RG6146 / Roche - LARVOL DELTA

Di-(2-ethylhexyl) phthalate-degrading functional microorganisms were identified in black soil based on high throughput analysis. (PubMed, Curr Res Microb Sci) - "Bacterial communities JQ104, JQ52, and JQ129 degraded >98 % of DEHP (400 mg/L) in 48 h, demonstrating remarkable degradation efficiency. This study demonstrated the dynamic impact of the indigenous microbiome on DEHP contamination and verified the degradation capabilities of key functional microorganisms."

Journal

Immune modulation in solid tumors: a phase 1b study of RO6870810 (BET inhibitor) and atezolizumab (PD-L1 inhibitor). (PubMed, BMC Cancer) - P1 | "The combination of BET inhibitor RO6870810 with the checkpoint inhibitor atezolizumab presents an unfavorable risk-benefit profile for ovarian cancer and TNBC (triple-negative breast cancer) patients due to the increased risk of augmented or exaggerated immune reactions, without evidence for synergistic antitumor effects."

IO biomarker • Journal • P1 data • Breast Cancer • Immune Modulation • Immunology • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • PD-1

Big data analysis and machine learning of the role of cuproptosis-related long non-coding RNAs (CuLncs) in the prognosis and immune landscape of ovarian cancer. (PubMed, Front Immunol) - "Drugs such as JQ12, PD-0325901, and sorafenib showed reduced IC50 values in the high-risk group, suggesting potential therapeutic benefits. Our study identified a prognostic risk model based on CuLncs and explored their potential as therapeutic targets in OC. The findings highlight the importance of CuLncs in OC prognosis and immune response, providing new insights for future research and clinical applications."

Biomarker • Journal • Oncology • Ovarian Cancer • Solid Tumor • Women's Health

Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes. (PubMed, J Biomol Struct Dyn) - "cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • PD-L2 • PIK3CA

[PREPRINT] Immune Modulation in Solid Tumors: A Phase 1b Study of RO6870810 (BET Inhibitor) and Atezolizumab (PD-L1 Inhibitor) (medRxiv) - P1 | N=36 | NCT03292172 | Sponsor: Hoffmann-La Roche | "The study was terminated prematurely due to a pronounced incidence of immune-related adverse effects in patients receiving combination of RO6870810 and atezolizumab. Anti-tumor activity was limited to 2 patients (5.6%) showing partial response. Although target engagement was confirmed by established BETi pharmacodynamic markers in both blood and tumor samples, BETi failed to markedly decrease tumor PD-L1 expression and had a suppressive effect on anti-tumor immunity. Immune effector activation in tumor tissue was solely observed with the atezolizumab combination, aligning with this checkpoint inhibitor's recognized biological effects."

P1 data • Preprint • Trial termination • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

Construction and Validation of Protein Expression-related Prognostic Models in Clear Cell Renal Cell Carcinoma. (PubMed, J Cancer) - "According to the IC50 values, CGP-60474, vinorelbine, doxorubicin, etoposide, FTI-277, JQ12, OSU-03012, pyrimethamine, and other drugs were more sensitive in the high-risk group. A prognostic model of protein expression in ccRCC was successfully constructed, which had good predictive ability for the prognosis of ccRCC patients. The ccRCC-related proteins in the model can be used as targets for studying the pathogenesis and targeted therapy."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

[VIRTUAL] Open Label, Multicenter, Dose-Escalation/ Expansion Phase Ib Study to Evaluate Safety and Activity of BET Inhibitor RO6870810 (RO), Given As Monotherapy to Patients (pts) with Advanced Multiple Myeloma (ASH 2020) - P1 | "Pts were refractory to immunomodulatory drugs (63%), proteasome inhibitors (46%), both (46%), or daratumumab (42%). Pharmacodynamics effects were evident at this dose, but as monotherapy in this R/R MM cohort, response rates were low and less durable. Future drug combination approaches may result in an improved benefit / risk ratio."

