Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia.

"Conflict-of-interest disclosure: A.A.L. received research support from 10.13039/100006483AbbVie and Stemline Therapeutics. A.A.L. received consulting fees from Cimeio Therapeutics, IDRx, Jnana Therapeutics, ProteinQure, and Qiagen, and has equity as an adviser for Medzown. J.S.G. served in advisory role for AbbVie, Astellas, Bristol Myers Squibb, Genentech, Gilead and Servier and had trial institutional funding from 10.13039/100006483AbbVie, 10.13039/100004328Genentech, 10.13039/100004319Pfizer, Prelude and 10.13039/100004325AstraZeneca. M.S. served on an advisory board for Novartis, Kymera, Sierra Oncology, GlaxoSmithKline, and Rigel; consulted for Boston Consulting and Dedham group, and participated in medical education activities for Novartis, Curis Oncology, Haymarket Media, and Clinical Care Options. T.M. is a senior consultant for Stemline Therapeutics. C.B. and I.V.G. are employees of Stemline Therapeutics. N.P. received honoraria from Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, Springer, Aptitude Health, NeoPharm, and CareDX; has a consulting or advisory role in Blueprint Medicines, Pacylex, Immunogen, Bristol Myers Squibb, ClearView Healthcare Partners, Astellas Pharma, Protagonist Therapeutics, Triptych Health Partners, and CTI BioPharma Corp; received research funding from 10.13039/100004336Novartis, Stemline Therapeutics, Samus Therapeutics, 10.13039/100006483AbbVie, Cellectis, Affymetrix/10.13039/100011033Thermo Fisher Scientific, 10.13039/501100022274Daiichi Sankyo, 10.13039/501100019697Plexxikon, and MustangBio; received travel, accommodation, and other expenses from Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology, and MustangBio. The remaining authors declare no competing financial interests."

"A.A.L. is supported by the National Cancer Institute (NCI) (R37 CA225191), the 10.13039/100014599Mark Foundation For Cancer Research, the 10.13039/100016394Ludwig Center at Harvard, and the Bertarelli Rare Cancers Fund. A.A.L. is a Scholar of the Leukemia & Lymphoma Society. A.A.L. and N.P. are supported by the 10.13039/100000005Department of Defense (W81XWH-20-1-0683). J.S.G. is supported by the NCI (K08 CA245209)."

"This study was registered on ClinicalTrials.gov (NCT03113643). All research was approved by each institution’s review board and all human participants provided written informed consent. Eligibility for cohorts testing doublet TAG-AZA and triplet TAG-AZA-VEN included patients aged 18 or higher with newly diagnosed AML, excluding acute promyelocytic leukemia, who declined or were ineligible for intensive induction chemotherapy due to age ≥75 or comorbidity, or had investigator perceived futility of standard chemotherapy, or had R/R AML. Eligibility for doublet TAG-AZA also included higher-risk MDS, defined as 10% or higher blasts in the bone marrow (MDS-EB2). Myeloblasts were required to demonstrate CD123 expression in marrow or blood by flow cytometry or immunohistochemistry, without specified minimum values for staining intensity or percentage-positive cells, as determined per each site’s local hematopathology standard. Other eligibility included Eastern Cooperative Oncology Group performance status ≤2, and adequate organ function, including albumin ≥3.2 g/dL, creatinine ≤1.5× the upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5× ULN, total bilirubin <1.5× ULN, and left ventricular ejection fraction greater than or equal to institutional normal. Patients receiving VEN needed to have white blood cell count of ≤20 x103/μL on day 1 of treatment (pretreatment hydroxyurea was permitted) and avoid strong CYP3A inducers. Prophylactic antibiotics were allowed per institutional standards. Certain strong and moderate CYP3A inhibitors were allowed, with modifications to the VEN dose, following VEN prescribing information. CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/−VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/− 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643."