Background:

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of NHL isolated to the central nervous system or vitreoretinal space. Despite high initial rates of responses to available therapies, most PCNLS relapse in two years, presenting a very poor prognosis. Combination with novel therapies may overcome resistance (Guidetti 2023a). Upregulation of the B-cell receptor (BCR/NF-κB) and toll-like receptor (TLR)/NF-κB) signaling axis have been identified as key pathways in the pathogenesis of PCNSL. MYD88 L265P, a widely expressed somatic mutation in more than 70% of PCNSL patients, activates NF-κB signaling through stimulation of BTK and IRAK4. Emavusertib (CA-4948) is a novel, potent oral inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Targeted inhibition of IRAK4 with emavusertib in PCNSL xenografts indicated sufficient blood brain barrier penetration of emavusertib, target inhibition, and antitumor activity (von Roemeling 2022). Further preclinical studies have demonstrated that emavusertib synergizes with ibrutinib and can re-sensitize and overcome resistance to BTK inhibitors (Guidetti 2023a and 2023b). Initial clinical data have reported responses in BTK-resistant PCNSL and good tolerance of the combination (Iqbal 2022; Grommes 2023).

Study Design:

This is an ongoing multi-center, open-label trial (NCT03328078) in adult patients with hematologic malignancies to evaluate the safety, PK, and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib. Part Bis an open trial expansion cohort with BTKi relapsed or refractory PCNSL. About 20 evaluable PCNSL patients will be enrolled globally. Patients will receive oral CA-4948 at 100 or 200 mg BID in combination with ibrutinib at 560 mg QD in 28-day cycles until disease progression or intolerable toxicity. The primary endpoint is expanded safety/tolerability; secondary endpoints include ORR, DOR, PFS, OS, and pharmacokinetics. Key inclusion criteria for this expansion cohort: pathologically confirmed diagnosis of PCNSL with evidence of disease progression, measurable disease, relapsed or refractory with no more than 3 lines of prior anti-PCNSL therapy (including BTKi), and absence of residual Grade ≥2 toxicity from prior therapy. Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.

Grommes:BTG International: Other: Provision of services; Ono Pharma: Other: Provision of services; Roche: Other: Provision of services. Nowakowski:Kite Pharma: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Debiopharm: Consultancy; Fate Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Selvita Inc: Consultancy; Seagen: Consultancy; Kymera Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Genentech: Consultancy; Blueprint Medicines: Consultancy; F Hoffmann-La Roche Limited: Consultancy; MEI Pharma: Consultancy; Zai Lab Limited: Consultancy; Curis: Consultancy; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ryvu Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy; Bantam Pharmaceutical LLC: Consultancy; Celgene Corporation: Consultancy; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lunning:Loxo: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Nurix: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; InstilBio: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Fate Therapeutics: Consultancy, Honoraria; EUSA: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; CRISPR: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Curis: Research Funding. Leslie:Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen/ J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Other: Travel support, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; SeaGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/ Bristol Myers Squibb: Other: Travel support, Speakers Bureau; Janssen/PCYC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; LLS: Other: Educational role/ Leadership role in LLS light the night events (unpaid); LRF: Other: Educational role; CLL: Other: Educational role; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dabrowska-Iwanicka:Abbvie: Other: Travel; Gilead: Other: travel. Ferreri:ADC Therapeutics, Amgen, BeiGene, BMS, Genmab, Gilead, Hutchison Medipharma, Novartis, Pharmacyclics, PentixaPharm, Pfizer, Roche: Research Funding; Ospedale San Raffaele srl.: Patents & Royalties; Gilead, Incyte, Novartis, PentixaPharm, Roche: Consultancy; Adienne: Speakers Bureau.

This content is only available as a PDF.
2023
Sign in via your Institution