Study of Tagraxofusp in Newly Diagnosed Secondary AML After Previous Exposure to Hypomethylating Agents

Study Overview
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Brief Summary
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A treatment cycle is 21 days for Cycle 1 and Cycle 2. Tagraxofusp will be administered at 12 mcg/kg IV over 15 minutes (-5 or +15 minutes) daily for 5 consecutive days (or 5 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution). Subjects with a marrow CR (See the protocol) after Cycle 2 will continue Tagraxofusp for Cycles 3 to 12 (up to 1 year of treatment) at 12 mcg/kg IV for 5 consecutive days every 28 days. In subjects without a marrow CR after 2 cycles of treatment, azacitidine 75 mg/m2 SQ or IV will be added on Days 1-7 every 28 days for up to 4 additional cycles of treatment. A treatment cycle is 28 days for Cycle 3 to Cycle 12. Subjects who achieve a marrow CR receiving tagraxofusp only after Cycle 4, will continue tagraxofusp at 12 mcg/kg IV for 5 consecutive days every 28 days until Cycle 12. Subjects who continue to achieve an overall response (CR, CRi, PR, MLFS, marrow CR) receiving tagraxofusp and azacitidine will continue tagraxofusp at 12 mcg/kg IV for 3 consecutive days and azacitidine 75 mg/m2 SQ or IV on Days 1-7 every 28 days until Cycle 12. Please see the protocol. Patients without an overall response to tagraxofusp + azacitidine after completion of 4 cycles of this combination will be discontinued from study treatment.

Official Title
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Phase II Study of Tagraxofusp in Newly Diagnosed Secondary AML After Previous Exposure to Hypomethylating Agents

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Tagraxofusp (Cycles 1-2)
* Drug: Azacitidine
* Drug: Tagraxofusp (Cycles 3-12)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must meet all of the following applicable inclusion criteria to participate in this study: Subjects must have newly diagnosed, untreated AML, as defined by ≥ 20% blasts in peripheral blood or bone marrow by manual aspirate differential, immunohistochemistry staining, or flow cytometry, as defined by standard WHO 2016 diagnostic criteria. Subjects must have documented CD123 positivity on leukemia cells by a centralized flow cytometry assay (Hematologics). Documented diagnosis of prior MDS, CMML, MDS/MPN overlap syndromes, or MPN's according to WHO criteria. Subjects must have received at least 2 cycles of hypomethylating agents (azacitidine or decitabine or oral decitabine/cedazuridine) for the management of MDS, CMML, MDS/MPN overlap syndromes, or MPN's. NOTE: Subjects who have enrolled on clinical trials with investigational agents in combination with HMA's will still be eligible. Investigational agents must have been discontinued >21 days prior to day 1 of Tagraxofusp. WBC < 30 x 109 /mL- subjects with WBC ≥ 30 x 109 /mL may still be eligible after receiving cytoreduction measures such as hydroxyurea, and/or leukapheresis, if WBC < 30 x 109 /mL prior to treatment initiation. Cytoreduction with hydroxyurea, leukapheresis and/or cyclophosphamide is allowed prior to treatment. Hydroxyurea must be discontinued ≥ 12 hours prior to treatment initiation. Cyclophosphamide must be discontinued ≥ 5 days prior to treatment initiation. Age ≥ 18 years at the time of consent. ECOG Performance Status of 0-2. Demonstrate adequate organ function within 28 days prior to registration. Left ventricular ejection fraction (LVEF) ≥ 45%. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Females of childbearing potential and male participants must be willing to use effective contraception as outlined in the protocol. Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. Patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Written informed consent and HIPAA authorization for release of personal health information. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Exclusion Criteria: Subjects meeting any of the criteria below may not participate in the study: Subjects who are suitable for and are willing to receive intensive chemotherapy. Diagnosis of acute promyelocytic leukemia. Known CNS involvement with AML. NOTE: Subjects with clinical suspicion or signs of neurologic deficit should undergo a screening lumbar puncture prior to enrollment to confirm lack of CNS leukemia. Subject has previously received tagraxofusp. Treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of study entry. NOTE: hydroxyurea, leukapheresis and/or cyclophosphamide are allowed prior to study entry per the protocol. Treatment with investigational drug within 14 days of study entry. Previous allogeneic stem cell transplant within 60 days. Receiving immunosuppression therapy, with the exception of prednisone ≤ 10mg/d, for the treatment or prophylaxis of GVHD. If the patient has been on immunosuppressant treatment or prophylaxis for GVHD, the treatment must have been discontinued at least 14 days prior to study treatment and there must be no evidence of Grade ≥ 2 GVHD. History of other malignancies (excluding MDS, CMML, MDS/MPN, MPN's) within 2 years prior to study entry, with the exception of: adequately treated in situ carcinoma of the cervix, breast, prostate; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. Subjects receiving maintenance or adjuvant therapy for organ-confined malignancy such as breast or prostate cancer are eligible. Maintenance and/or adjuvant chemotherapy must be discontinued >72 hours prior to treatment initiation. Those with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the sponsor-investigator before study entry. Clinically significant cardiovascular disease including: Uncontrolled CHF Cardiac insufficiency Grade III or IV per New York Heart Association (NYHA) classification Uncontrolled angina/hypertension/arrhythmia Clinically significant abnormalities on a 12-lead electrocardiogram History of myocardial infarction or stroke within 6 months of study entry Uncontrolled significant pulmonary disease (e.g., COPD, pulmonary hypertension) that in the opinion of the investigator would put the patient at significant risk for pulmonary complications during the study. Active uncontrolled or severe systemic infection. Enrollment is possible after control of infection, at discretion of the treating physician. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). Other severe medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results, and in the judgement of the investigator would make the patient inappropriate for enrollment in this study. This may include psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up.

