amredobresib (BI 894999) / Boehringer Ingelheim - LARVOL DELTA

Final results from the phase Ia/Ib study of the novel bromodomain and extra-terminal domain inhibitor, BI 894999, in patients with advanced solid tumors or diffuse large B-cell lymphoma. (PubMed, ESMO Open) - "The safety profile of BI 894999 was consistent with those of other BET inhibitors. Due to minimal efficacy results, further evaluation of BI 894999 as monotherapy is not planned."

Journal • P1 data • B Cell Lymphoma • Castration-Resistant Prostate Cancer • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • NUT Midline Carcinoma • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Testicular Cancer • Thrombocytopenia

Targeting the interplay between replication stress (RS) induced DNA damage response (DDR) and epigenetics in children with high-risk neuroblastoma and sarcoma (LCC 2025) - "ATR inhibitor (AZD6738/Cerelasertib) combinations with epigenetic drugs causing chromatin closing: bromodomain/histone acetyltransferase (HAT) inhibitors (BI-894999, CBP30, BMS-986158), histone demethylase (KDM) inhibitors (GSK-J4), or chromatin opening: DNA methyltransferase inhibitors (OTS186935, Decitabine), histone deacetylase (HDAC) inhibitors (Panobinostat, Entinostat, Vorinostat) were tested in neuroblastoma and sarcoma cell lines. These combinations offer superior efficacy than either drug alone. Functional studies will elucidate mechanisms responsible for observed synergy, and effective combinations will be validated in vivo."

Clinical • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • MYCN

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1 | N=174 | Completed | Sponsor: Boehringer Ingelheim | Phase classification: P1a/1b ➔ P1

Metastases • Phase classification • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Gastrointestinal Cancer • Lung Cancer • Lymphoma • NUT Midline Carcinoma • Oncology • Prostate Cancer • EGFR

Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours. (PubMed, Eur J Cancer) - P1a/1b | "The 1.5, 2.5, and 6.0/3.0 mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial."

Journal • Metastases • P1 data • Hematological Disorders • Hematological Malignancies • Oncology • Renal Disease • Solid Tumor • Thrombocytopenia

Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours (Eur J Cancer) - P1a/1b | N=174 | NCT02516553 | Sponsor: Boehringer Ingelheim | "Grade ≥3 dose-limiting toxicities (DLTs) were reported in 8/21, 5/25 and 9/31 patients for Schedules A, B and C, respectively. Thrombocytopenia was reported as a DLT in 28.6%, 4.8% and 9.7% for Schedules A, B and C, respectively. Other DLTs occurring in ≥1 patient were Troponin T increase (13.6%), hypophosphatemia (4.5%) and elevated creatine phosphokinase (3.0%). Disease control was achieved in 23.8%, 24.0% and 29.0% of patients for Schedules A, B and C, respectively. A partial response was achieved in 9.5% of patients with Schedule A and 4% with Schedule B. The best response with Schedule C was stable disease."

P1 data • Oncology • Solid Tumor

[VIRTUAL] SMAC mimetic and BET inhibitor - a promising combination for solid cancer treatment? (AACR 2021) - P1, P1a/1b | "Of the 60+ cancer cell lines, around 30% showed synergy when treated with the BI 891065 + BI 894999 combination, irrespective of indication. These preclinical in vitro and in vivo data are highlighting the potential of a SMACm/BETi combination for the treatment of solid cancers. The identification of patient selection markers for this combination will be necessary for advancing this concept into pivotal clinical trials."

Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Pancreatic Cancer • Solid Tumor • BRD4 • HEXIM1 • TNFA • XIAP

MEKi-based combination strategies for targeting KRAS-driven cancer (AACR-NCI-EORTC 2022) - "We also combine BI 3011441 with BI 1701963 and BI 894999 - two potent, selective, and orally bioavailable inhibitors of SOS1 and BET, respectively. In summary, we show that combining BI 3011441 with SOS1 or BET inhibitors may lead to improved responses in KRAS mutant tumors, likely by circumventing MAPK pathway-related adaptive resistance."

Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRAF • KRAS

"May be Prof. Ulrich Lauer from UK Tübingen can provide some info. He used to coordinate the phase 1 trial on BI 894999" (@RajivShahMD)

P1 data

Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma. (PubMed, Cancers (Basel)) - "Using NC cell lines harboring the BRD4-NUT fusion protein, the cytotoxicity of oncolytic virus talimogene laherparepvec (T-VEC) and the iBET compounds BI894999 and GSK525762 were assessed in vitro in monotherapeutic and combinatorial approaches. Of note, when applied in combination with iBETs, a reinforcing influence was observed, leading to an even stronger anti-tumor effect. These findings suggest combining virotherapy with diverse molecular therapeutics for the treatment of NC."

IO biomarker • Journal • Herpes Simplex • Infectious Disease • NUT Midline Carcinoma • Oncology • BRD4 • IFNB1

Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic. (PubMed, Br J Cancer) - "BI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials."

Journal • NUT Midline Carcinoma • Oncology • HEXIM1

Pancreatic clonal replica tumors display functional heterogeneity in response to KRAS pharmacological inhibition and reveal unique epigenetic vulnerabilities to overcome resistance (AACR 2022) - "Our study suggests that pre-existing heterogeneous subclones with epigenetic plasticity contribute to escaping direct KRAS inhibition in pancreatic cancer and provides a new avenue to overcome such resistance by combining KRAS inhibitors with BET inhibitors."

Heterogeneity • Late-breaking abstract • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRD3 • KRAS

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=174; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Clinical • Trial completion • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • Solid Tumor • EGFR • MRI

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=174; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • Solid Tumor • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=204; Recruiting; Sponsor: Boehringer Ingelheim; Trial primary completion date: Apr 2018 ➔ Jul 2022

Clinical • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • Solid Tumor • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=204; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: Aug 2022 ➔ Dec 2021; Trial primary completion date: Jul 2022 ➔ Nov 2021

Clinical • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • Solid Tumor • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=143; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: Nov 2019 ➔ May 2021

Clinical • Trial completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=143; Recruiting; Sponsor: Boehringer Ingelheim; Trial primary completion date: Jan 2018 ➔ Mar 2018

Clinical • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • NUT Midline Carcinoma • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1; N=143; Recruiting; Sponsor: Boehringer Ingelheim; N=106 ➔ 143

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=143; Recruiting; Sponsor: Boehringer Ingelheim; Phase classification: P1 ➔ P1a/1b

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=143; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=28; Active, not recruiting; Sponsor: Boehringer Ingelheim; N=143 ➔ 28; Trial primary completion date: May 2017 ➔ Oct 2016

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=143; Recruiting; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Recruiting; N=28 ➔ 143; Trial primary completion date: Oct 2016 ➔ Oct 2017; Active, not recruiting ➔ Recruiting; N=28 ➔ 143

Clinical • Enrollment change • Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1a/1b; N=176; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: May 2022 ➔ Aug 2022

Clinical • Trial completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1; N=106; Recruiting; Sponsor: Boehringer Ingelheim

Clinical • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR

BI 894999 First in Human Dose Finding Study in Advanced Malignancies (clinicaltrials.gov) - P1; N=106; Recruiting; Sponsor: Boehringer Ingelheim; Trial primary completion date: Aug 2016 ➔ Feb 2017

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • CD20 • EGFR