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

• ClinicalTrials.gov Identifier: NCT04379518
• Recruitment Status: Suspended
• First Posted: May 7, 2020
• Last Update Posted: March 6, 2023
• Sponsor: Roswell Park Cancer Institute
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Roswell Park Cancer Institute

Tracking Information

• First Submitted Date: May 6, 2020
• First Posted Date: May 7, 2020
• Last Update Posted Date: March 6, 2023
• Actual Study Start Date: November 17, 2020
• Estimated Primary Completion Date: November 17, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 3, 2021)

• Incidence of adverse events (AEs) [ Time Frame: Up to 30 days post treatment intiation ]
  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).
• Kinetics of viral load [ Time Frame: Up to 14 days post treatment initiation ]
  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.

Original Primary Outcome Measures (submitted: May 6, 2020)

• Incidence of adverse events (AEs) [ Time Frame: Up to 30 days post treatment intiation ]
  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).
• Reduction of progression of infection requiring hospitalization [ Time Frame: Up to 30 days post treatment initiation ]
• Reduction of acute respiratory distress syndrome (ARDS) [ Time Frame: Up to 30 days post treatment initiation ]
  ARDS will be defined by Berlin criteria.
• 30-day mortality [ Time Frame: At 30 days post treatment initiation ]
  The binary endpoint of 30-day mortality will be analyzed using a logistic regression model.

Current Secondary Outcome Measures (submitted: May 3, 2021)

• Clinical efficacy [ Time Frame: Up to 30 days post treatment initiation ]
  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.
• Kinetics of viral load [ Time Frame: Up to 14 days post treatment initiation ]
  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.
• Kinetics of changes of the immune subsets and circulating inflammatory mediators in peripheral blood [ Time Frame: Baseline up to day 14 post treatment initiation ]
  The circulatory inflammatory mediators include C-reactive protein (CRP), cytokines, chemokines, interferons.

Original Secondary Outcome Measures (submitted: May 6, 2020)

• Kinetics of viral load in the peripheral blood and nasal swabs [ Time Frame: During the course of treatment up to day 28 ]
  Will be analyzed using quantitative polymerase chain reaction (PCR).
• Kinetics of changes of the immune subsets and circulating inflammatory mediators in peripheral blood [ Time Frame: During the course of treatment up to day 28 ]
  The circulatory inflammatory mediators include C-reactive protein (CRP), cytokines, chemokines, interferons.

Current Other Pre-specified Outcome Measures (submitted: May 3, 2021)

Known mediators of antiviral immunity [ Time Frame: Up to 30 days post treatment initiation ]

Will assess the induction of known mediators of antiviral immunity that include (myxovirus resistance gene, MxA; protein Kinase R; oligoadenylate synthetase-2; RNAse-L, IFN-stimulated gene-15 (ISG15); IFN-induced proteins with tetratricopeptide repeats, and IFN-inducible transmembrane protein 3, TLR3, RIG-I, MDA5, IRF3, IRF7, in nasopharyngeal swabs material and blood cells of patients on all tiers of treatment. Will also assess the expression of ACE2 (receptor for severe acute respiratory syndrome coronavirus 2 [SARS-Cov-2] entry) and potentially other genes involved in SARS-CoV-2 infection will be tested in nasopharyngeal samples.

• Original Other Pre-specified Outcome Measures (submitted: May 6, 2020): ARDS severity [ Time Frame: Up to 30 days post treatment initiation ]

Descriptive Information

• Brief Title: Rintatolimod and IFN Alpha-2b for the Treatment of COVID-19 in Cancer Patients
• Official Title: Phase 1/2A Study of Rintatolimod and IFN Alpha Regimen in Cancer Patients With COVID-19
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Other: Best Practice
  Receive standard of care
  Other Names:

  • standard of care
  • standard therapy
• Biological: Recombinant Interferon Alfa-2b
  Given IV
  Other Names:

  • Alfatronol
  • Glucoferon
  • Heberon Alfa
  • IFN alpha-2B
  • Interferon alfa 2b
  • Interferon Alfa-2B
  • Interferon Alpha-2b
  • Intron A
  • Sch 30500
  • Urifron
  • Viraferon
• Drug: Rintatolimod
  Given IV
  Other Names:

  • Ampligen
  • Atvogen

Study Arms

• Experimental: Arm I (rintatolimod, recombinant interferon alfa-2b)
  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.
  Interventions:

  • Biological: Recombinant Interferon Alfa-2b
  • Drug: Rintatolimod
• Active Comparator: Arm II/IV (standard of care)
  Patients receive standard of care.
  Intervention: Other: Best Practice
• Experimental: Arm III (rintatolimod)
  Patients receive rintatolimod IV over 2.5-3 hours once.
  Intervention: Drug: Rintatolimod

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Suspended
• Estimated Enrollment (submitted: May 3, 2021): 64
• Original Estimated Enrollment (submitted: May 6, 2020): 80
• Estimated Study Completion Date: November 17, 2023
• Estimated Primary Completion Date: November 17, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04379518
• Other Study ID Numbers: I 659920; NCI-2020-02317 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); I 659920 ( Other Identifier: Roswell Park Cancer Institute ); P30CA016056 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Roswell Park Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Roswell Park Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brahm H Segal; Roswell Park Cancer Institute

• PRS Account: Roswell Park Cancer Institute
• Verification Date: March 2023