Tagraxofusp and Decitabine for the Treatment of Chronic Myelomonocytic Leukemia

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects, best dose, and effect of tagraxofusp and decitabine in treating patients with chronic myelomonocytic leukemia. Tagraxofusp consists of human interleukin 3 (IL3) linked to a toxic agent called DT388. IL3 attaches to IL3 receptor positive cancer cells in a targeted way and delivers DT388 to kill them. Chemotherapy drugs, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tagraxofusp and decitabine may help to control the disease in patients with chronic myelomonocytic leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety, tolerability and maximum tolerable dose (MTD) of tagraxofusp-erzs (tagraxofusp) in combination with decitabine. II. To assess overall response (OR) rate to tagraxofusp in combination with decitabine. SECONDARY OBJECTIVES: I. To assess overall survival (OS), duration of response, relapse-free survival (RFS) and safety profile. II. Correlative studies. OUTLINE: This is a phase I, dose-escalation study of tagraxofusp-erzs followed by a phase II study. Patients receive decitabine intravenously (IV) over 60 minutes on days 1-5, and tagraxofusp-erzs IV over 15 minutes on days 1-3. Cycles of decitabine repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment with tagraxofusp-erzs repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Official Title
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Phase I/II Study of Tagraxofusp in Combination With Decitabine for Patients With Chronic Myelomonocytic Leukemia

Conditions
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Chronic Myelomonocytic Leukemia, Chronic Myelomonocytic Leukemia-1, Chronic Myelomonocytic Leukemia-2, Myelodysplastic/Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: Decitabine
* Biological: Tagraxofusp-erzs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is >= 18 years old Diagnosis of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) subtype chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO) and: Phase 1 dose escalation portion: CMML-1 or CMML-2 by WHO and no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 (decitabine-cedazuridine) or relapse or progression after any number of cycles Phase 2 dose expansion portion: Relapsed cohort (Cohort A): CMML-1 or CMML-2 by WHO and no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 (decitabine-cedazuridine) or relapse or progression after any number of cycles Hypomethylating agents (HMA) naive cohort (Cohort B): CMML-1 or CMML-2 and intermediate-2 or high-risk International Prognostic Scoring System (IPSS) The patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 Left ventricular ejection fraction (LVEF) >= 50% as measured by multigated acquisition scan or 2-dimensional (2-D) echocardiogram (ECHO) within 28 days prior to start of therapy and no clinically significant abnormalities on a 12-lead electrocardiogram (ECG) Serum creatinine =< 1.5 mg/dL (or =< 114 umol/L) Serum albumin >= 3.2 g/dL (or >= 32 g/L) in the absence of receipt of (IV) albumin within the previous 72 hours Total Bilirubin =< 1.5 mg/dL (or =< 26 umol/L) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal (ULN) Creatine kinase (CK) =< 2.5 times the ULN If a woman of child bearing potential (WOCBP), the patient has a negative serum or urine pregnancy test within 1 week prior to tagraxofusp treatment (intervals shorter than 1 week are acceptable, if required by institutional guidelines) The patient or legally authorized representative has signed informed consent prior to initiation of any study-specific procedures or treatment The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for response assessments The patient (either male or female) agrees to use acceptable contraceptive methods for the duration of time in the study, and to continue to use acceptable contraceptive methods for 2 months after the last tagraxofusp infusion Patient has an absolute neutrophil count (ANC) >= 0.5 x 10^9/L Exclusion Criteria: Patient has persistent clinically significant toxicities grade >= 2 from previous chemotherapy not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue) Patient has received treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of study entry Patient has received treatment with another investigational agent within 14 days of study entry or concurrent treatment with another investigational agent Patient has previously received treatment with tagraxofusp or has a known hypersensitivity to any components of the drug product Patient has an active malignancy and/or cancer history (excluding myeloproliferative disorders and concomitant myeloid malignancies as specified in the inclusion criteria) that is requiring active therapy. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia, or organ- confined prostate cancer with no evidence of progressive disease Patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication) Patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator's opinion, would put the patient at significant risk for pulmonary complications during the study Patient has known active or suspected disease involvement of the central nervous system (CNS). If suspected due to clinical findings, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid Patient is receiving immunosuppressive therapy, with the exception of corticosteroids and tacrolimus, for treatment or prophylaxis of graft- versus-host disease (GVHD). If the patient has been on immunosuppressive treatment or prophylaxis for GVHD, the treatment(s) must have been discontinued at least 14 days prior to study drug and there must be no evidence of grade >= 2 GVHD Patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness that would limit compliance with study requirements Patient is pregnant or breast feeding Patient has known human immunodeficiency virus (HIV) Patient has evidence of active or chronic hepatitis B or hepatitis C infection Patient is oxygen-dependent Patient has any medical condition that in the Investigator's opinion place the patient at an unacceptably high risk for toxicities Hydroxyurea is permitted only in settings in which a patient had been receiving this agent prior to study entry; hydroxyurea may only be administered during Cycle 1. After Cycle 1, the use of hydroxyurea may be permitted in consultation with the Principal Investigator.

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 (decitabine, tagraxofusp-erzs)<br>Patients receive decitabine IV over 60 minutes on days 1-5, and tagraxofusp-erzs IV over 15 minutes on days 1-3. Cycles of decitabine repeat every 28 days in the absence of disease progression or unacceptable toxicity. Treatment with tagraxofusp-erzs repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Decitabine<br>* Given IV<br>* Other names: Dezocitidine;Biological: Tagraxofusp-erzs<br>* Given IV<br>* Other names: Tagraxofusp ERZS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerable dose (Phase I) |  | At end of cycle 1 (1 cycle = 28 days) | 
| Incidence of dose limiting toxicities (Phase I) |  | Up to end of cycle 1 (1 cycle = 28 days) | 
| Overall response (OR) (Phase II) | Will estimate the OR for the combination treatment along with the 95% credible interval. The association between OR rate and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate. | After 2 cycles of therapy (1 cycle = 28 days) |