Summary

This phase Ib/II trial finds the best dose of canakinumab and determines the safety and effect when it's given together with darbepoetin alfa in treating patients with lower-risk myelodysplastic syndromes who have failed erythropoietin stimulating agents. Canakinumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Darbepoetin alfa may help to stimulate the bone marrow to produce red blood cells. Giving canakinumab and darbepoetin alfa may kill more cancer cells.

Objectives

PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of canakinumab in combination with darbepoetin alfa as determined by DLTs occurring during the first treatment cycle. (Phase Ib)
II. To determine the rate of hematologic improvement-erythroid (HI-E) as per revised International Working Group (IWG) 2018 response criteria, defined as red blood cell transfusion independence (RBC-TI) of at least 8 weeks in transfusion dependent patients or a mean hemoglobin (Hgb) increase of >= 1.5 g/dL above baseline sustained for at least 8 weeks in non-transfusion dependent patients, during treatment with canakinumab. (Phase II)

SECONDARY OBJECTIVES:
I. To determine the duration of HI-E response.
II. To determine the degree of reduction in red blood cell transfusions.
III. To determine the complete response (CR) and overall response rate (ORR) by IWG 2006 response criteria in myelodysplastic syndrome (MDS).
IV. To determine the duration of response by IWG 2006 criteria.
V. To determine the overall survival (OS).
VI. To determine the progression free survival (PFS).
VII. To determine the effect on patient’s symptoms and quality of life (QoL).
VIII. To determine whether recurrent genetic mutations are predictive of response.
IX. To characterize in vivo IL-1beta inhibition with canakinumab.
X. To evaluate the relationship between changes in innate immune and pyroptosis biomarker indices with response to treatment.
XI. To determine the prevalence of infections, including opportunistic infections, associated with canakinumab therapy in MDS patients.

OUTLINE: This is a phase Ib, dose-escalation study of canakinumab followed by a phase II study.

Patients receive canakinumab subcutaneously (SC) on day 1 and darbepoetin alfa SC on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Eligibility

1. Subjects must have the nature of the study explained to them
2. 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
3. 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
4. Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization
5. The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject’s normal care
6. 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
7. 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
8. 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
9. Patients, must have a baseline Hgb of < 9.0 g/dL at time of study enrollment
10. Eastern Cooperative Oncology Group (ECOG) performance status =< 2
11. Creatinine < 2.0 X upper limit of normal (ULN) (obtained within 28 days prior to first dose)
12. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3.0 X ULN (obtained within 28 days prior to first dose)
13. 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)
14. Men and women, ages >= 18 years of age
15. Women of child bearing potential must have a negative serum or urine pregnancy test within 28 days prior to the start of study drug
16. 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.”

Treatment Sites in Georgia