E6201 / Eisai, Strategia Therap, JS InnoPharm - LARVOL DELTA

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=13 | Terminated | Sponsor: Mayo Clinic | N=25 ➔ 13 | Trial completion date: Dec 2026 ➔ Jun 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Nov 2024; Financial issues

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases from BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=25 | Active, not recruiting | Sponsor: Mayo Clinic | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: Mayo Clinic | N=18 ➔ 25 | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Enrollment change • Metastases • Trial completion date • Trial primary completion date • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Phase 1 trial of MEK1 inhibitor E6201 plus dabrafenib in patients (pts) with BRAF V600-mutated metastatic melanoma (MM) with central nervous system (CNS) metastases (mets) (AACR 2024) - P1 | "The study allows one prior BRAF/MEK inhibitor therapy.The primary objectives are to determine the MTD of E6201 when combined with dabrafenib and the response rate of brain mets. The secondary objectives include duration of response,extracranial response, progression free survival, overall survival, and impact of BRAF mutation subtype and safety of the combination.Clinicaltrials.gov: NCT05388877"

Clinical • Metastases • P1 data • Melanoma • Oncology • Solid Tumor • BRAF

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Mayo Clinic | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

E6201, a novel MEK1 inhibitor, suppresses the metastatic capability of triple-negative breast cancer cells (AACR 2018) - P1; "Background: Triple-negative breast cancer (TNBC) lacks the receptor targets ER, PR, and HER2 and thus it does not respond to receptor-targeted treatments such as hormonal therapy and trastuzumab, leaving chemotherapy as the mainstay of treatment...Two BRAF inhibitors (vemurafenib and dabrafenib) and two MEK inhibitors (trametinib and cobimetinib) have received U.S. Food and Drug Administration approval for treatment of melanoma, clinically validating the potential of MAPK pathway inhibition to meaningfully benefit patients with TNBC...To evaluate the anti-metastatic activity of E6201 in vitro and in vivo, a migration/invasion assay and an experimental/spontaneous metastasis assay were performed, respectively. In vitro cell proliferation data demonstrated that E6201 inhibited growth more effectively (half maximal inhibitory concentration [IC50] range: 0.05-5 M) than did other MEK inhibitors (selumetinib, pimasertib, and trametinib)... Taken together,

IO biomarker • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Melanoma • Triple Negative Breast Cancer

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Mayo Clinic | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Spirita Oncology, LLC Initiates a Phase 1 Clinical Trial of the Anti-Cancer Agent E6201 in Combination with Dabrafenib in Patients with Central Nervous System Metastases from BRAF V600 Mutated Metastatic Melanoma (Businesswire) - "Spirita Oncology, LLC, has initiated a Phase 1 clinical trial of anti-cancer agent E6201 in combination with dabrafenib in patients with BRAF V600-mutated metastatic melanoma that has spread to the central nervous system."

Trial status • Melanoma • Oncology • Solid Tumor

A Phase 1, Multicenter, Open-Label, Dose-Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of E6201 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=55 | Completed | Sponsor: Eisai Inc. | Unknown status ➔ Completed

Trial completion • Melanoma • Oncology • Solid Tumor • BRAF

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: Mayo Clinic | Initiation date: Jun 2022 ➔ Sep 2022

Trial initiation date • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: Mayo Clinic

New P1 trial • CNS Tumor • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Phase I-II Study of Crenolanib Combined with Standard Salvage Chemotherapy and Crenolanib Combined with 5-Azacitidine in Acute Myeloid Leukemia Patients with FLT3 Activating Mutations (ASH 2018) - "...Higher intensity chemotherapy options consisted of either IA (Idarubicin (Ida) 12 mg/m2 for 3 days (d) with cytarabine (AraC) 1.5 g/m2 for 4 d (3 d if age > 60 yrs)). On a later amendment two other options were added: FLAG-Ida (Fludarabine 30 mg/m2, AraC 2g/m2 each for 5 d, and Ida 8 mg/m2 for 3 d), or MEC (Mitoxantrone 8 mg/m2, etoposide 100 mg/m2, AraC 1g/m2 all for 5 d)...16 (57%) pts had received prior FLT3 inhibitors including sorafenib (n=11), quizartinib (n=3), E6201 (n=2)...ORR can reach up to 50% with the combination, even with prior exposure to FLT3 inhibitors, and particularly among Arm 1 pts with ≤ 2 prior therapies (mOS=8.6 mo). The study was terminated at the sponsor’s request."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Biosimilar • Immunology • Oncology • Pain

[VIRTUAL] Automated image registration and alignment facilitates assessment of change in pigmented lesions of patients at risk for melanoma (AACR 2021) - "Software has been designed, applied, and validated that dramatically improves detection of changes in nevi over time and enables quantification of these changes. It helped clinicians to identify numerous changes that were missed in the original unregistered images. We plan to incorporate an expanded ruler and color balance tape in future photographs for improved analyses of border, color, and size changes."