Clinical • Monotherapy • P1 data • Cardiovascular • Diffuse Large B Cell Lymphoma • Fatigue • Heart Failure • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • NUT Midline Carcinoma • Oncology • Septic Shock • Solid Tumor • Thrombocytopenia • ITGAM • MYC

Assessment of alterations in histone modification function and guidance for death risk prediction in cervical cancer patients. (PubMed, Front Genet) - "Patients with high HMAG scores were more suitable for the treatment of CHIR-99021, embelin, FTI-277, JNK-9L, JQ12, midostaurin, PF-562271, pyrimethamine, and thapsigargin, and patients with low HMAG scores were more suitable for the treatment of BMS-536924, CP466722, crizotinib, PHA-665752, rapamycin, and TAE684. We comprehensively evaluated the histone modification status in cervical cancer patients and revealed histone modification-associated prognostic genes to construct the HMAG signature, aiming to provide a new insight into prognosis prediction and precise clinical treatment."

Epigenetic controller • Journal • Cervical Cancer • Oncology • Solid Tumor

A highly selective probe for ratiometric imaging peroxynitrite in living cells and in vivo. (PubMed, Bioorg Chem) - "Meanwhile, JQ-2 can be used for diagnosing drug-induced liver injury by visualizing and monitoring the fluctuations of endogenous ONOO. Therefore, JQ-2 provided a potential tool for precisely detecting the fluctuation of ONOO in biological systems to understand physiological and pathological process."

Journal • Preclinical • Hepatology • Liver Failure

Agronomic and metabolomics analysis of rice-Tartary buckwheat (Fagopyrum tataricum Gaertn) bred by hybridization. (PubMed, Sci Rep) - "In this study, the first hybrid rice-Tartary buckwheat (RTB) variety Mikuqiao18 (M18), bred by the pedigree selection of crossbreeding 'Miqiao' (MQ) with 'Jingqiaomai2' (JQ2), was selected for an agronomic and metabolomics analysis...In addition, M18 was abundant in 4-aminobutyric acid, which is beneficial to human health. The current findings offer a theoretical foundation for breeding rice-Tartary buckwheat with high yield and quality and promoting the cultivation and consumption of rice-Tartary buckwheat as a daily functional cereal."

Journal

Phase Ib study of BET inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma. (PubMed, Blood Adv) - P1 | "Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use."

Clinical • Journal • P1 data • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Hepatology • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • ITGAM • MYC

[VIRTUAL] Dose-Finding / Expansion Phase Ib Study to Evaluate the Safety and Activity of BET Inhibitor RO6870810 (RO) and Atezolizumab (A) in Patients (pts) with Advanced Ovarian Cancer (OC) or Triple Negative Breast Cancer (TNBC) (AACR 2021) - P1 | "While suspected HLH/HLH is rare for RO or A given as monotherapy, the safety profile of the combination was considered unacceptable as noted by the high frequency and severity of irAEs including suspected HLH. A limited anti-tumor activity was observed with PR as best overall response in 2 pts. The trial was terminated early due to the unfavorable risk-benefit profile."

Clinical • Late-breaking abstract • P1 data • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CD47 • MYC • PD-L1

A phase 1b dose-escalation/expansion study of BET inhibitor RO6870810 in patients with advanced multiple myeloma. (PubMed, Blood Cancer J) - No abstract available

Clinical • Journal • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies (clinicaltrials.gov) - P1; N=66; Recruiting; Sponsor: Tensha Therapeutics

Clinical • New P1 trial • NUT Midline Carcinoma • Oncology • Solid Tumor • MYC

A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Hoffmann-La Roche; N=66 ➔ 120; Trial primary completion date: Mar 2016 ➔ May 2017

Clinical • Enrollment change • Trial primary completion date • NUT Midline Carcinoma • Oncology • Solid Tumor • MYC

A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Hoffmann-La Roche; Trial primary completion date: May 2017 ➔ Aug 2017

Clinical • Trial primary completion date • NUT Midline Carcinoma • Oncology • Solid Tumor • MYC

