vevorisertib (ARQ 751) / Merck (MSD) - LARVOL DELTA

Phase 1b study of pan-AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in PIK3CA/AKT/PTEN-mutated advanced solid tumors. (PubMed, Cancer) - P1b | "Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors."

Journal • Metastases • P1 data • Oncology • Solid Tumor • PIK3CA • PTEN

Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model. (PubMed, Int J Mol Sci) - "Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC."

Combination therapy • Journal • Preclinical • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor

Results of a phase I dose escalation study of ARQ 751 in adult subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations (AACR 2018) - "ARQ 751 demonstrated a manageable safety profile at Dose level up to 25 mg QD. The dose escalation is ongoing. PK and updated safety, efficacy data will be presented."

Clinical • P1 data • Breast Cancer • Endometrial Cancer • Head and Neck Cancer

Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor. (PubMed, Cancers (Basel)) - "The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation...We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities...The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting."

Journal • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • PDCD4

ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations (clinicaltrials.gov) - P1b; N=77; Terminated; Sponsor: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.); Completed ➔ Terminated; Business Reasons

Clinical • Combination therapy • Trial termination • Breast Cancer • Endometrial Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PIK3CA • PTEN

ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations (clinicaltrials.gov) - P1b; N=77; Completed; Sponsor: ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.); Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Endometrial Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PIK3CA • PTEN

Combinations of imatinib mesylate with AKT inhibitor (miransertib, ARQ 751) or FGFR inhibitor (derazantinib) show synergy in GIST cell lines and preclinical models (AACR 2018) - "Together, these studies demonstrate that IM in combination with the novel ArQule AKT inhibitors (Miransertib and ARQ 751) and FGFR inhibitor (Derazantinib) provide significantly improved efficacy compared to monotherapy in the tested models. These results provide justification for development of translational trials evaluating these combinations in GIST patients."

IO Biomarker • Preclinical • Gastrointestinal Cancer • Sarcoma

ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations (clinicaltrials.gov) - P1b; N=100; Active, not recruiting; Sponsor: ArQule; Recruiting ➔ Active, not recruiting; Trial completion date: Mar 2021 ➔ Jun 2021

Clinical • Combination therapy • Enrollment closed • Trial completion date • Endometrial Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

In vitro and in vivo combination of ARQ 751 with PARP inhibitors, CDK4/6 inhibitors, Fulvestrant and Paclitaxel (AACR-NCI-EORTC 2019) - "ARQ 751 is a second-generation AKT inhibitor, which has distinct physico-chemical properties as compared to ArQule’s first-generation inhibitor, miransertib (ARQ 092)...The combination of ARQ 751 and olaparib also suppressed anchorage-independent growth in MDA-MB-231 and HCC1143 cells. In combination with the CDK4/6 inhibitor, ribociclib, ARQ 751 demonstrated superior cell growth inhibition in comparison to the single agents...Combination of ARQ 751 at 25 mg/kg with either fulvestrant at 2.5 mg/kg or palbociclib at 50 mg/kg exerted tumor growth inhibition of 91% or 93%, respectively, as compared to 69% for ARQ 751, 68% for fulvestrant and 38% for palbociclib...Conclusion ARQ 751, a highly potent and selective next-generation AKT inhibitor, is combinable with various therapeutic agents including PARP inhibitors, an ER antagonist, CDK4/6 inhibitors, and a chemotherapeutic agent, in vitro and in vivo. The data support the rationale for testing these combinations in the clinic."

PARP Biomarker • Preclinical • AKT1

ArQule presents recent data on ARQ 751 at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Arqule, Inc Press Release) - "ArQule...announced new clinical and preclinical data demonstrating the potential of the company’s AKT inhibitor ARQ 751 in treating solid tumors characterized by mutations in the PI3K/AKT/mTOR pathway. The findings were detailed in two poster presentations at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics."

P1 data • Preclinical

The use of biomarkers and ctDNA in a phase 1 trial of ARQ 751 (AACR-NCI-EORTC 2019) - "ARQ 751 is a potent and highly selective pan-AKT inhibitor against AKT1, AKT2, and AKT3, and is currently in a phase 1b clinical trial as a single agent, or combination with paclitaxel or fluvestrant. Additionally, an evaluation of a limited set of pre and post treatment ctDNA data provides interesting new insights on patient’s responses to therapy. Additional data to be presented at the meeting."

Biomarker • P1 data

ArQule presents recent data on ARQ 751 at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Arqule, Inc Press Release) - P1, N=100; NCT02761694; Sponsor: ArQule; “ArQule, Inc….announced new clinical and preclinical data demonstrating the potential of the company’s AKT inhibitor ARQ 751 in treating solid tumors characterized by mutations in the PI3K/AKT/mTOR pathway….There is a high concordance (76%) between the pre-study mutation and the mutation as measured using ctDNA profiling, Though patient data are limited, analysis of the correlation between ctDNA mutational status and patient response suggest that PIK3CA H1047R has prognostic value…The combination of ARQ 751 with chemotherapy (paclitaxel) showed enhanced anti-tumor activity in comparison to single agents in vivo, The combination of ARQ 751 with PARP inhibitors (olaparib, talazoparib, rucaparib) showed enhanced anti-proliferative activity in vitro.”

P1 data • Preclinical

ArQule announces presentations on ARQ 751 at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Arqule, Inc Press Release) - P1, N=100; NCT02761694; Sponsor: ArQule; "ArQule...announced that it will be presenting data on the company’s AKT inhibitor, ARQ 751, in two poster presentations at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics being held from October 26th to October 30th, 2019 in Boston, Massachusetts. Presentations will detail clinical data demonstrating the correlation between biomarkers and patient response to treatment with ARQ 751 as well as preclinical in vivo and in vitro findings supporting the potential of ARQ 751 in combination with a variety of therapeutic agents."

P1 data • Preclinical

ArQule reports fourth quarter and full year 2018 financial results (Businesswire) - "Key catalysts & goals for 2019 - ARQ 531: Dual BTK Inhibitor in B-Cell Malignancies: (i) Complete the dose escalation portion of phase 1 trial; (ii) Determine a recommended phase 2 dose and initiate expansion cohort(s); [and] (iii) Present results of dose escalation phase 1 trial at major industry conference(s); ARQ 751 (and miransertib): AKT inhibitors in oncology: (i) Complete recruitment in ongoing clinical trials; [and] (ii) Present data sets at major medical conferences this year."

Clinical data • Enrollment status • P1 data • Trial completion date • Trial status

ARQ 751 as a Single Agent or in Combination With Other Anti-Cancer Agents, in Solid Tumors With PIK3CA / AKT / PTEN Mutations (clinicaltrials.gov) - P1b; N=100; Recruiting; Sponsor: ArQule; Phase classification: P1 ➔ P1b; Trial completion date: Mar 2020 ➔ Mar 2021; Trial primary completion date: Dec 2019 ➔ Dec 2020

Clinical • Combination therapy • Phase classification • Trial completion date • Trial primary completion date