CORONA: A Study Using DeltaRex-G Gene Therapy for Symptomatic COVID-19

NCT04378244 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: AF20-203
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. COVID-19 causes life threatening complications known as Cytokine Release Syndrome or Cytokine Storm and Acute Respiratory Distress Syndrome. These complications are the main causes of death in this global pandemic. Over 1000 clinical trials are on-going worldwide to diagnose, treat, and improve the aggressive clinical course of COVID-19. The investigators propose the first, and so far, only gene therapy solution that has the potential to address this urgent unmet medical need. Rationale

1. 1.There are striking similarities between the damaged lung environment of COVID-19 induced ARDS and the tumor microenvironment (exposed collagen from tissue destruction by invading tumor or by the virus-induced immune response, and presence of activated proliferative cells (cancer cells and tumor associated fibroblasts or activated T cells, macrophages and pulmonary fibroblasts in COVID-19);
2. 2.DeltaRex-G is a disease-seeking retrovector encoding a cytocidal dominant negative human cyclin G1 as genetic payload). When injected intravenously, the DeltaRex-G nanoparticles has a navigational system that targets exposed collagenous proteins (XC proteins) in injured tissues (e.g. inflamed lung, kidney, etc.), thus increasing the effective drug concentration at the sites of injury, in the vicinity of activated/proliferative T cells evoked by COVID-19. Our hypothesis is that DeltaRex-G then enters the rapidly dividing T cells and kills them by arresting the G1cell division cycle, hence, reducing cytokine release and ARDS;
3. 3.Intravenous DeltaRex-G has minimal systemic toxicity due to its navigational system (targeting properties) that limits the biodistribution of DeltaRex-G only to areas of injury where exposed collagenous (XC) proteins are abnormally found; and
4. 4.DeltaRex-G is currently available in FDA approved "Right to Try" or Expanded Access Program for Stage 4 cancers for an intermediate size population. To gain this approval, FDA requires DeltaRex-G to have demonstrated safety and efficacy in early clinical trials.

Conditions

COVID-19; Cytokine Storm; Acute Respiratory Distress Syndrome

Keywords

cyclin G1; gene therapy; activated T cells

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose

  The study will employ the standard "cohort of three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient escalation will take place.

  3 weeks

Secondary Outcomes (5)

• Survival

  2 months

• Hospital Stay

  3 weeks

• Ventilator Therapy

  3 weeks

• Intensive Care Unit Stay

  3 weeks

• Cytokine Pattern

  3 weeks

Study Arms (1)

DeltaRex-G

EXPERIMENTAL

Escalating doses of DeltaRex-G i.v daily for 7 days as follows: Dose Level I: 3-6 patients will receive 1 x 10e11 cfu/dose Dose Level II: 3-6 patients will receive 2 x 10e11 cfu/ dose Dose Level III: 3-6 patients will receive 3 x 10e11 cfu/dose

Drug: DeltaRex-G

Interventions

DeltaRex-G DRUG

This is an open label, dose-seeking phase 1/2 study using escalating doses of DeltaRex-G given intravenously for 7 days in a hospital setting. The study will employ the standard "Cohort of Three" design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. If no DLT occurs in 3 patients, escalation to the next dose level will be permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. No intra-patient dose escalation will take place. Patients who do not complete the 7-day treatment will be replaced.

Also known as: DeltaRex-G Retroviral Vector Encoding a Cyclin G1 Inhibitor

DeltaRex-G

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 18 years of age
• Confirmed COVID-19 positive by viral RT PCR
• Patients with severe disease as evidenced by presence of pneumonia, diagnosis of ARDS in hospitalized patients
• Ability to understand the purposes and risks of the study and has signed and dated a written informed consent form approved by the investigator's IRB/Ethics Committee
• Willingness to comply with all study procedures and availability for the duration of the study.
• Adequate hematologic, renal or hepatic function defined by any of the following screening laboratory
• Values:
• i) Neutrophils \>1000/uL ii) Platelets \> 75,000/uL iii) Serum creatinine \<1.5 x ULN or creatinine clearance \< 60 mL/min (using the Cockcroft Gault formula) iv) AST/ALT, alk phos \<3 x ULN vi) Total Bilirubin \<1.5 x ULN
• All women of childbearing potential must have a negative pregnancy test and all subjects must agree to use highly effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 2 months after the last dose.

