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. 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. 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. 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. 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.
Background and Proposed Research Importance
Coronavirus disease 2019 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. 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. DeltaRex-G is a disease-seeking retrovector encoding a cytocidal dominant negative human
cyclin G1 as genetic payload. The DeltaRex-G nanoparticles has a navigational system
that targets exposed collagenous proteins in injured tissues, thus increasing the
effective drug concentration at the sites of injury, in the vicinity of
activated/proliferative T cells evoked by COVID-19. The DeltaRex-G then enters the
rapidly dividing T cells and kills them by arresting the G1cell division cycle, hence,
reducing cytokine release;
3. Intravenous DeltaRex-G has minimal systemic toxicity due to its disease-seeking
properties that limits the biodistribution of DeltaRex-G only to areas of injury where
exposed collagenous proteins are abnormally found; and
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.
Study Design This is a dose-seeking phase 1/2 study using escalating doses of DeltaRex-G
given intravenously for 7 days in a hospital setting, with a randomization schema at the MTD.
The study will include up to three cohorts with increasing DeltaRex-G doses as shown below.
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 within the same cohort of 3 will be treated in a staggered manner, i.e., the next
subject will receive the product only after the previous subject has completed administration
of all doses and has been evaluated on Day 14 (or one week after last DeltaRex-G infusion) to
assess safety. At the MTD, after 3 subjects in same cohort have been evaluated with no DLT,
subjects in the same cohort may be treated simultaneously.
Patients who do not complete the 7-day treatment will be replaced except if patient developed
DLT.
Randomization Schema:
At the highest dose level or when MTD is determined, nine (9) additional patients will be
randomized to the treatment arm + standard of care (SOC) vs. standard of care alone (n = 6
patients DeltaRex-G and 3 SOC in each group). Patients will be matched according to
symptomatology (e.g. SpO2 >94% at the time of screening), age (within 10 years or at least
less than or greater than 65 years), race (black vs non-black), and gender.
Dose of DeltaRex-G: Escalating doses of DeltaRex-G i.v daily for 7 days:
Number of Pts. Dose Level Dose, cfu Max.Volume/24 hrs
3-6 I 1 x 10e11 200 ml 3-6 II 2 x 10e11 200 ml 3-6 III 3 x 10e11 200 ml
Monitoring Plan:
Patient's clinical status including need or duration of mechanical ventilation therapy,
change in oxygen saturation, blood counts, lung, liver and kidney function and vital signs,
proinflammatory cytokines, including IL-6, IL-12, and tumor necrosis factor α, CRP, LDH,
D-Dimer, serum ferritin, chest X-ray are monitored as specified in the protocol and as needed
in hospitalized patients during the treatment period, one week later, and every month for 6
months.
Analysis of Primary Endpoint Safety analysis will be performed. The study will employ the
standard "cohort of three" design. 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.
Dose limiting toxicity, maximum tolerated dose, incidence and severity of adverse events and
significant laboratory abnormalities is the primary endpoint. Safety analysis will be
performed on all patients.
Patient incidence of all treatment-related AEs will be tabulated by system organ class and
preferred term. Tables of fatal adverse events, serious adverse events, treatment-related
AEs, and adverse events leading to withdrawal from investigation product will also be
provided. Summary statistics will be provided for total number of doses, average dose
administered, and duration of each treatment.
Analysis of Secondary Endpoint Efficacy analysis will be conducted. Change in clinical status
such as duration of fever, respiratory destress, pneumonia, cough, sneezing, diarrhea will be
documented. ECOG score, mortality, length of hospital stay, duration of respirator therapy,
duration of intensive care unit stay, and changes in cytokine pattern will be compared to
historical controls.
Drug: DeltaRex-G
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.
Other Name: DeltaRex-G Retroviral Vector Encoding a Cyclin G1 Inhibitor
Inclusion Criteria:
Individuals must meet all of the inclusion criteria in order to be eligible to participate
in the study, as follows:
- 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.
Exclusion Criteria:
All individuals meeting any of the exclusion criteria at baseline will be excluded from
study participation, as follows:
- Females who are pregnant or breast-feeding
- Unwillingness or inability to comply with the study protocol for any reason
Erlinda M Gordon, MD
818-726-3278
egordon@avenifoundation.org
Victoria Chua-Alcala, MD
310-552-9999
vchua@sarcomaoncology.com
Sant P Chawla, MD, Principal Investigator
Mission Community Hospital