alobresib (GS-5829) / Gilead - LARVOL DELTA

Next Questions: Chronic Lymphocytic Leukemia (SOHO 2022) - "Even if second generation BTKis, such as acalabrutinib and zanubrutinib, exhibit a better cardiac safety profi le, it remains warranted to improve tolerability...• Are “triplets” combining BTKi, venetoclax and obinutuzumab more effective than combination of two targeted agents?...However, another type of mutation leading to resistance to pirtobrutinib was recently described...A BAFF-R inhibitor, VAY-736, increases ADCC and prevents BAFF signaling, and could be useful in case of ibrutinib resistance...A BET inhibitor, GS 5829, inhibits CLL proliferation and also impairs nurse-like cells growth. Another BET inhibitor, JQ1, increases venetoclax induced apoptosis...Longer follow up is warranted to evaluate if the current combinations are the best way to benefi t from the effi cacy of BTK and Bcl2 inhibitors, and we have to integrate more biological data to propose more personalized therapies. We should keep in mind that CLL treatment is not a sprint, but a long distance race."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Richter's Syndrome • CD19 • IGH • TP53

Phase 1b Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer. (PubMed, Clin Cancer Res) - "GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose-proportional increases in plasma concentrations in patients with mCRPC."

Journal • Monotherapy • P1 data • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Oncology • Prostate Cancer • Solid Tumor • HEXIM1

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 (Alobresib) as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=31; Terminated; Sponsor: Gilead Sciences; Completed ➔ Terminated

Clinical • Combination therapy • Trial termination • Genito-urinary Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Prostate Cancer • Solid Tumor

Ctnnb1 transcriptional upregulation compensates for Mdm2/p53-mediated β-catenin degradation in neutrophils following cardioembolic stroke. (PubMed, Gene) - "Compensatory Ctnnb1 transcriptional upregulation in neutrophils induced by ischemic neuron exposure may be involved in promoting neutrophil survival following cardioembolic stroke."

Journal • Cardiovascular • Ischemic stroke

The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment. (PubMed, Leukemia) - "The antileukemia activity of GS-5829 increased synergistically in combinations with B-cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In cocultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment. Collectively, these data provide a rationale for the clinical evaluation of BET inhibitors in CLL."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

GS-5829 in Combination With Fulvestrant or Exemestane in Women With Advanced Estrogen Receptor Positive, HER2 Negative-Breast Cancer (clinicaltrials.gov) - P1b/2; N=150; Recruiting; Sponsor: Gilead Sciences; Phase classification: P1b ➔ P1b/2

Phase classification • Biosimilar • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 in Adults With Advanced Solid Tumors and Lymphomas (clinicaltrials.gov) - P1; N=160; Recruiting; Sponsor: Gilead Sciences; Trial primary completion date: Mar 2017 ➔ Dec 2018

Trial primary completion date • Biosimilar • Breast Cancer • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hormone Receptor Breast Cancer • Lymphoma • Oncology

Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a biologically aggressive variant of Endometrial Cancer. (PubMed, Clin Cancer Res) - "GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy resistant USC overexpressing c-Myc. Clinical studies with GS-5829 in USC-patients harboring chemotherapy-resistant disease are warranted."

Journal

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=31; Completed; Sponsor: Gilead Sciences; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion

The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment (iwCLL 2019) - No abstract available.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - P1b/2; N=31; Active, not recruiting; Sponsor: Gilead Sciences; Trial completion date: Dec 2018 ➔ Sep 2019

Clinical • Combination therapy • Trial completion date