Koselugo (selumetinib)

P1, N=58, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P=N/A, N=150, Not yet recruiting, AstraZeneca

P1/2, N=14, Completed, Great Ormond Street Hospital for Children NHS Foundation Trust | Recruiting --> Completed | N=30 --> 14 | Trial primary completion date: Aug 2023 --> Feb 2024

Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.

P3, N=300, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025

UM in this study was divided into three CNV subtypes, and a model based on eight aneuploidy score-related genes was established to evaluate the prognosis and drug treatment efficacy of UM patients. The current results may have the potential to help the clinical decision-making process for UM management.

Our study demonstrates that selumetinib is effective in patients with NF1 and PN, significantly improving the serious complications associated with PN as well as having tolerable toxicities. Our findings help to increase clinicians' confidence in applying selumetinib and promote the clinical adoption and benefit of the new drug.

P1, N=19, Active, not recruiting, National Cancer Institute (NCI)

P1, N=40, Active, not recruiting, National Cancer Institute (NCI)

Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

P=N/A, N=125, Recruiting, AstraZeneca | Trial primary completion date: May 2027 --> May 2028

P1, N=344, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

P1/2, N=220, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P2 --> P1/2

Selumetinib was the first and, as of February 2024, is the only medicine that can be prescribed by doctors to help children with NF1-related PN. Clinical Trial Registration: NCT01362803 (SPRINT) (ClinicalTrials.gov).

P1, N=24, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Jan 2026

P2, N=248, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2025 --> May 2025 | Trial primary completion date: Nov 2025 --> May 2025

P1/2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kβ/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.

Drug sensitivity analysis demonstrated lower IC50 for AZD6244 and PD.0332991 in high-risk groups and lower IC50 for cisplatin, ATRA, QS11, and vinorelbine in the low-risk group. Furthermore, the differential expression of GRTTK-related signatures including CDK2, TCEA1, and TMEM209 were verified in ESCC tissues and paracancerous tissues. Overall, the novel GRTTK-based prognostic model can serve as indicators to predict the survival status and immunotherapy response of patients with ESCC, thereby providing guidance for the development of personalized treatment strategies.

P1, N=18, Recruiting, University of Chicago | Trial primary completion date: Sep 2023 --> Sep 2025

P2, N=57, Active, not recruiting, University Health Network, Toronto | Trial completion date: Feb 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

P=N/A, N=100, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Dec 2023

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2023 --> Dec 2024

P2, N=34, Active, not recruiting, Children's Hospital Medical Center, Cincinnati | Recruiting --> Active, not recruiting

P2, N=999, Completed, UNICANCER | Active, not recruiting --> Completed

P2, N=41, Not yet recruiting, University of Alabama at Birmingham | Trial completion date: Jan 2030 --> Jun 2030 | Trial primary completion date: Jan 2029 --> Jun 2029

P2, N=307, Active, not recruiting, GERCOR - Multidisciplinary Oncology Cooperative Group | Recruiting --> Active, not recruiting

Interestingly, whereas primary SC cultures reset proliferation after removal of single Selumetib treatment, Ogerin-Selumetinib combo elicited a permanent halt on SC expansion, also after drug removal. These results indicate that unbalancing the Ras and cAMP pathways by combining MEKi and cAMP elevators arises as a potential treatment for cNFs.

P=N/A, N=125, Recruiting, AstraZeneca | Trial completion date: May 2027 --> May 2028

P2, N=200, Not yet recruiting, University of Alabama at Birmingham

High-risk patients were more sensitive to some small molecules compounds like camptothecin_1003, cisplatin_1005, cytarabine_1006, nutlin-3a (-)_1047, gemcitabine_1190, WZ4003_1614, selumetinib_1736 and mitoxantrone_1810. In summary, our study comprehensively explored the role of NETosis-related genes in gastric cancer, which can provide direction for relevant studies.

P1, N=140, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

P1, N=32, Completed, AstraZeneca | Active, not recruiting --> Completed

P2, N=21, Completed, Sarcoma Alliance for Research through Collaboration | Active, not recruiting --> Completed

There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development...The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

P=N/A, N=100, Not yet recruiting, AstraZeneca

ADH1B synergized with Selumetinib (inhibitor of the MAPK signalling pathway) to attenuate the proliferation, invasion and migration of BRCA and TNBC cells (P<0.001)...Thus, ADH1B may inhibit the proliferation, invasion and migration of BRCA and TNBC cells by inactivating the MAPK signalling pathway. It may be a promising target for the clinical treatment of BRCA and TNBC.

Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited BCR-ABL T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, BCR-ABL, and Hsp90; in non-small cell lung cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged anticancer response both in vivo and in vitro cancer models by inhibiting the alternate MET activation-induced RAS/MAPK reactivation, thereby promoting cancer cell apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.

P1, N=156, Active, not recruiting, AstraZeneca | Phase classification: P1b --> P1 | Trial completion date: Sep 2023 --> Jun 2024