Rintatolimod and IFN Alpha-2b for the Treatment of COVID-19 in Cancer Patients

Study Overview
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Brief Summary
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This phase I/IIa trial studies the best dose and side effects of rintatolimod and interferon (IFN) alpha-2b in treating cancer patients with COVID-19 infection. Interferon alpha is a protein important for defense against viruses. It activates immune responses that help to clear viral infection. Rintatolimod is double stranded ribonucleic acid (RNA) designed to mimic viral infection by stimulating immune pathways that are normally activated during viral infection. Giving rintatolimod and interferon alpha-2b may activate the immune system to limit the replication and spread of the virus.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety of the combination of intravenous (i.v.) rintatolimod administered with or without i.v. IFN alpha (recombinant interferon alfa-2b [Intron A]) in patients with cancer with coronavirus disease 2019 (COVID-19). II. Determine the kinetics of viral load in nasopharyngeal swabs in the course of treatment and Days 7 and 14. SECONDARY OBJECTIVES: I. To assess the efficacy of the treatment combination in patients with cancer with COVID-19. II. Determine the kinetics of viral load in the peripheral blood in the course of treatment and Days 7 and 14. III. Determine the kinetics of changes of the immune subsets and circulating inflammatory mediators (including C-reactive protein [CRP], cytokines, chemokines, interferons) in peripheral blood in the course of treatment and Days 7 and 14. IV. Determine the induction of known mediators of antiviral immunity that include (myxovirus resistance gene, MxA; protein Kinase R (PKR); oligoadenylate synthetase-2 (OAS2); RNAse-L, IFN-stimulated gene-15 (ISG15); IFN-induced proteins with tetratricopeptide repeats (IFIT1) and IFN-inducible transmembrane protein 3 (IFITM3), TLR3, RIG-I, MDA5, IRF3, IRF7, in nasopharyngeal swabs material and blood cells of patients on all tiers of treatment. OUTLINE: This is a phase I, dose-escalation study of recombinant interferon alfa-2b followed by a phase II study. LEAD-IN PHASE: Patients receive rintatolimod IV over 2.5-3 hours on day 1 and day 3 (or 4). Subsequent patients are randomized to 1 of 2 arms. ARM I: Patients receive rintatolimod IV over 2.5-3 hours and recombinant interferon alfa-2b IV over 20 minutes on day 1 and on day 3 or 4 in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive standard of care. EXPANSION COHORT: Patients are randomized to 1 of 2 arms. ARM III: Patients receive rintatolimod IV over 2.5-3 hours once. ARM IV: Patients receive standard of care. Patients are followed up at days 7, 14 and 30 after initiation of the study regimen.

Official Title
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Phase 1/2A Study of Rintatolimod and IFN Alpha Regimen in Cancer Patients With COVID-19

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Symptomatic COVID-19 Infection Laboratory-Confirmed

