A Phase II, Open-Label, Study of Subcutaneous Canakinumab, an Anti-IL-1β Human Monoclonal Antibody, for Patients With Low or Int-1 Risk IPSS/IPSS-R Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well canakinumab works for the treatment of low- or intermediate-risk myelodysplastic syndrome or chronic myelomonocytic leukemia. Canakinumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the clinical activity of canakinumab in patients with low or intermediate-1 myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). SECONDARY OBJECTIVES: I. To study the safety profile of canakinumab in patients with low or intermediate-1 MDS or CMML. II. Rate of transfusion independence. III. Duration of response. IV. Progression-free survival (PFS), leukemia-free survival (LFS) and overall survival (OS). EXPLORATORY OBJECTIVE: I. Correlative studies (pharmacodynamic [PD] parameters of canakinumab). OUTLINE: Patients receive canakinumab subcutaneously (SC) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.

Official Title
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A Phase II, Open-Label, Study of Subcutaneous Canakinumab, an Anti-IL-1β Human Monoclonal Antibody, for Patients With Low or Int-1 Risk IPSS/IPSS-R Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Conditions
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Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Chronic Myelomonocytic Leukemia, Refractory Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: Canakinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of MDS or CMML according to World Health Organization (WHO) and low or intermediate-1 risk by International Prognostic Scoring System (IPSS) or revised International Prognostic Scoring System (IPSS-R) with a score of =< 3.5 Patients need to have not responded to prior therapy with erythrocyte stimulating agents (ESAs) or hypomethylating agents (HMAs). These could include azacitidine, decitabine, SGI-110, ASTX727, or CC-486. Patients will need to have received at least 4 cycles of HMA. Patients with relapse or progression after any number of cycles of HMA by International Working Group (IWG) 2006 criteria will also be candidates. Patients with evidence of del 5q alteration also are required to have been treated with lenalidomide Hemoglobin < 10 g/dL with symptomatic anemia or transfusion dependency defined as the need for prior transfusion in the past 8 weeks for a hemoglobin level less than 8 g/dl Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study Total bilirubin =< 3 X upper limit of normal (ULN) Aspartate transaminase (AST) or alanine transferase (ALT) =< 3 X ULN Serum creatinine clearance > 30mL/min and no end/stage renal disease (using Cockcroft-Gault) Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Hydroxyurea for control of leukocytosis is allowed at any time prior to or during study if considered to be in the best interest of the patient Exclusion Criteria: No prior therapy for MDS Uncontrolled infection not adequately responding to appropriate antibiotics Absolute neutrophil count (ANC) < 0.5 X 10^9 k/ul Female patients who are pregnant or lactating Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine devices [IUD], double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the study. Reproductive potential is defined as no previous surgical sterilization or females that are not post-menopausal for 12 months. Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening. History of an active malignancy within the past 2 years prior to study entry, with the exception of: Adequately treated in situ carcinoma of the cervix uteri Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy (within 14 days of initiating study treatment)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (canakinumab)<br>Patients receive canakinumab SC on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Canakinumab<br>* Given SC<br>* Other names: Ilaris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematological improvement (HI) | Will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey. Will estimate the HI rate for canakinumab, along with the 95% credible intervals. The association between HI rate and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test. | After 2 cycles (each cycle is 28 days) | 
| Incidence of adverse events | Will be monitored simultaneously using the Bayesian approach of Thall, Simon, Estey. Safety data of the patients will be summarized using descriptive statistics such as mean, standard deviation, median and range. Toxicity type, severity and attribution will be summarized for each patient using frequency tables. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transfusion independence |  | Up to 2 years | 
| Duration of response | Will be summarized using descriptive statistics such as mean, standard deviation, median and range. | Up to 2 years | 
| Progression-free survival (PFS) | Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-time event endpoints by important subgroups will be made using the log-rank tests. | Up to 2 years | 
| Leukemia-free survival (LFS) | Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-time event endpoints by important subgroups will be made using the log-rank tests. | Up to 2 years | 
| Overall survival (OS) | Will be estimated using the method of Kaplan and Meier. Comparisons of time-to-time event endpoints by important subgroups will be made using the log-rank tests. | Up to 2 years |