Tagraxofusp-erzs, Azacitidine and Venetoclax for the Treatment of Untreated, Relapsed, or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

This phase I trial studies the side effects and best dose of tagraxofusp-erzs (SL-401) when given together with azacitidine, or azacitidine and venetoclax, in treating patients with acute myeloid leukemia that is untreated, has come back (relapsed), or does not respond to treatment (refractory) or myelodysplastic syndrome. Combinations of biological substances in tagraxofusp-erzs may be able to carry cancer-killing substances directly to cancer cells. Drugs used in chemotherapy, such as azacitidine, 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. Venetoclax may stop the growth of cancer cells by blocking a protein called Bcl-2 needed for cell growth. Giving tagraxofusp-erzs with azacitidine and venetoclax may work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome compared to standard therapy.

Inclusion Criteria

• 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

Exclusion Criteria

• 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

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVES:

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

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Andrew Lane

• Primary ID 17-056
• Secondary IDs NCI-2017-01200
• Clinicaltrials.gov ID NCT03113643