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: Experimental Group<br>During Cycle 1 and Cycle 2: Tagraxofusp will be administered intravenously (12 mcg/kg) on days 1-5 of Cycle 1-2 (Cycle is 21 days) During Cycles 3-12: Subjects with a marrow CR after Cycle 2 will continue tagraxofusp ONLY for Cycles 3-12 (up to a year of treatment) on Days 1-5 of a 28 day cycle. For subjects without a marrow CR, azacitidine will be administered intravenously (75 mg/m2) on days 1-7 of Cycle 3-12 (Cycle is 28 days) and tagraxofusp will be administered intravenously (12 mcg/kg) on days 1-3 of Cycle 3-12 (Cycle is 28 days). Subjects who achieve a marrow CR receiving tagraxofusp only after Cycle 4, will continue tagraxofusp at 12 mcg/kg IV for 5 consecutive days every 28 days until Cycle 12. Subjects who continue to achieve an overall response (CR, CRi, PR, MLFS, marrow CR) receiving tagraxofusp and azacitidine will continue tagraxofusp at 12 mcg/kg IV for 3 consecutive days and azacitidine 75 mg/m2 SQ or IV on Days 1-7 every 28 days until Cycle 12. | Drug: Tagraxofusp (Cycles 1-2)<br>* 12 mcg/kg intravenously Days 1-5<br>Drug: Azacitidine<br>* 75 mg/m2 intravenously Days 1-7 (Cycle 3-12)<br>Drug: Tagraxofusp (Cycles 3-12)<br>* 12 mcg/kg intravenously Days 1-3<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response | The CR rate based on ELN AML response criteria in subjects with newly diagnosed AML with p-HMA receiving tagraxofusp with or without azacitidine | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess adverse events | Describe overall toxicity of tagraxofusp and azacitidine. The frequency and nature of adverse events will be assessed by NCI CTCAE v5.0. | 4 months | 
| Rate of CR + CRh | Estimate the rate of CR + CRh in subjects with newly diagnosed AML with p-HMA receiving tagraxofusp with or without azacitidine.The rate of CR + CRh is defined as bone marrow myeloblasts of < 5% combined with both absolute neutrophil count > 500/μL and platelet count > 50 × 109/L. | 5 years | 
| Rate of CR without evidence of Minimal Residual Disease (MRD) | CR without evidence of MRD in subjects with newly diagnosed AML with p-HMA receiving tagraxofusp with or without azacitidine based on ELN AML response criteria. | 5 years | 
| Overall Response Rate (ORR) | Estimate the ORR in patients who receive tagraxofusp + azacitidine in subjects without a response to 2 cycles of tagraxofusp . ORR (partial remission [PR] + CR + CRi + morphological leukemia-free state [MLFS]) as defined by ELN-2017. | 5 years | 
| Overall Survival (OS) | Estimate OS in subjects with newly diagnosed AML with p-HMA receiving tagraxofusp with or without azacitidine. OS is defined as time from initiation of treatment until death or last follow-up. | 5 years | 
| Disease Free Survival (DFS) | Estimate the DFS in subjects with newly diagnosed AML with p-HMA after receiving tagraxofusp with or without azacitidine. DFS is defined as time from CR/CRi until relapse, death, or last follow-up, as based on ELN-2017. | 5 years | 
| Recurrence Free Survival (RFS) | Estimate the recurrence free survival (RFS) in subjects with newly diagnosed AML with p-HMA after receiving tagraxofusp with or without azacitidine. RFS is defined as time from ORR until progression, relapse, or death. Subjects who have not progressed will be right-censored at the date of the last disease evaluation. | 5 years | 
| Event-Free Survival (EFS) | Estimate the event-free survival (EFS) in subjects with newly diagnosed AML with p-HMA receiving tagraxofusp with or without azacitidine. EFS is defined as time from initiation of treatment until no response (after 2 cycles of tagraxofusp), relapse or death. | 5 years | 
| Rate of allogeneic stem cell transplant | Estimate the rate of allogeneic stem cell transplant in subjects with newly diagnosed AML with p-HMA receiving tagraxofusp with or without azacitidine. | 4 months |