Tocilizumab for Patients With Cancer and COVID-19 Disease

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT04370834
• Collaborator: (none)
• Enrollment: 1
• Locations: 5
• Arm: 1
• Actual Duration (Months): 7.6
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II expanded access trial will study how well tocilizumab works in reducing the serious symptoms including pneumonitis (severe acute respiratory distress) in patients with cancer and COVID-19. COVID-19 is caused by the SARS-CoV-2 virus. COVID-19 can be associated with an inflammatory response by the immune system which may also cause symptoms of COVID-19 to worsen. This inflammation may be called "cytokine storm," which can cause widespread problems in the body. Tocilizumab is a medicine designed to block the action of a protein called interleukin-6 (IL-6) that is involved with the immune system and is known to be a key factor for problems with excessive inflammation. Tocilizumab is effective in treating "cytokine storm" from a type of cancer immunotherapy and may be effective in reducing the inflammatory response and "cytokine storm" seen in severe COVID-19 disease. Treating the inflammation may help to reduce symptoms, improve the ability to breathe without a breathing machine (ventilator), and prevent patients from having more complications.

Condition or Disease	Intervention/Treatment	Phase
Hematopoietic and Lymphoid Cell Neoplasm; Malignant Solid Neoplasm; Pneumonia; Pneumonitis; Severe Acute Respiratory Distress Syndrome; Symptomatic COVID-19 Infection Laboratory-Confirmed	Biological: Tocilizumab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To enhance access to tocilizumab for patients who cannot participate in the randomized COVACTA trial with specific emphasis on patients with cancer, especially those who belong to high-risk and minority populations and children.

2. To provide observations on clinical outcomes associated with tocilizumab administration in cancer patients with severe acute respiratory syndrome (SARS) coronavirus 2 (COVID-19) disease.

SECONDARY OBJECTIVE:

1. To estimate the proportion of patients whose level of institutional care does not further escalate following administration of tocilizumab.

EXPLORATORY OBJECTIVES:

1. To estimate the number of days intensive care unit (ICU) patients spent in the ICU.

II. To evaluate the mortality rate of patients:

IIa. 30-day and 60-day mortality in patients in the ICU.

IIb. Evaluate the 14-, 30- and 60-day mortality rate following infusion of tocilizumab.

1. To evaluate overall survival.

2. To describe the proportion of patients progressing to ventilator support after tocilizumab therapy.

3. Evaluate the clinical course following administration of tocilizumab.

Va. To evaluate the development of additional infections.

Vb. To evaluate the side effects following tocilizumab.

Vc. To evaluate impact on inflammatory markers.

VI. Evaluate the duration of time:

VIa. To removal from mechanical ventilator support.

VIb. To step-down of institutional care requirements.

VIc. To discharge from the ICU to lower level.

VId. To hospital discharge.

VIe. To resolution of clinical symptoms.

VIf. To time of defervescence.

VIg. To normalization of disease-related laboratory abnormalities.

1. Exploratory biologic correlates.

VIIa. To evaluate cytokine levels pre and post-tocilizumab, specifically evaluating IL-6.

VIIb. To evaluate SARS-coronavirus (CoV)-2 viral loads pre and post-tocilizumab.

VIIc. To determine the pharmacokinetics of tocilizumab in order to facilitate exposure-response analysis.

VIId. To correlate clinical outcomes with changes in cytokine levels and SARS-CoV-2 viral loads.

OUTLINE:

Patients receive tocilizumab intravenously (IV) over 60 minutes. A second dose may be given if there is sustained or recurrent fever, no decrease or not more than a 1-category improvement on the 7-category ordinal scale (only stabilization or partial improvement following first dose), or a >= 1-category worsening on the 7-category ordinal scale from nadir.

After completion of study treatment, patients are followed up for at least 60 days, and, when possible, up to 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Tocilizumab in Hospitalized Cancer Patients With Coronavirus 2019 (SARS-CoV-2) and Severe Complications of Coronavirus Disease 19 (COVID-19)
• Actual Study Start Date: May 28, 2020
• Actual Primary Completion Date: Jan 14, 2021
• Actual Study Completion Date: Jan 14, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Other (tocilizumab) Patients receive tocilizumab IV over 60 minutes. A second dose may be given if there is sustained or recurrent fever, no decrease or not more than a 1-category improvement on the 7-category ordinal scale (only stabilization or partial improvement following first dose), or a >= 1-category worsening on the 7-category ordinal scale from nadir.	Biological: Tocilizumab; Given IV; Other Names: Actemra Immunoglobulin G1, Anti-(Human Interleukin 6 Receptor) (Human-Mouse Monoclonal MRA Heavy Chain), Disulfide with Human-Mouse Monoclonal MRA Kappa-Chain, Dimer MRA R-1569 RoActemra

