Canakinumab and Darbepoetin Alfa for the Treatment of Lower-Risk Myelodysplastic Syndromes in Patients Who Have Failed Erythropoietin Stimulating Agents

Inclusion Criteria

• Subjects must have the nature of the study explained to them
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, bone marrow collection and other requirements of the study
• Subjects must provide a signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines
• Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization
• The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject’s normal care
• After signing the ICF and HIPAA Authorization, subjects will be evaluated for study eligibility during the Screening Period (no more than 28 days before study drug administration) according to the following further inclusion/exclusion criteria
• Documented diagnosis of myelodysplastic syndrome (MDS) by World Health Organization (WHO) criteria, further meeting the following criteria according to disease risk classification: * Lower risk (International Prognostic Scoring System [IPSS]-Risk [R] very low, low or int.) non-del(5q) patients: failed prior treatment with an erythropoiesis stimulating agent (ESA), defined as no response to at least 8 weeks of treatment, loss of response at any time point or progressive disease; or patients who would not be expected to benefit from frontline ESA therapy based on a baseline erythropoietin (EPO) level of > 500mU/mL. Patients receiving prior therapy with lenalidomide will also be included. * Lower risk (IPSS-R very low, low or int.) del(5q) patients: failed prior therapy with an ESA (as defined above) AND failed prior treatment with at least 4 cycles started of lenalidomide defined as no response to treatment, loss of response at any time point, or progressive disease/intolerance to therapy or patients who are not candidates for treatment with lenalidomide
• Patients must be transfusion dependent, defined as requirement for transfusion of at least 3 units of packed red blood cells (PRBCs) in the preceding 16 weeks for a Hgb < 9.0g/dL (see Appendix 4), or, in non-transfusion dependent patients (< 3 units of PRBCs transfused in the preceding 16 weeks), must have a baseline Hgb of < 9.0 g/dL at time of study enrollment
• Patients, must have a baseline Hgb of < 9.0 g/dL at time of study enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Creatinine < 2.0 X upper limit of normal (ULN) (obtained within 28 days prior to first dose)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3.0 X ULN (obtained within 28 days prior to first dose)
• Bilirubin < 1.5 X ULN or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range only in patients with well documented Gilbert’s syndrome or hemolysis or who required regular blood transfusions (obtained within 28 days prior to first dose)
• Men and women, ages >= 18 years of age
• Women of child bearing potential must have a negative serum or urine pregnancy test within 28 days prior to the start of study drug
• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence; tubal ligation, partner’s vasectomy) prior to cycle 1 day 1 (C1D1) and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. No contraception is required for male study participants. * A woman is considered to be of childbearing potential when a sexually mature female: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months.”

Exclusion Criteria

• Use of chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 14 days of the first day of study drug treatment
• Previous treatment with a hypomethylating agent (such as azacitidine, decitabine or investigational hypomethylating agent)
• Use of concurrent growth factors such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or thrombopoietin mimetics during study except in cases of febrile neutropenia, where G-CSF can be used for short term. Growth factors must be stopped two weeks prior to study
• Patient has any of the following cardiac abnormalities: * Uncontrolled, symptomatic congestive heart failure as designated by the treating physician * Myocardial infarction =< 6 months prior to enrollment * Unstable angina pectoris as designated by the treating physician * Serious uncontrolled cardiac arrhythmia as designated by the treating physician. * Uncontrolled hypertension as designated by the treating physician
• Known prior history of human immunodeficiency virus (HIV) (no laboratory testing is required), or active infection with hepatitis B or hepatitis C
• Active tuberculosis (Tb) infection or documented, untreated latent Tb infection (all patients should undergo Tb risk evaluation prior to enrollment with Tb screening performed as per local guidelines
• Active, uncontrolled infection at the time of enrollment, except in cases of localized infections that are unlikely to lead to a systemic infection such as onychomycoses or dental caries. * Patients with new fever (T > 38.0 Celsius degree [C]) or respiratory symptoms are required to undergo laboratory screening for COVID-19
• Have undergone prior allogeneic hematopoietic cell transplant (allo-HSCT) for the treatment of MDS, or other hematologic disorder, or prior solid organ transplant
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
• Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
• Subjects with a condition requiring systemic treatment with corticosteroids within 14 days of study drug administration (prednisone at doses of > 10 mg daily). Inhaled or topical steroids, and adrenal/pituitary replacement doses > 10 mg daily prednisone equivalents are permitted. * Subjects undergoing concurrent treatment with agents targeting tumor necrosis factor alpha (TNFalpha) or IL-1 within 28 days of study enrollment will not be permitted. * Subjects who have received a live-virus vaccine within 30 days before study drug administration (patients should not be treated with live-virus vaccine while undergoing therapy)
• Evidence of acute or chronic active hepatitis B infection (HBV, excludes any patient with prior hepatitis B vaccination or a positive HBV surface antibody) or chronic active hepatitis C infection (HCV). Subjects with history of a positive HBV core antibody (and who also have a negative HBV surface antibody) or history of positive HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HBV deoxyribonucleic acid (DNA) or HCV ribonucleic acid (RNA)
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• History of allergy or hypersensitivity to either darbepoetin alfa or the study drug or its components
• Women of child bearing potential who are pregnant or breastfeeding
• Women with a positive pregnancy test at enrollment or prior to administration of study medication
• Prisoners or subjects who are involuntarily incarcerated, or other vulnerable populations (study is exempt from 45 CFR 46 Subparts B, C, and D)
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness