Study of Canakinumab in Patients With Myelofibrosis

Study Overview
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Brief Summary
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This is an open label, multicenter, phase 2 trial of Canakinumab in patients with primary myelofibrosis (PMF), post essential thrombocythemia/polycythemia vera related MF (Post ET/PV MF). Eligible patients will receive Canakinumab administered as a subcutaneous injection on day 1 of a 21 day cycle for a core study period of 8 cycles. Canakinumab will be given by subcutaneous injection (SC) injection at a starting dose of 200 mg (one 150 mg/mL syringe and one 50 mg/0.5 mL syringe) every 3 weeks. The interim analysis will be performed when the number of enrolled patients reaches 10. If no responses OR 4 or more patients have unacceptable toxicity, the study will not proceed to the second stage. If the total number of patients reaches the maximum sample size of 26, the treatment is deemed acceptable if the number of responses in the efficacy endpoint are greater than 3, and the number of toxicities are less than 7.

Official Title
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A Phase 2 Study of Canakinumab in Patients With Myelofibrosis Myeloproliferative Neoplasms Research Consortium [MPN-RC 122]

Conditions
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Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, ET-MF, Post-polycythemia Vera Related Myelofibrosis, PV-MF

Intervention / Treatment
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* Drug: Canakinumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: The following are required for inclusion in the study: Patients must voluntarily sign informed consent form (ICF) and be willing and able to adhere to the study visit schedule and all protocol requirements. Patients must be ≥ 18 years of age at the time of signing the ICF. Patients must have a pathologically confirmed diagnosis of primary myelofibrosis (PMF) as per the World Health Organization (WHO) diagnostic criteria44 or post-essential thrombocythemia (ET) / post-polycythemia vera (PV) MF according to International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.45 Patients must have at least one of the following: Hemoglobin < 10 g/dL; Transfusion-dependency (at least 6 units of packed red blood cells (PRBC) in the 12 weeks prior to study enrollment, for a hemoglobin < 8.5 g/dL, in the absence of bleeding or treatment-induced anemia with the most recent transfusion having occurred in the 28 days prior to study enrollment; Splenomegaly palpated ≥ 5 cm below the left costal margin (LCM); MF-SAF version 4.0 score ≥ 10. A bone marrow biopsy must be performed within the 30-day screening period; however, a bone marrow biopsy obtained within 90 days of screening without intervening treatments and approved by the study chair may suffice. Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. Life expectancy of at least 6 months. At least two weeks must have elapsed between the last dose of any MF-directed drug treatments (including investigational therapies and excluding hydroxyurea) and study enrollment. Not eligible for ruxolitinib/fedratinib therapy due to a platelet count of < 50 x 109/L, previously treated and lack/loss of response as defined by at least one of the following: Treatment for ≥ 3 months with inadequate efficacy response defined as < 10% spleen volume reduction by MRI or <30% decrease from baseline in spleen length by physical examination or regrowth to these parameters following an initial response and/or; Treatment for ≥ 28 days complicated by either: Development of a red blood cell transfusion requirement (at least 2 units/month for two months) and/or; National Cancer Institute (NCI) CTCAE grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while being treated with a dosage of < 20 mg BID. Recovery to ≤ grade 1 or baseline of any toxicities due to prior systemic treatments excluding alopecia. Women of childbearing potential (WCBP) must have a negative urine or serum pregnancy test within 28 days of starting the study drug. Men and women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence, tubal ligation, vasectomy) prior to cycle 1 day 1 and for 130 days after stopping study treatment. Vasectomy must be performed a minimum of 3 months before study start. Must have adequate organ function as demonstrated by the following: ALT/AST ≤ 3.0X ULN, or ≤ 4X ULN (unless if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis (EMH) related to MF); Direct bilirubin ≤ 1.5 x ULN or ≤ 2.0 x ULN (unless if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis related to MF or documented Gilbert's syndrome); Serum creatinine ≤ 2.0 mg/dL; Platelet count ≥ 25 x 109/L (patient must not have had platelet transfusion in the 14 days prior to screening platelet count); ANC ≥ 1000/μL. Patient must be willing to receive red blood cell and/or platelet transfusions if indicated. EXCLUSION CRITERIA: Any of the following is a criterion for exclusion from the study: 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. 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 designated by treating physician; Serious uncontrolled cardiac arrhythmia as designated by treating physician; Uncontrolled hypertension as designated by treating physician. Known 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 a new fever (T>38.0o C) or respiratory symptoms are required to undergo laboratory screening for COVID-19. Have undergone prior allo-HSCT for treatment of any hematological disorder or prior solid organ transplant. Any serious or uncontrolled psychiatric or medical disorder that, in the opinion of the investigator, may increase the risk associated with the study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Women who are pregnant or breastfeeding. Patients undergoing concurrent treatment with agents targeting tumor necrosis factor alpha (TNFα) or IL-1 within 28 days of study enrollment. Patients who have received a live vaccination within 30 days before study drug administration (patients should not be treated with live-virus vaccine while undergoing therapy and 130 days after Canakinumab discontinuation). Patients with a condition requiring systemic treatment with corticosteroids within 14 days of study drug administration (i.e. prednisone at doses of > 10 mg). Inhaled or topical steroids and adrenal/pituitary replacement doses ≤ 10mg daily of prednisone or equivalent are permitted.

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: Canakinumab<br>Canakinumab will be given by subcutaneous injection (SC) injection at a starting dose of 200 mg (one 150 mg/mL syringe and one 50 mg/0.5 mL syringe) every 3 weeks. | Drug: Canakinumab<br>* Canakinumab administered as a subcutaneous injection on day 1 of a 21 day cycle for a core study period of 8 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participant with response based on IWG-MRT criteria | Efficacy of Canakinumab as measured by number of participant with response based on the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. A response is considered any one of the following: complete response, partial response, or clinical improvement (inclusive of anemia response, spleen response, or symptom response). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | The safety and tolerability of Canakinumab as measured by the adverse event profile of Common Terminology Criteria for Adverse Events version 5.0 | 24 weeks | 
| Response using IWG-MRT | To assess the efficacy of Canakinumab as determined by response assessment using IWG/ELN criteria. Participant's response will be categorized as negative, stable, or positive. | 12 weeks | 
| Response using IWG-MRT | To assess the efficacy of Canakinumab as determined by response assessment using IWG/ELN. Participant's response will be categorized as negative, stable, or positive. | 24 weeks | 
| Number of participants with clinical improvement | Clinical improvement (CI) is defined by IWG-MRT criteria. Participants meet CI if meet any of the following: Anemia (Patients will meet IWG-MRT criteria for clinical improvement if their hemoglobin increase by 2g/dl from baseline and/or become transfusion independent.) Splenomegaly (Patients will meet IWG-MRT criteria for clinical improvement if their spleen decreases by ≥30% from baseline volume.) Disease-related symptoms (Patients will meet IWG-MRT criteria for clinical improvement if their MPN-SAF symptom score decreases by ≥50% from baseline) | 12 weeks | 
| Number of participants with clinical improvement | Clinical improvement (CI) is defined by IWG-MRT criteria. Participants meet CI if meet any of the following: Anemia (Patients will meet IWG-MRT criteria for clinical improvement if their hemoglobin increase by 2g/dl from baseline and/or become transfusion independent.) Splenomegaly (Patients will meet IWG-MRT criteria for clinical improvement if their spleen decreases by ≥30% from baseline volume.) Disease-related symptoms (Patients will meet IWG-MRT criteria for clinical improvement if their MPN-SAF symptom score decreases by ≥50% from baseline) | 24 weeks | 
| Change in Spleen Volume | Change in Spleen Volume as compared to baseline | 12 weeks | 
| Change in Spleen Volume | Change in Spleen Volume as compared to baseline | 24 weeks | 
| Overall Survival (OS) | OS is defined as the time from the first dose of study treatment to the date of death (whatever the cause). | 24 weeks | 
| Progression free survival (PFS) | PFS is defined as the duration of time from start of treatment to the first occurrence of disease progression or death on study from any cause, whichever occurs earlier. | 12 weeks | 
| Progression free survival (PFS) | PFS is defined as the duration of time from start of treatment to the first occurrence of disease progression or death on study from any cause, whichever occurs earlier. | 24 weeks |