Outcome Measures

Primary Outcome Measures

1. Number of Participants With at Least 1 Point Reduction in Score on 7-category Clinical Status Ordinal Scale [Day 14 after tocilizumab administration]

   7-category Clinical Status Ordinal Scale: Discharge Non-ICU, hospital ward, No O2 Non-ICU, hospital ward, on O2 ICU or non-ICU, requires non-invasive ventilatory support or high flow O2 ICU requires mechanical or imminent ventilation/intubation ICU requires ECMO and additional O2 support and organ support, e.g. vasopressors, renal replacement therapy Death

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must have an active cancer diagnosis or have completed therapy within 12 months of initiation of protocol specified therapy. This includes:

• Subjects with a new cancer diagnosis who have not yet initiated cancer therapy

• Subjects on active or have recently completed cancer-directed therapy including chemotherapy, radiation therapy, immunotherapy or hormonal therapy amongst others

• Myelosuppressive chemotherapy for patients in remission (e.g., adjuvant chemotherapy for breast cancer, acute myeloid leukemia [AML] consolidation) is prohibited until clinical recovery (1 or 2 on the 7-category ordinal scale)

• Subjects on any investigational therapy for their underlying cancer, investigational COVID-19 anti-viral agents, or convalescent serum aimed at treating COVID-19 disease are eligible. Investigators are reminded to check whether the other investigational study(s) the patient is participating on specifically exclude tocilizumab and to adjudicate best clinical management decision for the specific patient

• Subjects who have undergone hematopoietic stem cell transplant within the past 12 months, or are continued on graft versus host disease (GVHD) therapy, are also eligible

• COVID-19 Diagnosis: Patients hospitalized with COVID-19 pneumonia confirmed by:

• Radiographic findings concerning for COVID-19 pneumonia AND

• Confirmatory SARS-CoV-2 positive result using any testing assay, or (with or without a confirmatory test) with suspicion of COVID-19 disease owing to belonging to a high-risk demographic group or living and/or working in high-risk settings or with known exposure AND

• Oxygen saturation (SpO2) on room air =< 93% or PaO2/FiO2 < 300 mmHg

• Age >= 2 years

• Patients must have adequate organ function as assessed by the treating investigator to administer tocilizumab

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 10 x institutional upper limit of normal

• Patients with low blood counts attributable to cancer therapy or underlying malignancy are eligible

• Patients may be on other therapies for COVID-19 including investigational and not limited to corticosteroids, azithromycin, chloroquine, hydroxychloroquine

• For patients already enrolled on other investigational studies for COVID-19, study investigators should verify that co-enrollment on this study is permissible as per the eligibility of the other study

• Human immunodeficiency virus (HIV)-infected patients are eligible for this trial unless they have opportunistic complications of acquired immunodeficiency syndrome (AIDS) other than the cancer they have

• For patients with evidence of chronic hepatitis B virus (HBV) infection, should be on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection should be on treatment if indicated

• The effects of tocilizumab on the developing human fetus are unknown

• Pregnancy: Based on animal data, may cause fetal harm. Tocilizumab may be given if in the physician's judgment the patient's life is threatened without potential effective therapy

• Women of childbearing potential must agree to use birth control or remain abstinent for the duration of the study and for at least 28 days following the last dose of tocilizumab. Pregnancy tests should be done based on the discretion of the patient and physician.

• Nursing mothers: Discontinue drug or nursing taking into consideration importance of drug to mother

• Men must agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, for the duration of the study and for at least 28 days following the last dose of tocilizumab

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

• Prior or concurrent utilization of IL-6 specific targeting strategies for treatment of COVID-19 that showed no benefit after maximum dosing; (patients who have only received 1 prior dose and there was evidence of potential benefit may be eligible)

• This includes siltuximab, tocilizumab, and sarilumab

• Known hypersensitivity or history of severe allergic reaction to tocilizumab or other monoclonal antibodies

• Any serious medical condition or active uncontrolled infections (besides COVID-19) that, in the investigator's judgement, preclude the subject's safe participation in the study

• Examples: Active tuberculosis (TB) infection

• Active diverticulitis because of severe flairs in disease leading risk of bowel perforation

• Patients in whom, in the opinion of the treating physician, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments, will be excluded from the study

• Patients receiving or planning to receive any investigational agents other than tocilizumab are ineligible for this study, with the following exceptions:

• Investigational agents directed at a patient's underlying cancer are allowed.

