Safety, Pharmacokinetics and Activity of CA-4948, an IRAK4 Inhibitor, for Treatment of Patients with Relapsed or Refractory Hematologic Malignancies: Results from the Phase 1 Study
Authors: Nowakowski Grzegorz S. , Leslie Lori A. , Younes Anas , Rosenthal Allison C. , Lunning Matthew A. , Patel Krish , Landsburg Daniel J. , Martinez Elizabeth , von Roemeling Reinhard , Lieberman Christopher , Tun Han W. 
Published: February 2021

Introduction

CA-4948 is a novel oral small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 is part of the Myddosome signaling pathway, and is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in immune cells including B lymphocytes. . Dysregulated signaling in these pathways is frequently observed in Non-Hodgkin Lymphomas (NHL), particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM)[1]. Furthermore, IRAK4 activation has recently been identified as a driver of an adaptive resistance mechanism of malignancies [2]. CA-4948 is the first clinical candidate targeting IRAK4 to be evaluated in cancer patients. Here we present Phase I results of CA-4948 in patients with relapsed/refractory hematologic malignancies.

Method

CA-4948-101 is a phase I trial dose escalation trial with a 3 + 3 design. Seven dosing cohorts were assessed including 50 and 100 mg daily (QD), and 50, 100, 200, 300, or 400 mg twice daily (BID) continuous oral monotherapy in 21-day cycles. Objectives included safety and tolerance (primary), pharmacokinetic (PK), pharmacodynamics (PD) and early efficacy (secondary), and biomarker correlations (exploratory). As of July 2020, 30 patients with relapsed or refractory, NHL have been enrolled, including DLBCL (n=14), FL (n=6), transformed HGBL (n=1), WM (n=3), LPL (n=2), MZL (n=2) and MCL (n=2). Median age is 68.5 (range 50 - 87; 5 female / 25 male). Median number of prior treatments is 4 (range 1 - 8, incl. 5 CAR-T-cell or ASCT treatments).

Results

CA-4948 has been generally well tolerated. Eight patients were exposed at the highest dose level of 400 mg BID: 2 of 5 DLT-evaluable patients had Grade 3 rhabdomyolysis (DLTs), without complications and reversible after treatment interruption and hydration / analgesic treatment - both subsequently continued treatment at lower doses of 200 or 300 mg BID, respectively. Six patients have tolerated 300 mg BID well without DLT. Most non-hematologic TEAEs were Grade 1 or 2 and manageable, including diarrhea, vomiting, fatigue, dyspnea, and myalgia. Hematologic TEAEs including neutropenia, anemia, thrombocytopenia was mild/moderate and without complications. There were only 4 Grade 3 combined episodes in 18 patients at dose levels ranging between 200 and 400 mg BID without complications (Table 1). Drug discontinuation occurred in only 3 cases for rash, fatigue, and asymptomatic amylase/lipase elevation at lower dose levels. No toxic deaths occurred. Favorable and predictable PK characteristics included rapid absorption with Tmax at 2-3 hours, T1/2 of 6 hours (supporting bid dosing), moderate accumulation, and dose-proportional increases in exposure. Dose proportional PD changes were shown for inflammatory cytokine reductions. Treatment duration ranged between 15 days and 19+ months with sustained disease control. Eight of 28 evaluable patients experienced overall tumor burden decreases of ≥20% from baseline - more at higher doses (Table 2). A WM patient with 6 prior lines of treatment, sustained PR underwent intra-patient dose escalation and had a dose/response relationship and very good treatment tolerance (Figure 1). The median duration at doses of 200 or 300 mg bid was &gt;6 months (range 1-19+; including 3 cases of 11, 14, and 19+ mo.). Downstream pharmacodynamic markers of IRAK4 and molecular characteristics including cell-of-origin will be presented.

Conclusion

CA-4948 demonstrates good safety profile, desirable pharmacokinetic properties, and preliminary clinical activity. Enrollment is ongoing to support the anticipated RP2D of 300 mg bid. These encouraging results provide clinical validation of IRAK4 as a viable, novel therapeutic target in B-cell malignancies will lead to clinical combinations with synergistic drugs including BTK or BCL2 inhibitors [3] in patients with advanced hematological malignancies. Clinical trial: NCT03328078.

References:

1. Treon, S. P. et al., 2012. N Engl J Med, 367: 826-33

2. Melgar, K. et al., 2019. Sci Transl Med, 11: eaaw8828

3. Booher R, Grayson D., 2019. Waldenstrom Roadmap Symposium, www.Curis.com

Disclosures

Nowakowski: Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Kymera: Consultancy; Seattle Genetics: Consultancy. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Younes:Curis: Consultancy; Daiichi Sankyo: Consultancy; HCM: Consultancy; Epizyme: Consultancy; Takeda: Consultancy; Novartis: Consultancy; BioPath: Consultancy; BMS: Consultancy; Janssen: Consultancy; AstraZeneca: Current Employment. Lunning:Gilead: Consultancy, Honoraria; Curis: Research Funding; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding. Patel:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Genentech: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.