ACP-319 / AstraZeneca - LARVOL DELTA

Acalabrutinib (ACP-196) in Combination With ACP-319, for Treatment of B-Cell Malignancies (clinicaltrials.gov) - P1/2 | N=40 | Active, not recruiting | Sponsor: Acerta Pharma BV | Trial completion date: Dec 2025 ➔ Apr 2026

Combination therapy • Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

ACE-CL-002: Acalabrutinib in Combination With ACP-319, for Treatment of Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Acerta Pharma BV | Trial completion date: Dec 2025 ➔ May 2026

Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Acalabrutinib combined with PI3K inhibitor ACP-319 in patients (pts) with relapsed/refractory (R/R) B-cell malignancies. (ASCO 2018) - P1/2; "The combination of acalabrutinib + ACP-319 was tolerable with manageable AEs; in DLBCL, response rate was high in non-GCB pts."

Clinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Indolent Lymphoma

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. (PubMed, Nature) - P2a | "Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no...Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T cells, accompanied by expansion of pathogenic T helper 17 (T17) and type 17 CD8 T (T17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity."

Journal • Gastroenterology • Gastrointestinal Disorder • Head and Neck Cancer • Immunology • Oncology • Solid Tumor • PIK3CD

Phase 1/2 study of acalabrutinib and the PI3K delta inhibitor ACP-319 in relapsed/refractory B-cell Non-Hodgkin lymphoma. (PubMed, Leuk Lymphoma) - No abstract available

Journal • P1/2 data • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Acalabrutinib combined with PI3K inhibitor ACP-319 in patients (pts) with relapsed/refractory (R/R) B-cell malignancies. (ASCO 2018) - P1/2; "The combination of acalabrutinib + ACP-319 was tolerable with manageable AEs; in DLBCL, response rate was high in non-GCB pts."

Clinical • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Indolent Lymphoma

Acalabrutinib (ACP-196) in Combination With ACP-319, for Treatment of B-Cell Malignancies (clinicaltrials.gov) - P1/2; N=40; Active, not recruiting; Sponsor: Acerta Pharma BV; Trial completion date: Mar 2020 ➔ Dec 2025; Trial primary completion date: Mar 2020 ➔ Jun 2020

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Impaired airway epithelial barrier integrity was mediated by PI3Kδ in a mouse model of lipopolysaccharide-induced acute lung injury. (PubMed, Int Immunopharmacol) - "Treatment with either IC87114 or AMG319 not only attenuated LPS-induced edema, lung injury and neutrophilc inflammation, reduced total protein concentration and IL-6, TNF-α secretion in BALF, but also restored epithelial E-cadherin and claudin-2 expression. In summary, our results showed that LPS can induce a delayed effect on airway epithelial barrier integrity that is mediated by PI3Kδ in a mouse model of ALI."

Journal • Preclinical • Acute Lung Injury • Immunology • Inflammation • Respiratory Diseases • CDH1 • IL6 • TNFA

Distinct roles of PI3Kδ and PI3Kγ in a toluene diisocyanate-induced murine asthma model. (PubMed, Toxicology) - "Sellective inhibitors of PI3Kδ (IC-87114, AMG319) and PI3Kγ (AS252424, AS605240) were respectively given to the mice after each airway challenge...While mice treated with AS252424 or AS605240 had increased AHR, more severe ASM thickening, larger numbers of neutrophils and eosinophils, more M1 but less M2 macrophages, and higher BALF levels of IL-4, IL-5, IL-6, IL-10, IL-12, IL-18 when compared with those treated with vehicle. These data revealed that pharmacological inhibition of PI3Kδ attenuates TDI-induced airway inflammation while PI3Kγ inhibition exacerbates TDI-induced asthma, indicating distinct biological functions of PI3Kδ and PI3Kγ in TDI-induced asthma."

Journal • Preclinical • Asthma • Immunology • Inflammation • Respiratory Diseases • IL10 • IL12A • IL18 • IL4 • IL5 • IL6

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 in pre-clinical models of aggressive lymphomas. (PubMed, Br J Haematol) - "Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on-going current trials with acalabrutinib and ACP-319 as single agents and provide the basis for the investigation of their combination as well."

Journal • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Cellular Cytotoxicity of Next Generation CD20 Monoclonal Antibodies. (PubMed, Cancer Immunol Res) - "...ADCP and ADCC induction by rituximab, ofatumumab, obinutuzumab, or ocaratuzumab was measured using treatment-naïve chronic lymphocytic leukemia (CLL) target cells and either human monocyte-derived macrophages (for ADCP) or natural killer (NK) cells (for ADCC). Specific effects on ADCP were evaluated for clinically relevant drug combinations using BTK inhibitors (ibrutinib and acalabrutinib), PI3Kδ inhibitors (idelalisib, ACP-319, and umbralisib), and the BCL2 inhibitor venetoclax...Overall, ADCP was a better measure of clinically relevant mAb-induced cellular cytotoxicity, and next generation mAbs could activate ADCP at significantly lower concentrations, suggesting the need to test a wide-range of dose sizes and intervals to establish optimal therapeutic regimens. Complement activation by mAbs can contribute to ADCP, and venetoclax, acalabrutinib, and umbralisib are preferred candidates for multi-drug therapeutic regimens."

Journal

Acalabrutinib (ACP-196) in Combination With ACP-319, for Treatment of B-Cell Malignancies (clinicaltrials.gov) - P1/2; N=40; Active, not recruiting; Sponsor: Acerta Pharma BV; Recruiting ➔ Active, not recruiting; N=126 ➔ 40; Trial completion date: Nov 2017 ➔ Mar 2020; Trial primary completion date: Aug 2017 ➔ Mar 2020

Clinical • Combination therapy • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date

Acalabrutinib in Combination With ACP-319, for Treatment of Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1; N=12; Active, not recruiting; Sponsor: Acerta Pharma BV; Trial primary completion date: Sep 2018 ➔ Jul 2020

Clinical • Combination therapy • Trial primary completion date