KO-947 / Kura Oncology, Araxes Pharma - LARVOL DELTA

Advances in ERK1/2 inhibition: a medicinal chemistry perspective on structure and regulation. (PubMed, J Enzyme Inhib Med Chem) - "Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics."

Journal • Review • Oncology • MAPK1 • MAPK3

A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors. (PubMed, ESMO Open) - "Intravenous KO-947 had a generally tolerable safety profile with minimal gastrointestinal toxicity compared with oral administration of other ERK inhibitors."

Journal • P1 data • Gastrointestinal Disorder • Hypotension • Oncology • Solid Tumor

From Lab Formulation Development to CTM Manufacturing of KO-947 Injectable Drug Products: a Case Study and Lessons Learned. (PubMed, AAPS PharmSciTech) - "An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at -20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial."

Clinical • Journal

First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - P1; N=62; Terminated; Sponsor: Kura Oncology, Inc.; N=100 ➔ 62; Trial completion date: Dec 2020 ➔ Jun 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Dec 2020 ➔ Jun 2020; Due to a strategic business decision Kura has stopped development of KO-947. Neither safety nor efficacy reasons were the cause of study termination.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck

11q13 amplification selects for sensitivity to the ERK inhibitor KO-947 in squamous cell carcinomas (AACR 2018) - "A key role for ANO1 in driving ERK-dependent tumor growth in 11q-AMP cases was further indicated by the observation that ANO1 expression was silenced in some 11q-AMP models and these tumors failed to respond the ERK inhibition. The results suggest that 11q13 amplification in SCCs can drive tumor growth and survival in a MAPK-dependent manner and that 11q-AMP may be a useful biomarker for predicting clinical response to ERK inhibitors."

Head and Neck Cancer • Melanoma

First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - P1; N=100; Active, not recruiting; Sponsor: Kura Oncology, Inc.; Trial completion date: Aug 2020 ➔ Dec 2020; Trial primary completion date: Feb 2020 ➔ Dec 2020

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • BRAF • KRAS • NRAS

Kura Oncology reports first quarter 2020 financial results (GlobeNewswire) - "Three abstracts highlighting data from tipifarnib in HRAS mutant solid tumors have been accepted for presentation, including an oral presentation featuring matured clinical outcome data from the Phase 2 clinical trial of tipifarnib in HRAS mutant HNSCC, at the upcoming 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program....Earlier this year, Kura’s Phase 1 trial of KO-947 was placed on a partial clinical hold due to a dose-limiting adverse drug reaction in a single patient on study. Although the Company was successful in lifting the partial clinical hold and continues to have an interest in 11q13-amplified solid tumors, Kura has opted to terminate further development of KO-947 in order to focus its resources on programs with the highest potential to benefit patients and create value."

Clinical data • Discontinued • P2 data • Head and Neck Cancer • Oncology • Solid Tumor

First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - P1; N=100; Active, not recruiting; Sponsor: Kura Oncology, Inc.; Recruiting ➔ Active, not recruiting; N=72 ➔ 100; Trial completion date: Apr 2020 ➔ Aug 2020; Trial primary completion date: Oct 2019 ➔ Feb 2020

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date

Kura Oncology reports fourth quarter and full year 2019 financial results (GlobeNewswire) - "Upcoming Milestones: Open expansion cohort of patients with HNSCC and ESCC with 11q13 amplifications in Phase 1 trial of KO-947 in 2020; Achievement of a recommended Phase 2 dose in the Phase 1/2 dose-escalation trial of KO-539 by the end of 2020."

Enrollment status • Trial status

Targeting ERK1/2 protein-serine/threonine kinases in human cancers. (PubMed, Pharmacol Res) - "The best treatments include the combination of B-Raf and MEK inhibitors (dabrafenib and trametinib, encorafenib and binimetinib, vemurafenib and cobimetanib)...Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors...The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway."

Journal • Review

Kura Oncology reports third quarter 2019 financial results and provides corporate update (GlobeNewswire) - “Upcoming Milestones: Completion of the dose-escalation portion of the Phase 1 trial of KO-947 by the end of 2019 or early 2020; Initiation of tumor-specific extension cohort(s) in the Phase 1 trial of KO-947 in 2020; Achievement of a recommended Phase 2 dose in the Phase 1 dose-escalation trial of KO-539 in 2020.”

Trial status

Kura Oncology reports second quarter 2019 financial results and provides corporate update (GlobeNewswire) - "Upcoming Milestones: (i) Additional data from the ongoing Phase 2 trial of tipifarnib in HRAS mutant HNSCC and other SCCs in the fourth quarter of 2019; (ii) Additional data from the AITL expansion cohort in the ongoing Phase 2 trial of tipifarnib in the fourth quarter of 2019; (iii) Completion of the dose-escalation portion of the Phase 1 trial of KO-947 by the end of 2019; (iv) Additional data from the ongoing Phase 2 trial of tipifarnib in chronic myelomonocytic leukemia (CMML) in the first half of 2020; (v) Initiation of a proof-of-concept study of tipifarnib in pancreatic cancer in the first half of 2020."

New trial • P2 data • Trial status

Kura Oncology Reports First Quarter 2019 Financial Results and Highlights Upcoming Milestones (GlobeNewswire, Kura Oncology, Inc.) - "Additional data from the ongoing Phase 2 trial of tipifarnib in PTCL, including duration of response data from the AITL cohort and additional data from the CXCL12-positive PTCL cohort, at EHA and ICML in June 2019; Additional data on biomarkers associated with elevated CXCL12 expression at EHA and ICML in June 2019; Additional data from the ongoing Phase 2 trial of tipifarnib in HRAS mutant solid tumors, including HNSCC and other SCCs, in the second half of 2019; Additional data from the ongoing Phase 2 trial of tipifarnib in CMML in 2019; Data from the Phase 1 dose-escalation trial of KO-947 in 2019."

Biomarker • Clinical • Clinical data • P1 data • P2 data

Kura Oncology Reports Fourth Quarter and Full Year 2018 Financial Results (GlobeNewswire, Kura Oncology, Inc.) - "Additional data from the ongoing Phase 2 trial of tipifarnib in PTCL, including duration of response data from the AITL cohort and additional data from the CXCL12-high PTCL cohort, in mid-2019; Additional data from the ongoing Phase 2 trial of tipifarnib in HRAS mutant solid tumors, including HNSCC and other squamous cell carcinomas (SCCs), in the second half of 2019; Additional data from the ongoing Phase 2 trial of tipifarnib in chronic myelomonocytic leukemia (CMML) in 2019; Additional data on the molecular mechanisms of action of tipifarnib in 2019; Data from the Phase 1 dose-escalation trial of KO-947 in 2019."

Clinical • Clinical data • P1 data • P2 data