Clinical • Late-breaking abstract • Melanoma • Oncology • Solid Tumor

Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas. (PubMed, Cancer Cell) - "Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs."

Clinical • Journal • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor

Advanced pancreatic cancer clinical trials: The continued underrepresentation of older patients. (PubMed, J Geriatr Oncol) - "Enrollment of older adults in phase III pancreatic cancer clinical trials has not increased over time, despite increasing number of older patients seen in clinic. Increased efforts are needed to enhance enrollment of older patients in clinical trials, and to promote trials specifically for older patients, in order to improve the evidence base for treating this patient population."

Clinical • Journal • Review • Gastrointestinal Cancer • Hematological Disorders • Immunology • Oncology • Pancreatic Cancer

The dual MEK/FLT3 inhibitor E6201 exerts cytotoxic activity against acute myeloid leukemia cells harboring resistance-conferring FLT3 mutations. (PubMed) - Cancer Res - "Furthermore, E6201 markedly reduced leukemia burden and improved the survival of mice in a human FLT3-mutated AML model. Collectively, our data provide a preclinical basis for the clinical evaluation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FLT3-targeted monotherapy."

Journal • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Mechanism-Based Combinatorial Strategy for Overcoming FLT3-Inhibitor Resistance in Dual FLT3 ITD and TKD Point Mutations (ASH 2016) - "Results demonstrated massive apoptosis induction in MSC co-culture systems (apoptosis induction was 23.9% vs. 91.8% in the absence vs. presence of plerixafor). targeting FLT3/MEK and PI3K/mTOR with E6201 and voxtalisib has potential of preventing the development of FLT3-inhibitor resistance."

Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

Boston Strategics enters into an innovative risk-sharing agreement with the MD Anderson Cancer Center to conduct a phase 1/2a clinical trial of E6201 in patients with advanced hematologic malignancies including acute myeloid leukemia (Businesswire) - "Boston Strategics Corporation (BSC)...announced that it has entered into a risk-sharing agreement with...(MD Anderson) to conduct a Phase 1/2a clinical trial of E6201 in patients with advanced hematologic malignancies, including...(AML)....Under this innovative agreement, MD Anderson commits its own resources to conduct the clinical study, while BSC provides the drug supply, study execution, safety monitoring, and data management."

Anticipated new P1/2 trial • Licensing / partnership • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases. (PubMed, Invest New Drugs) - "Correlative preclinical studies demonstrated broad activity for E6201 across BRAF V600E mutant melanoma cell lines and effective BBB penetration in vivo. Together, these results suggest that E6201 may represent a potential new treatment option for BRAF-mutant MM patients with BM."

IO Biomarker • Journal

The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission. (PubMed, Haematologica) - "Moreover, while Jak2-inhibitors alone increased BMP4 production by mesenchymal cells, the addition of the newly described BMPR1B inhibitor (E6201) impaired BMP4-mediated production by stromal cells. Altogether, our data demonstrate that targeting both BMPR1B and Jak2/Stat3 efficiently impacts persisting and dormant leukemic stem cells hidden in their bone marrow microenvironment."

Clinical • Journal

Phase 1 trial of MEK1 inhibitor E6201 Plus Dabrafenib in patients (pts) with BRAF V600- mutated metastatic melanoma (MM) with central nervous system (CNS) metastases (mets) (SMR 2019) - P1; "A second pt who received prior RT x 2, dabrafenib/trametinib, pembro, nivo/ ipi achieved CNS SD and a CR in a leg melanotic lesion for 4 cycles. E6201 has been well tolerated; 1 drug-related AE, thrombocytopenia (Gr 2) was observed, reversible. The Combination Safety Run-in Phase is open."

Clinical • IO Biomarker • P1 data • PD(L)-1 Biomarker • BRAF

Anti-tumor and anti-metastasis efficacy of E6201, a MEK1 inhibitor, in preclinical models of triple-negative breast cancer. (PubMed, Breast Cancer Res Treat) - "These results indicate that E6201 exhibits anti-tumor efficacy against TNBC in vitro and anti-metastasis efficacy against TNBC in vivo. These results provide a rationale for further clinical development of E6201 as a MAPK-pathway-targeted therapy for TNBC."

Journal • Preclinical

Safety, pharmacokinetics, and preliminary efficacy of E6201 in patients with advanced solid tumours, including melanoma: results of a phase 1 study. (PubMed, Br J Cancer) - "An intermittent regimen of E6201 320 mg/m IV qw for the first 3 weeks of a 28-day cycle was feasible and reasonably well-tolerated in patients with advanced solid tumours, including melanoma with brain metastases, with evidence of clinical efficacy."

Clinical • Journal • P1 data • PK/PD data