A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies (clinicaltrials.gov) - P1; N=120; Active, not recruiting; Sponsor: Hoffmann-La Roche; Recruiting ➔ Active, not recruiting; Trial primary completion date: Aug 2017 ➔ Dec 2017

Clinical • Enrollment closed • Trial primary completion date • NUT Midline Carcinoma • Oncology • Solid Tumor • MYC

A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies (clinicaltrials.gov) - P1; N=52; Completed; Sponsor: Hoffmann-La Roche; Active, not recruiting ➔ Completed; N=120 ➔ 52

Clinical • Enrollment change • Trial completion • NUT Midline Carcinoma • Solid Tumor • MYC

A Two Part Study of RO6870810. Dose-Escalation Study in Participants With Advanced Solid Tumors and Expansion Study in Participants With Selected Malignancies (clinicaltrials.gov) - P1; N=66; Recruiting; Sponsor: Tensha Therapeutics; Trial primary completion date: Feb 2015 ➔ Mar 2016

Clinical • Trial primary completion date • NUT Midline Carcinoma • Oncology • Solid Tumor • MYC

A dose escalation study of RO6870810/TEN-10 in patients with acute myeloid leukemia and myelodysplastic syndrome. (PubMed, Leuk Lymphoma) - P1 | "For MDS, two patients experienced SD. Further development of RO as monotherapy was discontinued due to lack of efficacy, but combinations with other agents are under consideration."

Clinical • Journal • Acute Myelogenous Leukemia • Cardiovascular • Congestive Heart Failure • Fatigue • Heart Failure • Hematological Malignancies • Hypertension • Leukemia • Myelodysplastic Syndrome • Oncology • ITGAM

A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma. (PubMed, Br J Cancer) - P1 | "This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations."

Clinical • Journal • P1 data • Dermatology • Diffuse Large B Cell Lymphoma • Fatigue • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • NUT Midline Carcinoma • Oncology • Solid Tumor • Testicular Cancer • ITGAM • MYC

[VIRTUAL] Sensitizing cancer cells to TNF induced cell death by the BET-inhibitor RG6146 (AACR-II 2020) - "Even though treatment of this co-culture with the CEATCB alone increased bystander killing of cancer cells expressing low CEA levels, addition of RG6146 significantly enhanced this effect.We used syngeneic recipient mice to validate our findings in vivo. While single agent treatment of CEATCB or BETi decreased tumor growth, the combination of both molecules caused tumor regression.Taken together this data establishes a paradigm where BETi can rewire NF-κB signaling, leading to enhanced sensitivity to cytotoxic lymphocyte-derived TNF and therapeutically augmenting the anti-tumor activity of IO agents."

IO Biomarker • Oncology • CASP8 • GZMB • IFNG • PD-L1 • TNFA

A Study to Evaluate Safety, Pharmacokinetics, and Clinical Activity of Combination of RO6870810 and Venetoclax, With or Without Rituximab, in Participants With Relapsed/Refractory DLBCL and/or High-Grade B-Cell Lymphoma and/or High Grade B-Cell Lymphoma With MYC and/or BCL2 and/or BCL6 (clinicaltrials.gov) - P1; N=39; Completed; Sponsor: Hoffmann-La Roche; Active, not recruiting ➔ Completed; Trial completion date: Mar 2020 ➔ Aug 2019; Trial primary completion date: Mar 2020 ➔ Aug 2019

Clinical • Trial completion • Trial completion date • Trial primary completion date • BCL2

Study of Bromodomain and Extra-Terminal Protein (BET) Inhibitor RO6870810 as Mono- and Combination Therapy in Advanced Multiple Myeloma (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Hoffmann-La Roche; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion

"$RHHBY discontinuations: RG6109 undiscl ADC; RG6123 anti-CEA MAb; RG6146 bromodomain inh; RG6148 undisclosed (Her2+ breast cancer); RG7625 cathepsin S inh" (@JacobPlieth)