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.
Drug: Ibrutinib
Given PO
Other Name: Array
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Inclusion Criteria:
- REGISTRATION INCLUSION
- (COHORT 1): Age >= 18 years
- COHORT 1: Laboratory confirmed diagnosis of COVID-19 through confirmation of
SARS-Co-V2 via reverse transcriptase polymerase chain reaction (RT-PCR) or any Food
and Drug Administration (FDA) approved method. The date of test result is required to
be =< 7 days prior to registration (NOTE: please use the date the test was resulted
and NOT the date when the test was collected)
- COHORT 1: Patient is on ibrutinib for the following approved FDA indications,
including:
- Chronic lymphocytic leukemia/Small lymphocytic lymphoma
- Mantle cell lymphoma
- Waldenstrom macroglobulinemia
- Marginal zone lymphoma
- COHORT 1: Patients have been on standard dose ibrutinib therapy (420 mg daily for
chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL] and
Waldenstrom/Waldenstrom macroglobulinemia, and 560 mg daily for mantle cell lymphoma
and marginal zone lymphoma) for at least 6 months prior to diagnosis of COVID-19
infection; and there is no evidence of disease progression of the primary malignancy
for which ibrutinib is being used
- NOTE: Patients are allowed to receive standard treatment as per local
institutional guidelines for the treatment of COVID-19 at the same time the
patient is enrolled on this trial
- COHORT 1: Provide informed written consent =< 7 days prior to registration
- COHORT 1: Willing to return to enrolling institution for follow-up (during the active
monitoring phase of the study)
- Note: During the active monitoring phase of a study (i.e., active treatment and
clinical follow-up), participants must be willing to return to the consenting
institution for follow-up. All of these visits will be virtual (phone or video)
ONLY
- COHORT 1: Willing to provide blood specimens for correlative research purposes
- RANDOMIZATION INCLUSION
- COHORT 2: Age >= 18 years
- COHORT 2: Laboratory confirmed diagnosis of COVID-19 through confirmation of
SARS-Co-V2 via RT-PCR or any FDA approved method. The date of test result is required
to be =< 7 days prior to registration (NOTE: please use the date the test was resulted
and NOT the date when the test was collected)
- COHORT 2: Patient is on ibrutinib for the following approved FDA indications,
including:
- Chronic lymphocytic leukemia/Small lymphocytic lymphoma
- Mantle cell lymphoma
- Waldenstrom macroglobulinemia
- Marginal zone lymphoma
- COHORT 2: Patients have been on standard dose ibrutinib therapy (420 mg daily for
CLL/SLL and Waldenstrom macroglobulinemia, and 560 mg daily for mantle cell lymphoma
and marginal zone lymphoma) for at least 6 months prior to diagnosis of COVID-19
infection; and there is no evidence of disease progression of the primary malignancy
for which ibrutinib is being used
- NOTE: Patients are allowed to receive standard treatment as per local
institutional guidelines for the treatment of COVID-19 at the same time the
patient is enrolled on this trial
- COHORT 2: Provide informed written consent =< 7 days prior to registration
- COHORT 2: Willing to return to enrolling institution for follow-up (during the Active
Monitoring Phase of the study)
- Note: During the Active Monitoring Phase of a study (i.e., active treatment and
clinical follow-up), participants must be willing to return to the consenting
institution for follow-up. All of these visits will be virtual (phone or video)
ONLY
- COHORT 2: Willing to provide blood specimens for correlative research purposes
- COHORT 2: Absolute neutrophil count (ANC) > 750 cells/mm^3 (0.75 x 10^9/L)
- COHORT 2: Platelet count > 50,000 cells/mm^3 (50 x 10^9/L)
- COHORT 2: Estimated creatinine clearance (CrCl) >= 30 mL/min (Cockcroft-Gault)
- COHORT 2: Bilirubin =< 2.0 x upper limit of normal (ULN) (unless bilirubin rise is due
to Gilbert's syndrome or of non-hepatic origin)
- COHORT 2: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 5 x ULN
- COHORT 2: Prothrombin time (PT)/International normal ratio (INR) < 1.5 x (upper limit
of normal) ULN and partial thromboplastin time (PTT) (activated partial thromboplastin
time [aPTT]) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or
bleeding disorder)
Exclusion Criteria:
- REGISTRATION EXCLUSION
- COHORT 1: Patient is receiving ibrutinib therapy for chronic graft-versus-host disease
(cGVHD)
- COHORT 1: Patient is currently receiving (or has in the past 6 months) another
treatment in combination with ibrutinib, such as anti-CD20 monoclonal antibody, BCL-2
antagonists such as venetoclax, or other novel treatments or chemotherapeutic agents.