You may not qualify if:

• Females who are pregnant or breast-feeding
• Unwillingness or inability to comply with the study protocol for any reason

Sponsors & Collaborators

• Aveni Foundation: lead

Related Publications (12)

• Behrens A, Gordon EM, Li L, Liu PX, Chen Z, Peng H, La Bree L, Anderson WF, Hall FL, McDonnell PJ. Retroviral gene therapy vectors for prevention of excimer laser-induced corneal haze. Invest Ophthalmol Vis Sci. 2002 Apr;43(4):968-77.

  PMID: 11923236 BACKGROUND

• Chawla SP, Chua VS, Fernandez L, Quon D, Saralou A, Blackwelder WC, Hall FL, Gordon EM. Phase I/II and phase II studies of targeted gene delivery in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and osteosarcoma. Mol Ther. 2009 Sep;17(9):1651-7. doi: 10.1038/mt.2009.126. Epub 2009 Jun 16.

  PMID: 19532136 BACKGROUND

• Gordon EM, Zhu NL, Forney Prescott M, Chen ZH, Anderson WF, Hall FL. Lesion-targeted injectable vectors for vascular restenosis. Hum Gene Ther. 2001 Jul 1;12(10):1277-87. doi: 10.1089/104303401750270931.

  PMID: 11440621 BACKGROUND

• Chawla SP, Bruckner H, Morse MA, Assudani N, Hall FL, Gordon EM. A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer. Mol Ther Oncolytics. 2018 Dec 14;12:56-67. doi: 10.1016/j.omto.2018.12.005. eCollection 2019 Mar 29.

  PMID: 30705966 BACKGROUND

• Gordon EM, Hall FL. Rexin-G, a targeted genetic medicine for cancer. Expert Opin Biol Ther. 2010 May;10(5):819-32. doi: 10.1517/14712598.2010.481666.

  PMID: 20384524 BACKGROUND

• Hall FL, Gordon EM, Wu L, Zhu NL, Skotzko MJ, Starnes VA, Anderson WF. Targeting retroviral vectors to vascular lesions by genetic engineering of the MoMLV gp70 envelope protein. Hum Gene Ther. 1997 Dec 10;8(18):2183-92. doi: 10.1089/hum.1997.8.18-2183.

  PMID: 9449372 BACKGROUND

• Wu L, Liu L, Yee A, Carbonarohall D, Tolo V, Hall F. Molecular-cloning of the human cycg1 gene encoding a g-type cyclin - overexpression in human osteosarcoma cells. Oncol Rep. 1994 Jul;1(4):705-11. doi: 10.3892/or.1.4.705.

  PMID: 21607426 BACKGROUND

• Xu F, Prescott MF, Liu PX, Chen ZH, Liau G, Gordon EM, Hall FL. Long term inhibition of neointima formation in balloon-injured rat arteries by intraluminal instillation of a matrix-targeted retroviral vector bearing a cytocidal mutant cyclin G1 construct. Int J Mol Med. 2001 Jul;8(1):19-30. doi: 10.3892/ijmm.8.1.19.

  PMID: 11408944 BACKGROUND

• Zhu NL, Wu L, Liu PX, Gordon EM, Anderson WF, Starnes VA, Hall FL. Downregulation of cyclin G1 expression by retrovirus-mediated antisense gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation. Circulation. 1997 Jul 15;96(2):628-35. doi: 10.1161/01.cir.96.2.628.

  PMID: 9244236 BACKGROUND

• Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.

  PMID: 31978945 BACKGROUND

• Wu KJ, Yee A, Zhu NL, Gordon EM, Hall FL. Characterization of differential gene expression in monkey arterial neointima following balloon catheter injury. Int J Mol Med. 2000 Oct;6(4):433-40.

  PMID: 10998433 BACKGROUND

• Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.

  PMID: 32142651 BACKGROUND

MeSH Terms

Conditions

COVID-19; Cytokine Release Syndrome; Respiratory Distress Syndrome

Interventions

retrovector encoding mutant anti-cyclin G1

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Respiration Disorders

Study Officials

• Sant P Chawla, MD

  Mission Community Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Sequential assignment

Study Record Dates

• First Submitted: May 4, 2020
• First Posted: May 7, 2020
• Study Start: December 12, 2022
• Primary Completion: December 12, 2023
• Study Completion: July 12, 2024
• Last Updated: February 24, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share