Tagraxofusp-erzs, Azacitidine and Venetoclax for the Treatment of Untreated, Relapsed, or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
- Histologically confirmed diagnosis of acute myeloid leukemia (AML) (Cohort B) or myelodysplastic syndrome (MDS) (Cohort A) or BPDCN (Cohort C) per 2016 World Health Organization (WHO) criteria
- CD123/IL3RA expression on the subject’s AML or MDS blasts or BPDCN cells determined locally within 3 months of first protocol treatment
- With relapsed or refractory AML (hydroxyurea is not considered a prior treatment regimen) (Cohort B) OR with treatment-naive AML who decline intensive induction chemotherapy or who are unfit due to co-morbidity or other factors (hydroxyurea is not considered a prior treatment regimen) (Cohort B) OR with MDS and >= 10% myeloblasts in the bone marrow (Cohort A) OR with relapsed or refractory BPDCN (hydroxyurea is not considered a prior treatment regimen) (Cohort C)
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Albumin >= 3.2 g/dL (in the absence of receipt of intravenous albumin in the previous 72 hours)
- Serum creatinine =< 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN
- Total bilirubin < 1.5 x ULN (if thought to be > 1.5 x ULN due to Gilbert’s disease or the patient’s AML, must discuss with the principal investigator [PI])
- Creatine phosphokinase (CPK) =< 2.5 x ULN
- Left ventricular ejection fraction >= institutional lower limit of normal by multi-gated acquisition (MUGA) scan or echocardiogram within 30 days of first protocol treatment
- COHORTS B and C: White blood cell (WBC) < 20,000/uL on day of first therapy, cytoreduction may be achieved using hydroxyurea
- Ability to understand and the willingness to sign a written informed consent document
- Able to adhere to study visit schedule and other protocol requirements including follow-up for survival assessment
- Women of child-bearing potential must agree to use adequate contraception for the duration of study participation and for 2 months after completion of protocol treatment; men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and 2 months after completion of protocol treatment
- Prior treatment with venetoclax (Cohorts B or C), unless it was last taken > 2 months before protocol therapy
- Diagnosis of acute promyelocytic leukemia
- Received treatment with chemotherapy, radiation, or biologic cancer therapy within 14 days of first protocol treatment; prior and concurrent hydroxyurea is permitted
- Hematopoietic stem cell transplantation (HSCT) within 60 days of screening, or active graft-versus-host-disease
- Active CNS involvement by AML or BPDCN; screening lumbar puncture (LP) required for patients with BPDCN; if history of treated CNS involvement, must have had two consecutive negative LPs since last CNS involvement, which may include the screening LP
- Known positive status for human immunodeficiency virus (HIV) infection; known active hepatitis B or hepatitis C infection
- Clinically significant cardiopulmonary disease including uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure, uncontrolled angina, uncontrolled hypertension, uncontrolled arrhythmia, myocardial infarction or stroke within 6 months of first protocol treatment, or corrected QT (QTc) > 480 ms
- Patients with known active advanced malignant solid tumors are excluded (except for basal or squamous skin cancers, or carcinomas in situ); patients with additional hematologic malignancies that require treatment are excluded
- Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in the developing fetus with SL-401, azacitidine, and venetoclax (negative urine or serum pregnancy test required within 14 days of Cycle 1, Day 1); because nursing infants have unknown potential for adverse events secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with SL-401, azacitidine, and venetoclax
- Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control; patients with active infection are permitted to enroll provided that the infection is controlled
- COHORTS B and C: Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis)
- COHORTS B and C: Patients on strong CYP3A inducers within 7 days of first dose of study treatment
I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of tagraxofusp-erzs (SL-401) in combination with azacitidine or in combination with azacitidine and venetoclax in this patient population and evaluate the safety of this regimen.
I. To estimate the complete remission (CR)/CR with incomplete count recovery (CRi)/morphologic leukemia-free state (MLFS) rate within 6 cycles of combination therapy consisting of SL-401 administered with azacitidine or in combination with azacitidine and venetoclax in subjects with acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS), or blastic plasmacytoid dendritic cell neoplasm (BPDCN).
II. To estimate the time to response and the duration of remission (response) with SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax.
III. To estimate the 1 and 2-year progression free survival (PFS) and overall survival (OS) with SL-401 in combination with azacitidine or in combination with azacitidine and venetoclax.
I. To characterize IL-3R/CD123 expression on leukemia cells in peripheral blood and bone marrow over time on therapy.
II. To evaluate other potentially relevant biomarkers for response to SL-401 + azacitidine or for SL-401 + azacitidine + venetoclax in leukemia cells from peripheral blood and bone marrow over time on therapy.
OUTLINE: This is a dose-escalation study of tagraxofusp-erzs. Patients are assigned to 1 of 3 cohorts.
COHORT A: Patients with MDS receive azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7 and tagraxofusp-erzs IV over 15-20 minutes on days 1-3 or 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unexpected toxicity.
COHORTS B and C: Patients with AML or BPDCN receive azacitidine IV or SC on days 1-7, tagraxofusp-erzs IV over 15-20 minutes on days 4-6, and venetoclax orally (PO) on days 1-21. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unexpected toxicity.
After completion of study treatment, patients are followed up for 2 years.
Trial Phase Phase I
Trial Type Treatment
Dana-Farber Harvard Cancer Center
- Primary ID 17-056
- Secondary IDs NCI-2017-01200
- Clinicaltrials.gov ID NCT03113643