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About
This phase II trial tests how well canakinumab works to prevent progression to cancer in patients with clonal cytopenias of unknown significance (CCUS). CCUS is a blood condition defined by a decrease in blood cells. Blood cells are composed of either red blood cells, white blood cells, or platelets. In patients with CCUS, blood counts have been low for a long period of time. Patients with CCUS also have a mutation in one of the genes that are responsible for helping blood cells develop. The combination of genetic mutations and low blood cell counts puts patients with CCUS at a higher risk to develop blood cancers in the future. This transformation from low blood cell counts to cancer may be caused by inflammation in the body. Canakinumab is a monoclonal antibody that may block inflammation in the body by targeting a specific antibody called the anti-human interleukin-1beta (IL-1beta).
Full description
PRIMARY OBJECTIVE:
I. To evaluate the length of time until development of a myeloid neoplasm (ie myelodysplastic syndrome [MDS], myeloproliferative neoplasm [MPN], chronic myelomonocytic leukemia [CMML], or acute myeloid leukemia [AML]) in high-risk clonal cytopenia of undetermined significance (CCUS) patients receiving canakinumab as therapeutic intervention compared to the control arm.
SECONDARY OBJECTIVES:
I. To determine the effect of canakinumab on hematological overall response rate.
II. To determine the effect of canakinumab on complete hematological response rate.
III. To determine the effect of canakinumab on response duration. IV. To determine the effect of canakinumab on overall survival. V. To determine the effect of canakinumab on mutational burden. VI. To determine the effect of canakinumab on infection-related adverse events. VII. To determine the effect of canakinumab on recovery of blood cell populations.
VIII. To determine the effect of canakinumab on cardiovascular episodes compared to a control arm.
IX. Patient reported outcomes will be collected using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C3).
EXPLORATORY OBJECTIVES:
I. To quantify changes in the bone marrow (BM) microenvironment according to immune cell constitution and cytokine levels over the course of canakinumab treatment compared to a control arm.
II. To characterize the inflammatory milieu in peripheral blood (PB) and BM samples by serial measurement and characterization of key cytokines (IL-1, IL-2, IL-6, TNF alpha and beta, and IFN-gamma), sensitivity of patient samples to these cytokines and relationships to various genes involved in clonal hematopoiesis.
III. To determine the dynamics of change in clone size of various CH genes in serial patient treatment and control samples, during the study, by a variety of assays including single cell sequencing, copy number alterations, and variant allele frequency (VAF) measurement to characterize differences in disease evolution.
IV. To collect serial measurement of immune cell populations in PB and BM of serial patient treatment and control samples, during the study, to characterize various immune cells involving both the innate and adaptive immune system including natural killer (NK) cell, T cell subsets namely effector, regulatory and memory T cells as well as various cell surface molecules such as checkpoint modulators (PD-1/PD-L1/TIM-3, LAG-3).
V. To understand the effect of global effects on the BM microenvironment of CH status/post (s/p) canakinumab treatment compared to the control patients using ribonucleic acid (RNA) sequencing and global methylation assays to further characterize unique genomic signatures in these patients.
OUTLINE: Patients are randomized to one of two arms.
ARM I: Patients receive canakinumab subcutaneously (SC) on study.
ARM II: Patients receive placebo SC on study.
All patients also undergo echocardiogram (ECHO) and chest x-ray during screening, collection of blood samples during screening and follow up, and bone marrow biopsy and aspiration throughout the trial.
Enrollment
Sex
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Volunteers
Inclusion criteria
Patients with age >= 18 with high-risk CCUS
Must meet ALL the following criteria:
Unexplained, clinically meaningful cytopenias (greater than 4 months) in one or more of the following lineages: erythroid cells, neutrophils, platelets. Clinically meaningful cytopenia is institution specific and threshold may vary on age, sex, and race. Decision-making should depend upon lab values specific to the institution and supersede public works. Based upon published work, significant cytopenias are defined as the following (must meet criteria in at least one lineage):
Erythroid Cells:
White Blood Cells:
Platelets:
MDS criteria not fulfilled
No other evidence of hematological malignancy
No or only mild (< 10%) bone marrow dysplasia
Blast cells < 5% detected via morphologic examination of blood and/or bone marrow smears which can also be supported by flow cytometry and/or immunohistochemical studies
Any of the following:
Ability to understand and willingness to sign the written informed consent document
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
Patients with a history of hypertension or active hypertension are strongly encouraged to optimize blood pressure control
Creatinine clearance greater than 45 ml/min using Cockcroft-Gault
Total bilirubin =< 1.5 x ULN
Aspartate transaminase (AST) < 3 x ULN
Alanine transaminase (ALT) < 3 x ULN
Exclusion criteria
Concurrent malignancy requiring active systemic therapy
Diagnosis of MDS or any other myeloid malignancy in the patient's lifetime
History of Hypersensitivity to canakinumab or drug of a similar class
Active infection requiring prompt evaluation and treatment or history of recurrent infections
Known active or recurrent hepatic disorder including cirrhosis, hepatitis B and C (via positive or indeterminate central laboratory [lab] results)
Subjects with active tuberculosis. In subjects with a history of tuberculosis but without active tuberculosis, if the results of the evaluation require treatment per local guidelines, then the treatment should be initiated before randomization (unless otherwise required by Health Authorities or Institutional Review Board (IRB) in which case curative treatment must be completed prior to screening)
Subjects with suspected or proven immunocompromised state or infections. If the results of this screening per local treatment guidelines or clinical practice require treatment for said infection then the patient is not eligible. Suspected or proven immunocompromised states or infections include:
Those with any other medical condition such as active infection, treated or untreated, which in the opinion of the investigator places the subject at an unacceptable risk for participation in immunomodulatory therapy. If in the opinion of the investigator, the patient's immunocompromised state does not pose an unacceptable risk for participation, in the absence of uncontrolled infection, and the patient does not have a history of serious infections (such as tuberculosis); then the patient may participate in this study.
Known history of testing positive for human immunodeficiency virus (HIV) infections. For countries where HIV status is mandatory: testing positive for HIV during screening using a local test.
Allogeneic bone marrow or solid organ transplant (history of any or within a certain period of time?)
Those requiring systemic or local treatment in doses with systemic effects e.g.:
Live or attenuated vaccination within 3 months prior to first dose of study drug (e.g. Measles/Mumps/Rubella [MMR], Yellow Fever, Rotavirus, Smallpox, etc.) and after initiation of canakinumab treatment
Use of erythropoietin stimulating agents (ESA) or growth factors within four weeks prior to the start of the study
Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment and for up to 130 days after last dose of study drug. Basic contraception methods include:
Primary purpose
Allocation
Interventional model
Masking
110 participants in 2 patient groups, including a placebo group
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Central trial contact
The Ohio State University Comprehensive Cancer Center
Data sourced from clinicaltrials.gov
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