This phase II trial studies the effects of ibrutinib in treating patients with B-cell malignancies who are infected with COVID-19. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ibrutinib is a first in class Bruton tyrosine kinase inhibitor (BTKi), for the treatment of B-cell malignancies. This study is being done to determine if taking ibrutinib after contracting COVID-19 will make symptoms better or worse.
PRIMARY OBJECTIVES: I. To characterize and describe the patterns of temporary interruption vs. continuation of ibrutinib after their coronavirus disease 2019 (COVID-19) diagnosis and their corresponding rates of hospitalization and/or death by day 28 in an observational cohort of COVID-19 infected patients treated with ibrutinib therapy as their standard of care. (Cohort 1) II. To determine if continuation of ibrutinib during COVID-19 infection among patients who are hospitalized can result in decreased need for mechanical ventilation and decreased mortality by day 28 compared to patients who suspend temporarily ibrutinib treatment after their COVID-19 diagnosis. (Cohort 2) SECONDARY OBJECTIVES I. To determine the average length of time from diagnosis of COVID-19 infection to need for hospitalization due to worsening disease. (Cohort 1) II. To determine the rate of viral clearance on days 15, 28, 42, and 56 after registration. (Cohort 1) III. To evaluate coagulation parameters at baseline, and on days 15 and 28 after registration. (Cohort 1) IV. To determine the incidence of arterial and venous thrombosis as well as bleeding complications. (Cohort 1) V. To evaluate patient-reported health status and quality of life using the patient reported outcome (PRO)-Common Terminology Criteria for Adverse Events (CTCAE). (Cohort 1) VI. To determine if patients develop a "flare phenomenon" if ibrutinib is stopped. (Cohort 1) VII. To evaluate the patterns and timing of restarting ibrutinib in those patients who suspended their ibrutinib treatment after their COVID-19 diagnosis. (Cohort 1) VIII. To evaluate the association of patient outcomes stratified by the Charlson Co-morbidity index (CCI). (Cohort 1) IX. To evaluate the safety and tolerability of continuation of ibrutinib. (Cohort 1) X. To evaluate if continued treatment with ibrutinib can reduce the proportion of patients who die due to any cause in the 28 days after randomization compared to patients who stop ibrutinib in COVID-19 positive patients who are hospitalized at the time of study enrollment. (Cohort 2) XI. To evaluate the incidence of mechanical ventilation in hospitalized patients, and whether continued ibrutinib therapy reduces this incidence compared to stopping ibrutinib. (Cohort 2) XII. To determine whether continued ibrutinib can significantly improve the viral clearance rate at baseline, and on days 8, 15, 28, 42 and 56 days after randomization compared to those who temporarily interrupt ibrutinib. (Cohort 2) XIII. To evaluate coagulation parameters at baseline, and on days 8, 15, and 28 after randomization among patients who continue ibrutinib compared to those who discontinue ibrutinib. (Cohort 2) XIV. To determine the incidence of arterial and venous thrombosis as well as bleeding complications in patients who continue ibrutinib compared to those who stop it. (Cohort 2) XV. To determine if patients who are randomized to stopping ibrutinib develop "flare phenomenon". (Cohort 2) XVI. To evaluate the association of patient outcomes stratified by the Charlson Co-morbidity index (CCI). (Cohort 2) CORRELATIVE RESEARCH OBJECTIVES: I. To evaluate the association of inflammatory status with COVID severity. II. To determine the proportion of patients who develop antibodies to SARS-CoV2, especially given that patients with B cell malignancies tend to have inadequate responses to vaccines and often suffer from hypogammaglobulinemia. III. To determine changes in the immune profile by advanced flow cytometry given that the status of the immune system , both innate and adaptive , may dictate ultimate host management and clearance of COVID infections. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT I: Patients may continue to receive ibrutinib orally (PO) daily or stop ibrutinib per provider's discretion. COHORT II: Patients are randomized to 1 of 2 arms. ARM 2A: Patients continue to receive ibrutinib PO daily in the absence of disease progression or unacceptable toxicity. ARM 2B: Patients undergo temporary interruption of ibrutinib for up to 28 days unless they are discharged home and are thought to be medically fit by the primary caregiver to resume therapy according to their primary treating oncologist. After completion of study treatment, patients are followed up at 42, 56, and 84 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Given PO
Ancillary studies
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Proportion of patients who require hospitalization for their COVID-19 disease or die (Cohort 1)
Will calculate the proportion of patients who were outpatient at the time of study entry, and evaluate whether or not patients in this cohort required hospitalization associated with their coronavirus disease 2019 (COVID-19) infection.
