A Phase 1, Open Label Dose Escalation Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome
Authors: Garcia-Manero Guillermo , Platzbecker Uwe , Tarantolo Stefano R. , Gropper Stefanie , Talati Chetasi , Götze Katharina S. , Dugan James , Winer Eric S. , Martinez Elizabeth , Lieberman Christopher , von Roemeling Reinhard 
Published: November 2020

Introduction:
CA-4948 is a novel small molecule oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways These pathways are frequently dysregulated in Non-Hodgkin Lymphomas (NHL) and AML/MDS. [1] Oncogenic IRAK4-L, which is driven by spliceosome mutation (including SF3B1 and U2AF1), is preferentially expressed in &gt;50% of AML/MDS patients [2,3]. Recently, activated IRAK4 has been identified as a driver of adaptive resistance in AML and other tumors [4]. CA-4948 not only strongly inhibits IRAK4, but also FLT3-ITD AML in vitro and in-vivo models. It has shown safety and activity in patients with relapsed or refractory NHL and will now be evaluated in patients with high-risk MDS and AML.
Study Design and Methods:
This is a multicenter, open-label, single arm Phase 1 dose escalation study of orally administered CA-4948 monotherapy in adult patients with AML or high risk MDS (NCT04278768). This study will be conducted in 2 parts: an initial dose escalation and dose expansion phase. The starting dose level is 200 mg BID which was determined to be safe, capable of achieving relevant levels of drug exposure and has demonstrated signs of biologic activity and clinical efficacy in an ongoing NHL study CA-4948-101. Three patients with AML or MDS will be enrolled at the starting dose. If none of the first 3 patients experience a DLT during the first cycle, patients may be enrolled into the next higher dose level of 300 mg BID.
Dose escalation is expected to enroll approximately 18 patients to establish the initial RP2D. The safety population will include all patients in the study who received any dose of CA-4948, and the efficacy population will include patients who have a valid baseline and post-baseline disease assessment and received at least one dose of the study drug. Each treatment cycle of CA-4948 will be 28 days in length and repeated in the absence of unacceptable toxicity or disease progression.
The major study inclusion and exclusion criteria are as follows: Relapsed or refractory AML (primary or secondary, including treatment-related) after at least one standard treatment (including chemotherapy, re-induction therapy or stem cell transplantation) based on the assessment of the investigator or high/very high risk relapsed/refractory MDS (IPSS-R criteria), following at least 6 cycles of hypomethylating agents [HMA] or evidence of early progression. Patients diagnosed with acute promyelocytic leukemia (APL, M3), blast phase of CML, allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up-titration of immunosuppressive medications prior to start of CA-4948 are excluded.
The primary objective is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for CA-4948 based on the safety and tolerability, DLTs and PK/PD findings. Secondary objective is characterization of the pharmacokinetic (PK) parameters and preliminary efficacy. Exploratory objective (1)is to assess the potential association between target-related biomarkers (including IRAK4-L and downstream signaling parameters), selected genetic mutations (including spliceosome mutations), gene expression signatures, cell of origin, or other molecular classification subtypes and anti-leukemic activity (including central morphology review), and (2) to assess the pharmacodynamic effects of CA-4948 on selected biomarkers in peripheral blood and bone marrow.
As of 03 August 2020, the trial has enrolled 3 patients in Cohort 1. Clinical updates will be later reported. After the RP2D has been determined, it may be subsequently amended including patient selection and combination therapy in a controlled design.
References:Rhyasen, GW, Starczynowski DT, 2015. Brit J Cancer 112, 232-Smith MA. et al., 2019 Nat Cell Biol. 21(5): 640-650Choudhary G et al.2019. Blood 134 (Suppl 1): 4224.Booher R. et al.: 2019: EHA Annual Meeting, Abstr. PS991Melgar, K. et al., 2019. Sci Transl Med, 11: eaaw8828

Disclosures
Garcia-Manero: Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Talati:Jazz: Speakers Bureau; BMS: Honoraria; Astellas: Speakers Bureau; Pfizer: Honoraria; AbbVie: Honoraria. Götze:Celgene: Research Funding.