Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.
All Patients (Stages 2 and 3A):
1. The patient is ≥18 years old.
2. The patient has a life expectancy of >6 months.
3. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.
4. The patient has adequate baseline organ function, including cardiac, renal, and hepatic function:
• Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal as measured by multigated acquisition scan (MUGA) 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.
• Serum albumin ≥3.2 g/dL (or ≥32 g/L) in the absence of receipt of IV albumin within the previous 72 hours.
• Bilirubin ≤1.5 mg/dL.
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times the upper limit of normal (ULN).
• Creatine phosphokinase (CPK) ≤2.5 times the ULN.
• Absolute neutrophil count (ANC) ≥0.5 x 109/L.
5. 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).
6. 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 1 week after the last tagraxofusp infusion.
7. The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
8. The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for response assessments.
Additional Abbreviated Inclusion Criteria Specific to Patients with MF (Stage 2):
1. Patient meets the 2016 WHO diagnostic criteria for MF and has an IPSS/DIPSS/DIPSS-plus intermediate-2 or high-risk disease. Patients with IPSS/DIPSS/DIPSS-plus low or intermediate-1 risk disease who have at least one of the following symptoms are also eligible: MF-related anemia (Hb <10 g/dL), splenomegaly (palpable size >10 cm), leukocytosis (WBC >25 x 109/L), marked thrombocytosis (platelet count >1000 x 109/L), or constitutional symptoms (weight loss >10%, during prior 6 months or fever [>37.5°C or drenching night sweats for >6 weeks]), as recommended by the ELN/IWG 2018 criteria (Barbui 2018).
2. Patient is approved JAK therapy (JAK1/JAK2 or JAK 2) resistant/refractory or intolerant, in accordance with the ELN/IWG 2018 criteria (Barbui 2018), and at least 4 weeks have elapsed between the last dose of any MF-directed drug treatments, excluding HU, and study enrollment (first dose). HU can be continued until 2 weeks prior to study enrollment.
3. Patient is not eligible for an immediate allogeneic stem cell transplantation (SCT).
Additional Abbreviated Inclusion Criteria Specific to Patients with CMML (Stage 3A):
1. Patient has a 2016 WHO-defined diagnosis of CMML (persistent monocytosis ≥1x109/L for at least 3 months, with other causes excluded, and monocytes ≥10% of WBC in peripheral blood, no criteria and no previous history of CML, ET, PV, and acute promyelocytic leukemia; if eosinophilic, neither PDGFRA, PDGFRB, FGFR1 rearrangements nor PCM1-JAK2 translocation; <20% blasts in peripheral blood and bone marrow aspirate; >1 following criteria: dysplasia in >1 myeloid lineage, acquired clonal cytogenetic or molecular abnormality in hematopoietic cells).
2. Patient has 2016 WHO-defined CMML-1 (2-4% blasts in peripheral blood and/or 5-9% blasts in bone marrow) and CMML-2 (5-19% blasts in peripheral blood and/or 10-19% blasts in bone marrow, and/or presence of Auer rods) (Arber 2016).
3. Patient is refractory/resistant/intolerant, as defined for the purposes of this study (in the absence of a standard definition for CMML) below, to HMAs, or HU, or intensive chemotherapy, including:
• Resistance/intolerance to HU is defined as:
o Uncontrolled myeloproliferation, (platelets >400x109/L and WBC >10x109/L after 3 months of at least 2 g/day of HU); or
o Myelosuppression at a clinically relevant dose; or
o Presence of unacceptable HU-related non-hematological toxicities, such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of HU.
Conventional definition for HMA failure is defined for the purposes of this study (in the absence of a standard definition for CMML) as:
o Disease progression following at least 4 to 6 cycles of 5-azacitidine or decitabine; or
o Relapse after achieving response; or
o Intolerance to 5-azacitidine or decitabine at the prescribed dose.
• Patient is classified as high-risk based on the presence of morphological features, as described by the 2016 WHO prognostic system (Arber 2016), and the clinical and molecular features described in molecularly-integrated prognostic systems, such as the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM), and the CMML specific prognostic model (CPSS-Mol) (Woo 2020), and thus is not expected to benefit from HMAs.
4. Patient is ineligible for an immediate allogeneic stem cell transplantation (SCT).
All Patients (Stages 2 and 3A):
1. Patient has persistent clinically significant toxicities Grade ≥2 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue).
2. Patient has received treatment with any disease-related therapy, including radiation therapy within 14 days of study entry.
3. Patient has received an allo-SCT within 3 months of study entry.
4. Patient has received treatment with another investigational agent within 14 days of study entry or concurrent treatment with another investigational agent.
5. Patient has previously received treatment with tagraxofusp or has a known hypersensitivity to any components of the drug product.
6. Patient has an active malignancy and/or cancer history (excluding myeloproliferative disorders and concomitant myeloid malignancies as specified in the inclusion criteria) that can confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) and/or ongoing active malignancy or substantial potential for recurrence must be discussed with the Sponsor before study entry. 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.
7. 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).
8. 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.
9. 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.
10. Patient is receiving immunosuppressive therapy, with the exception of corticosteroids as specified in the inclusion criteria 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.
11. 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.
12. Patient is pregnant or breast feeding.
13. Patient has known human immunodeficiency virus (HIV).
14. Patient has evidence of active or chronic Hepatitis B or Hepatitis C infection.
15. Patient is oxygen-dependent.
16. Patient has any medical condition that in the Investigator’s opinion places the patient at an unacceptably high risk for toxicities.
Additional Exclusion Criteria Specific to Patients with MF (Stage 2) apply.
1. Patient has a platelet count <20x109/L and either a history of a recent or active bleed or known acquired von Willebrand disease.
2. Patient fulfills the 2016 WHO criteria defining leukemic transformation of MF (presence of peripheral blood or bone marrow blast count >20%).
3. Patient received splenic irradiation within 28 days prior to study entry.
Additional Exclusion Criteria Specific to Patients with CMML (Stage 3A) apply.
1. Patient requires corticosteroid therapy at a dose of >20 mg daily >7 days or has had changes to their steroid regimen within 28 days of screening.
2. Patient has 2016 WHO-defined transformation to leukemia.
3. Patient has AML M4 (French-American-British subtype; myelomonocytic). (NB if this is suspected, the NPM1 gene must be assessed to determine eligibility.)