• Investigational SARS-CoV-2 anti-viral agents

• Convalescent serum directed at COVID-19 disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute	Rockville	Maryland	United States	20850
2	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
3	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
4	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
5	Valley Medical Center	Renton	Washington	United States	98055

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Richard F Little, National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 4, 2020

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04370834
• Other Study ID Numbers: NCI-2020-02987; NCI-2020-02987; TRC-10446; TRC-10446
• First Posted: May 1, 2020
• Last Update Posted: Jul 20, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: COVID-19; Pneumonia; Laboratory Infection; Neoplasms; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Immunoglobulins; Immunoglobulin G

Study Results

Participant Flow

Arm/Group Title	Other (Tocilizumab)
Arm/Group Description	Patients receive tocilizumab IV over 60 minutes. A second dose may be given if there is sustained or recurrent fever, no decrease or not more than a 1-category improvement on the 7-category ordinal scale (only stabilization or partial improvement following first dose), or a >= 1-category worsening on the 7-category ordinal scale from nadir. Tocilizumab: Given IV
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Other (Tocilizumab)
Arm/Group Description	Patients receive tocilizumab IV over 60 minutes. A second dose may be given if there is sustained or recurrent fever, no decrease or not more than a 1-category improvement on the 7-category ordinal scale (only stabilization or partial improvement following first dose), or a >= 1-category worsening on the 7-category ordinal scale from nadir. Tocilizumab: Given IV
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	0 0%
>=65 years	1 100%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Cohort (Count of Participants)
Cohort A1	1 100%
Cohort A2	0 0%
Cohort B1	0 0%
Cohort B2	0 0%
Cancer type (Count of Participants)
Hematologic	1 100%
Solid tumor	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With at Least 1 Point Reduction in Score on 7-category Clinical Status Ordinal Scale
Description	7-category Clinical Status Ordinal Scale: Discharge Non-ICU, hospital ward, No O2 Non-ICU, hospital ward, on O2 ICU or non-ICU, requires non-invasive ventilatory support or high flow O2 ICU requires mechanical or imminent ventilation/intubation ICU requires ECMO and additional O2 support and organ support, e.g. vasopressors, renal replacement therapy Death
Time Frame	Day 14 after tocilizumab administration

Outcome Measure Data

Analysis Population Description

No patients were accrued to Cohorts A2, B1, or B2.

Arm/Group Title	Cohort A1	Cohort A2	Cohort B1	Cohort B2
Arm/Group Description	Clinical Status Ordinal Scale 3-4, Not on mechanical ventilation at time of registration and no immediate plan for intubation, At least 30 kg	Clinical Status Ordinal Scale 3-4, Not on mechanical ventilation at time of registration and no immediate plan for intubation, Less than 30 kg	Clinical Status Ordinal Scale 5-6, On mechanical ventilation at time of enrollment or imminent intubation indicated, At least 30 kg	Clinical Status Ordinal Scale 5-6, On mechanical ventilation at time of enrollment or imminent intubation indicated, Less than 30 kg
Measure Participants	1	0	0	0
Count of Participants [Participants]	1 100%

Adverse Events

Time Frame	30 days after tocilizumab administration
Adverse Event Reporting Description	One patient was enrolled to this trial. This patient enrolled to Cohort A1.
Arm/Group Title	Cohort A1		Cohort A2		Cohort B1		Cohort B2
Arm/Group Description	Clinical Status Ordinal Scale 3-4, Not on mechanical ventilation at time of registration and no immediate plan for intubation, At least 30 kg		Clinical Status Ordinal Scale 3-4, Not on mechanical ventilation at time of registration and no immediate plan for intubation, Less than 30 kg		Clinical Status Ordinal Scale 5-6, On mechanical ventilation at time of enrollment or imminent intubation indicated, At least 30 kg		Clinical Status Ordinal Scale 5-6, On mechanical ventilation at time of enrollment or imminent intubation indicated, Less than 30 kg
All Cause Mortality
	Cohort A1		Cohort A2		Cohort B1		Cohort B2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Cohort A1		Cohort A2		Cohort B1		Cohort B2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Anemia	1/1 (100%)	1	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0
General disorders
Death	1/1 (100%)	1	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0
Infections and infestations
Sepsis	1/1 (100%)	1	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Cohort A1		Cohort A2		Cohort B1		Cohort B2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Investigations
Alanine aminotransferase increased	1/1 (100%)	1	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0
Aspartate aminotransferase increased	1/1 (100%)	1	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0
Blood bilirubin increased	1/1 (100%)	1	0/0 (NaN)	0	0/0 (NaN)	0	0/0 (NaN)	0

Limitations/Caveats

Early termination as randomized data did not support continuation.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.