For clarification regarding specific medications not listed here, please discuss with
the principal investigator
- COHORT 1: Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug and while
on study
- COHORT 1: Concomitant use of a strong CYP3A inhibitor
- COHORT 1: Vaccinated with a live, attenuated vaccine within 4 weeks
- COHORT 1: Patients with chronic liver disease and hepatic impairment meeting Child
Pugh class C
- COHORT 1: History of stroke or intracranial hemorrhage within 6 months before
registration
- COHORT 1: History of bleeding diathesis (e.g. hemophilia, von Willebrand/Waldenstrom
disease)
- COHORT 1: Clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to registration
- COHORT 1: Chemotherapy for other malignancies
- COHORT 1: Concurrent systemic immunosuppressant therapy within 21 days of the first
dose of study drug with the exception of that which is part of the standard of care
for COVID-19
- COHORT 1: Major surgery within 4 weeks of registration
- COHORT 1: Female subjects who are pregnant, or breastfeeding, or planning to become
pregnant while enrolled in this study or within 1 month of last dose of study drug.
Male subjects who plan to father a child while enrolled in this study or within 3
months after the last dose of study drug
- RANDOMIZATION EXCLUSION
- COHORT 2: Patient is receiving ibrutinib on a clinical trial for their underlying
B-cell malignancy
- COHORT 2: Patient is receiving ibrutinib therapy for chronic graft-versus-host disease
(cGVHD)
- COHORT 2: Patient is currently receiving (or has in the past 6 months) another
treatment in combination with ibrutinib, such as anti-CD20 monoclonal antibody, BCL-2
antagonists such as venetoclax, or other novel treatments or chemotherapeutic agents.
For clarification regarding specific medications not listed here, please discuss with
the principal investigator
- COHORT 2: Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug and while
on study
- COHORT 2: Concomitant use of a strong CYP3A inhibitor
- COHORT 2: Vaccinated with a live, attenuated vaccine within 4 weeks of registration
- COHORT 2: Patients with chronic liver disease and hepatic impairment meeting Child
Pugh class B and C
- COHORT 2: History of stroke or intracranial hemorrhage within 6 months before
registration
- COHORT 2: History of bleeding diathesis (e.g. hemophilia, von Willebrand disease)
- COHORT 2: Clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome within 6 months prior to registration
- COHORT 2: Chemotherapy for other malignancies
- COHORT 2: Concurrent systemic immunosuppressant therapy =< 21 days of the first dose
of study drug with the exception of that which is part of the standard of care for
COVID-19
- COHORT 2: Major surgery within 4 weeks of registration
- COHORT 2: Female subjects who are pregnant, or breastfeeding, or planning to become
pregnant while enrolled in this study or within 1 month of last dose of study drug.
Male subjects who plan to father a child while enrolled in this study or within 3
months after the last dose of study drug
- COHORT 2: Patients stopped ibrutinib >= 7 days prior to registration, for any reason
- COHORT 2: Patient is an active participant on investigational therapy through an
Institutional Review Board (IRB) approved clinical trial for COVID-19 (NOTE:
Participation through compassionate use protocol or expanded access is permitted)
- COHORT 2: At time of registration, the patient requires:
- Endotracheal intubation and mechanical ventilation
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Sameer A Parikh, Principal Investigator
Academic and Community Cancer Research United