Time frame: Up to 28 days after study registration
Proportion of patients who require mechanical ventilation and/or die (Cohort 2)
Time frame: Up to 28 days after study entry
Rate of "flare phenomena" (Cohort I)
Will characterize and calculate the proportion of patients who develop a "flare phenomenon" if ibrutinib is stopped. Will calculate corresponding 95% exact binomial confidence intervals for these outcomes. These will be graphically and quantitatively compared, where chi-square or Mantel-Haenszel-Cochran tests will be used to compare the numbers of patients who have the incident event of interest between treatment arms or other groups of interest.
Time frame: Up to 84 days
Patient-reported health and symptom status (Cohort I)
We will evaluate and characterize baseline status and changes in 8 primary COVID-19 related symptoms in these outpatient subjects: fever, loss of smell, cough, shortness of breath, fatigue, aching muscles, diarrhea, and decreased appetite. These will be assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Resolution of symptoms will be defined as no fever, no loss of smell, and severity or frequency of the remaining six symptoms rated as 0 (none/never) or 1 (mild/rarely) on the PRO-CTCAE.
Time frame: Up to 84 days
Patterns on ibrutinib therapy during COVID-19 infection (Cohort I)
We will characterize and summarize overall and by B-cell histologic diagnosis whether or not patients suspend their ibrutinib therapy while in an outpatient setting during the first 28 days on study, and patterns of resumption of ibrutinib. Specifically, we will evaluate this outcome by assessing the number of days patients received ibrutinib in the first 28 days after enrollment on this trial.
Time frame: Up to 84 days
Reasons for hospitalization (Cohort I)
Time frame: Up to 84 days
Mortality (Cohort II)
Time frame: Up to 84 days
Time to hospital discharge (Cohort II)
Time frame: Up to 84 days
Intubation and oxygen supplementation (Cohort II)
Will characterize and summarize the need for and duration of oxygen supplementation.
Time frame: Up to 84 days
Incidence of "flare phenomena" (Cohort II)
Time frame: Up to 84 days
Viral clearance
The proportions of patients who are documented as having viral clearance at the various time points will be summarized at each time point within each treatment arm. These proportions will be evaluated within as well as across the cohorts. Within each cohort, we will compare these rates at each of the time points using chi-square or Mantel-Haenszel-Cochran tests to assess differences between treatment arms or groups. Further, logistic regression models will be used to assess incidence of viral clearance and how treatment arm and other demographic and clinical factors affect the ability of patients to achieve viral clearance.
Time frame: On days 15, 28, 42, and 56 after registration
Development of COVID-19 antibodies
The proportion of patients who are able to develop COVID-19 antibodies by days 15 and 28, defined as the number of patients who have a threshold level of detectable COVID-19 antibodies divided by the total number of patients in the specific cohort/arm.
Time frame: Up to 28 days
Coagulopathy and thrombosis measures
Time frame: Up to 28 days
Cytokine measures
Will evaluate the baseline as well as change in plasma cytokines between treatment arms: IL-1beta, IL-1Ralpha, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL- IL-9, IL-10, IFNgamma, IP10, TNFalpha in longitudinal samples.
Time frame: Up to 84 days
Immune subset measures
Will evaluate the baseline as well as change in several immune cell subsets, including CD3 T cells, CD4 T-helper cells (and their subsets), CD8 T-suppressor cells (and their subsets), NK cells, B cells, and monocytes.
Time frame: Up to 84 days
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