Intervention / Treatment
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* Other: Best Practice
* Biological: Recombinant Interferon Alfa-2b
* Drug: Rintatolimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: INCLUSION CRITERIA (MAIN COHORT): Patients with cancer, with the exception of patients with active acute leukemia and allogeneic hematopoietic stem cell transplant recipients. Patients may be on active therapy or received therapy (e.g., chemotherapy, radiation or surgery) within 7 years. Patients with active cancer who have not yet been treated (e.g. newly diagnosed cancer or early stage myelodysplastic syndrome [MDS] or chronic lymphocytic leukemia [CLL]) are eligible. Basal cell cancer and carcinoma in situ treated with local excision alone do not qualify for inclusion Presence of symptomatic infection, defined by fever (temperature [T] >= 38 degrees Celsius [C]) OR respiratory symptoms (cough, nasal congestion, or shortness of breath) OR lung infilitrates on chest X-ray or CT imaging. Diagnosis of COVID-19 is based on polymerase chain reaction (PCR) testing of respiratory samples. Age equal to >= 18 years or older (children are excluded because COVID-19 typically has a milder course in children, and lack of safety data of this regimen in children) Platelet >= 75,000/uL Hemoglobin >= 9 g/dL Hematocrit >= 27% Absolute neutrophil count (ANC) >= 1000/uL Creatinine clearance >= 50 mL/min (Cockcroft-Gault Equation-note: plasma creatine instead of serum is used at Roswell Park) Total bilirubin =< 2 X institutional upper limit of normal (ULN) Aspartate transaminase (AST) (plasma) and alanine transferase (ALT) (plasma) =< 2 X institutional ULN Plasma amylase and lipase =< 2 X institutional ULN In the absence of COVID-19, a life expectancy of 6 months is expected Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure NOTE: For blood chemistry labs, Roswell Park clinical blood chemistries are performed on plasma unless otherwise indicated EXPANSION COHORT: Patients with cancer or allogeneic stem cell transplant recipients with and without a cancer diagnosis Patients with cancer may be on active therapy or received therapy (e.g., chemotherapy, radiation or surgery) within 7 years Patients with active cancer who have not yet been treated (e.g. newly diagnosed cancer or early stage MDS or CLL) are eligible Basal cell cancer and carcinoma in situ treated with local excision alone do not qualify for inclusion Presence of symptomatic infection, defined by fever (T >= 38.0 degrees C ) OR respiratory symptoms (cough, nasal congestion, or shortness of breath) OR lung infiltrates by chest X-ray or CT imaging. Diagnosis of COVID-19 is based on PCR testing of respiratory samples. Severe infection is excluded Age equal to >= 18 years or older (children are excluded because COVID-19 typically has a milder course in children, and lack of safety data of this regimen in children). In the absence of COVID-19, a life expectancy of 6 months is expected Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure. There may be specific instances when the patient can't provide informed consent, e.g. they require mechanical ventilation and are sedated, in which case a health care proxy will be able to provide informed consent. Patients with temporary cognitive impairment will be consented once their capacity has returned. Patients with chronic cognitive impairment, e.g. dementia, that precludes informed consent will not be enrolled. Exclusion Criteria: EXCLUSION CRITERIA (MAIN COHORT): Patients with severe COVID-19 infection defined by pulmonary infiltrates on chest x-ray or computed tomography (CT) imaging plus one of the following: room air oxygen saturation (SaO2) =< 92%, room air partial pressure of oxygen (PaO2) < 70 mm Hg, or partial pressure of oxygen in arterial blood (PaO2)-PaO2 (alveolar gas) >= 35 mm Hg Contraindication to recombinant (r)-INFalpha based on prior hypersensitivity, autoimmune hepatitis, decompensated liver disease Patients who have active acute myeloid leukemia or acute lymphoid leukemia or are allogeneic hematopoietic stem transplant recipients. Acute leukemia in remission and chronic leukemias are not exclusion criteria Cardiac events: Acute coronary syndrome, myocardial infarction, or ischemia within past 3 months New York Heart Association classification of III or IV congestive heart failure Unwilling or unable to follow protocol requirements Patients with known serious mood disorders Any additional condition, such as pre-existing inflammatory lung disease, which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs Concurrent infections, e.g. bacterial pneumonia or sepsis, that would make it difficult to evaluate clinical response to therapy or study drug toxicities Therapies known to cause cytokine release syndrome (CRS), e.g. engineered T cells, within 30 days Patients at high risk for tumor lysis syndrome Concurrent active pneumonitis predating COVID-19, such as from checkpoint inhibitor therapy, chemotherapy-associated toxicity, or radiation pneumonitis Autoimmune disease that requires systemic immunosuppression Protocol-defined baseline abnormalities in cell counts, renal, or hepatic function Any additional condition which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs EXCLUSION CRITERIA: EXPANSION COHORT: Patients with respiratory failure requiring mechanical ventilation with FIO2 of > 60%. Allogeneic hematopoietic stem cell transplant recipients with active pulmonary graft versus host disease (GvHD) (any grade) Cardiac events: Acute coronary syndrome, myocardial infarction, or ischemia within past 3 months, New York Heart Association classification of III or IV congestive heart failure Unwilling or unable to follow protocol requirements Any additional condition which in the investigator's opinion deems the participant an unsuitable candidate to receive the study drugs Cognitively impaired adults/adults with impaired decision-making capacity Individuals who are not yet adults (infants, children, teenagers) Pregnant women Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (rintatolimod, recombinant interferon alfa-2b)<br>Patients receive rintatolimod IV over 2.5-3 hours and recombinant interferon alfa-2b IV over 20 minutes on day 1 and on day 3 (or 4) in the absence of disease progression or unacceptable toxicity. | Biological: Recombinant Interferon Alfa-2b<br>* Given IV<br>* Other names: Viraferon;Drug: Rintatolimod<br>* Given IV<br>* Other names: Atvogen;|
| Active Comparator: Arm II/IV (standard of care)<br>Patients receive standard of care. | Other: Best Practice<br>* Receive standard of care<br>* Other names: standard therapy;|
| Experimental: Arm III (rintatolimod)<br>Patients receive rintatolimod IV over 2.5-3 hours once. | Drug: Rintatolimod<br>* Given IV<br>* Other names: Atvogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | This refers to the frequency of grade 3 or 4 AEs considered to be probably or definitely related to the treatment regimen. Toxicity will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE version [v] 5.0). | Up to 30 days post treatment intiation | 
| Kinetics of viral load | Will be assessed as cycle threshold values in nasopharyngeal swabs based on quantitative polymerase chain reaction (PCR) in the course of treatment and days 7 and 14. | Up to 14 days post treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy | Will be assessed by the frequency of these complications: (i) progression of infection requiring hospitalization; (ii) respiratory failure requiring mechanical ventilation (primary efficacy endpoint); and (iii) death within 30 days. If present, acute respiratory distress syndrome will be graded by Berlin criteria. | Up to 30 days post treatment initiation | 
| Kinetics of viral load | Will be assessed as cycle threshold values in the peripheral blood and nasopharyngeal swab based on quantitative PCR in the course of treatment and days 7 and 14. | Up to 14 days post treatment initiation | 
| Kinetics of changes of the immune subsets and circulating inflammatory mediators in peripheral blood | The circulatory inflammatory mediators include C-reactive protein (CRP), cytokines, chemokines, interferons. | Baseline up to day 14 post treatment initiation |