assessment of quantitative content of plasmid DNA (pTKhGM) in patients' peripheral blood at:

Day -1 (baseline), Day 1 (4 h and 8 h after drug administration), Day 2 (24 h after drug administration), Day 3 (48 h after drug administration), Days 5, 7, 12, 17, 25, 30±3, 60±5, 90±7, 130±3 for patients from 1st step of the study; Day -1 (baseline), Day 1 (4 h and 8 h after drug administration), Day 2 (24 h after drug administration), Day 3 (48 h after drug administration), Day 6 (before drug administration and 8 h after drug administration), Days 7, 12, 17, 25, 30±3, 60±5, 90±7, 130±3 for patients from 2nd step of the study; Day -1 (baseline), Day 1 (4 h and 8 h after drug administration), Day 2 (24 h after drug administration), Day 3 (48 h after drug administration), Day 6 (before drug administration and 8 h after drug administration), Day 7, Day 11 (before drug administration and 8 h after drug administration), Days 12, 17, 25, 30±3, 60±5, 90±7, 130±3 for patients from 3rd step of the

Assessment of quantitative content of plasmid DNA (pTKhGM) in patients' urine at:

Day -1 (baseline), Day 1 (4 h and 8 h after drug administration), Day 2 (24 h after drug administration), Day 3 (48 h after drug administration), Days 5, 7, 12, 17, 25, 30±3, 60±5, 90±7, 130±3 for patients from 1st step of the study; Day -1 (baseline), Day 1 (4 h and 8 h after drug administration), Day 2 (24 h after drug administration), Day 3 (48 h after drug administration), Day 6 (before drug administration and 8 h after drug administration), Days 7, 12, 17, 25, 30±3, 60±5, 90±7, 130±3 for patients from 2nd step of the study; Day -1 (baseline), Day 1 (4 h and 8 h after drug administration), Day 2 (24 h after drug administration), Day 3 (48 h after drug administration), Day 6 (before drug administration and 8 h after drug administration), Day 7, Day 11 (before drug administration and 8 h after drug administration), Days 12, 17, 25, 30±3, 60±5, 90±7, 130±3 for patients from 3rd step of the study.

Gene Surgery LLC

Spots Global Cancer Trial Database for intratumoral administration of stimotimagene copolymerplasmid