Abstract 3702
Background
ARQ761 (β-lapachone) is a hydroquinone analog that exploits the unique elevation of NQO1 found in 90% of pancreatic cancer cells and causes tumor-specific cell death by eliciting a futile redox cycle generating high levels of reactive oxygen species and ultimately PARP1 hyperactivation-dependent cell death. ARQ761 induces cell death which is: (i) not dependent on p53 status; (ii) not dependent on cell cycle status; (iii) not affected by known oncogenic driver or carrier mutations; and (iv) not affected by loss of caspases. We demonstrated that ARQ761 has synergistic antitumor activity with chemotherapy in pancreatic cancer preclinical models.
Methods
This was a single arm phase-1b clinical trial of ARQ-761 plus gemcitabine and nab-paclitaxel for patients with pancreatic cancer. The primary objective was to determine the maximum tolerated dose of ARQ 761 in combination with chemotherapy. Secondary objectives were to assess clinical activity, safety, tolerability and pharmacodynamic effects. Patients with metastatic pancreatic adenocarcinoma not treated with prior gemcitabine with adequate hematologic, renal and liver function and good performance status were enrolled. Dose levels are described in the table. Immunohistochemistry was used to assess for NQO1 expression.
Results
Fifteen patients were evaluable for safety, 67% were male, 53% had received prior chemotherapy and 96% tested positive for NQO1 expression. The most common treatment related toxicities were anemia and fatigue. The following dose limiting toxicities were observed (dose level 1: neutropenia, anemia, dose level -1 fatigue). The maximum tolerated dose of ARQ761/gemcitabine/nab-paclitaxel is 156/800/100mg/m2. Tumour response was stable disease in 53% Pharmacodynamic analysis was performed on post treatment biopsies.
Conclusions
We report results of a phase 1b clinical trial of the novel NQO1 bioactivatable compound, ARQ761, in combination with gemcitabine/nab-paclitaxel. Treatment related toxicities were observed which were noted in preclinical models and managed with routine dose adjustment.
Clinical trial identification
NCT02514031.
Editorial acknowledgement
Legal entity responsible for the study
UT Southwestern Medical Center.
Funding
Pancreatic Cancer Action Network, Rising Tide, Gateway, Arqule Pharmaceuticals.
Disclosure
M.S. Beg: Research grant / Funding (institution): Arqule; Advisory / Consultancy: Array; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Guardant; Advisory / Consultancy: Genentech. D. Boothman: Research grant / Funding (institution): Arqule; Advisory / Consultancy: Toray global; Speaker Bureau / Expert testimony: systems oncology. Y. Arriaga: Full / Part-time employment: IBM. A. Sanjeeviaiah: Advisory / Consultancy, 1500$: Guardant health. B. Schwartz: Full / Part-time employment: Arqule. All other authors have declared no conflicts of interest.
Resources from the same session
2670 - Molecular subtypes of metastatic(met) gastric cancer(GC) (MoTriGastric): new biomarkers closer to the clinics
Presenter: Maria Alsina Maqueda
Session: Poster Display session 2
Resources:
Abstract
3797 - Exploring candidate signal transduction pathways for targeted therapy in esophageal cancer
Presenter: Aafke Creemers
Session: Poster Display session 2
Resources:
Abstract
5485 - Clinical implication of CLDN18, RhoGAP, and E-cadherin in gastric signet ring cell carcinoma
Presenter: Hyunho Kim
Session: Poster Display session 2
Resources:
Abstract
1970 - Identification of a spectrum of germline mutations for hereditary diffuse gastric cancer in the Russian population by next-generation sequencing.
Presenter: IRINA EFIMOVA
Session: Poster Display session 2
Resources:
Abstract
4989 - The molecular profiling and prognostic value of Chinese gastric signet ring cell carcinoma patients
Presenter: Jia Wei
Session: Poster Display session 2
Resources:
Abstract
7145 - A phase 2 basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors
Presenter: Alison Schram
Session: Poster Display session 2
Resources:
Abstract
1406 - Simultaneous Resection of Pancreatic Cancer and Liver Oligometastases After Induction Chemotherapy in Stage IV Patients:an Open-Label Prospective Randomized Multicenter phase 3 trial(CSPAC-1)
Presenter: Miaoyan Wei
Session: Poster Display session 2
Resources:
Abstract
1530 - Multicenter randomized phase II trial of 5-Fluorouracil/leucovorin (5-FU/LV) with or without liposomal irinotecan (nal-IRI) in metastatic biliary tract cancer (BTC) as second-line therapy after progression on gemcitabine plus cisplatin (GemCis): NIFTY trial
Presenter: Changhoon Yoo
Session: Poster Display session 2
Resources:
Abstract
1563 - A randomized phase II study of Maintenance therapy with multiepitope vaccine Tedopi (OSE2101) ± nivolumab or FOLFIRI after induction chemotherapy (CT) with FOLFIRINOX in patients (Pts) with advanced Pancreatic ductal adenocarcinoma (aPDAC) (TEDOPaM – PRODIGE 63 GERCOR study)
Presenter: Cindy Neuzillet
Session: Poster Display session 2
Resources:
Abstract
2780 - A phase 3, randomized, double-blind, placebo-controlled, international study of durvalumab in combination with gemcitabine plus cisplatin for patients with advanced biliary tract cancers: TOPAZ-1
Presenter: Do-Youn Oh
Session: Poster Display session 2
Resources:
Abstract