Cotellic (cobimetinib)

P1/2, N=340, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Oct 2026 --> Jan 2025 | Trial primary completion date: Oct 2025 --> Jan 2025

P2/3, N=1000, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=15, Recruiting, OHSU Knight Cancer Institute | Trial primary completion date: Dec 2024 --> Dec 2025

Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS. ClinicalTrials.gov Identifier: NCT03181100.

Co-administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines...Similar events occurred in highly bortezomib-resistant (PS-R) cells, in the presence of patient-derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1/2 (trametinib) inhibitors...Finally, the ATR inhibitor/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib-resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR/MEK1/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.

P3, N=514, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2, N=410, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Aug 2024 --> Apr 2025

P2, N=176, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2028 --> May 2028 | Trial primary completion date: May 2028 --> Feb 2028

P2, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=3791, Recruiting, American Society of Clinical Oncology | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2026

Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation...A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance.

We found that the IC50 values ranged from 74 to 372 nM, which are within the achievable and tolerable ranges for cobimetinib. This finding positions cobimetinib as a promising potential candidate for future canine clinical trials and enhances our understanding of the molecular defects in these challenging cancers.

Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.

In summary, this work describes BRAF/MEK-inhibitor-resistant melanoma cells, allowing for better understanding the underlying mechanisms of resistance. The results may thus contribute to the development of new, more effective therapeutic strategies.

P2, N=167, Active, not recruiting, Uppsala University Hospital | Recruiting --> Active, not recruiting

Purpose: This study explores the potential of preclinical in vitro cell line response data and computational modeling in identifying optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Further, our analysis suggests the importance of drug dosing strategies to optimize synergy based on mutational context, yet highlights the real-world challenges of maintaining a narrow dose range. This approach establishes a framework for translational investigation of drug responses in the refinement of combination therapy, balancing the potential for synergy and practical feasibility in cancer treatment planning.

P2, N=48, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

P2, N=385, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Jun 2024 --> Sep 2024

Due to the up-regulation of PD-1/PD-L1 receptors in tumors treated with BRAF/MEK inhibitor therapy, further studies included a third combination agent, anti-PD-1/PD-L1 inhibitors. This triple combination therapy may have superior efficacy and a manageable safety profile when compared with single or double agent therapy regimens.

In this study, we explored the suppression mechanism of the phosphorylation process in the presence of MEK allosteric inhibitors, such as selumetinib, trametinib, cobimetinib, and CH5126766, by employing molecular dynamics simulations accompanied by principal component analysis. The results conclude that a strong interaction of allosteric inhibitors with the activation loop restricts the movement of Ser222 toward Mg-ATP, which could be the dominant factor for the suppression of phosphorylation in MEK1. This research will provide novel insights to design effective anticancer therapeutics for targeting MEK1 in the future.

VEM+COB is active in a range of advanced solid tumours and 1L NSCLC with a BRAF V600 mutation.

P1/2; Active, not recruiting --> Completed

Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors.

P1/2 | N=320 | Active, not recruiting | Sponsor: Centre Leon Berard | Recruiting ➔ Active, not recruiting

BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults...Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes.

P2; Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Aug 2023 | Trial primary completion date: Dec 2022 --> Aug 2023

Effects could be rescued by inhibitors of Mek (cobimetinib) or Raf (dabrafenib). Taken together, these results show that miR-142 functionally regulates SOS1/Ras/Raf/Mek/Erk signaling initiated through the BCR and consequently, restricts EBV entry into the lytic cycle.

P2, N=528, Active, not recruiting, Hoffmann-La Roche | N=790 --> 528

P2, N=21, Recruiting, City of Hope Medical Center

P1/2, N=675, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Jun 2026 --> Sep 2025 | Recruiting --> Active, not recruiting | Trial completion date: Sep 2027 --> Nov 2026

P2, N=30, Recruiting, Mayo Clinic | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=24, Active, not recruiting, Alliance for Clinical Trials in Oncology | Recruiting --> Active, not recruiting | N=36 --> 24

P2, N=186, Completed, University Hospital, Essen | Trial completion date: Jun 2024 --> Mar 2024 | Active, not recruiting --> Completed

P1, N=53, Terminated, ABM Therapeutics Corporation | N=112 --> 53 | Trial completion date: Jan 2025 --> Apr 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Apr 2024; Not related to safety concerns or lack of efficacy

P2, N=29, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2026

P2, N=176, Active, not recruiting, Hoffmann-La Roche | N=550 --> 176

P=N/A, N=1, Completed, Pfizer | Active, not recruiting --> Completed | Trial completion date: Jul 2024 --> Dec 2023 | Trial primary completion date: Jul 2024 --> Dec 2023

P1/2, N=1163, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: May 2024 --> Oct 2024

P2, N=154, Recruiting, Uppsala University Hospital | Trial completion date: Dec 2022 --> Oct 2024 | Trial primary completion date: Dec 2022 --> Jan 2024

P2, N=385, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Feb 2024 --> Jun 2024

P2, N=1044, Completed, Hoffmann-La Roche | N=609 --> 1044

P1/2, N=16, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | N=31 --> 16 | Trial completion date: Nov 2024 --> Jan 2027 | Trial primary completion date: Nov 2022 --> Jan 2025