Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment

Abstract

Purpose: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL.

Patients and methods: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.

Results: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders.

Conclusions: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.

Figure 1.

Target lesion size (best percentage change from baseline) waterfall plot. Best change in target lesion size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction.

Figure 2.

Cell-free DNA concentrations in plasma (A) and variant allele frequency (B) over time by response. a, Patient 7 achieved SD on Day 52. b, Patient 2 achieved CR on Day 53. c, Patient 1 achieved CR on Day 54. C, cycle; D, day; SFU, safety follow-up.

Figure 3.

Example patient with early CR (patient #1). A, PET/CT scan (screening and end C2); B, copy-number variations; C, cfDNA concentration in plasma. The green star indicates MRD negativity based on peripheral blood by clonoSEQ. C, cycle; D, day; MRD, minimal residual disease.

Figure 4.

Copy-number dynamics of CR (A) versus PD (B). AF, allele frequency; C, cycle; D, day.