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
1109 - First Canadian Interim Analysis from the Phase IIIb CompLEEment-1 Ribociclib + Letrozole HR+ HER2- Advanced Breast Cancer Trial
Presenter: Cristiano Ferrario
Session: Poster Display session 2
Resources:
Abstract
4401 - Real-world effectiveness of first-line palbociclib + letrozole for metastatic breast cancer 4 years post approval in the US
Presenter: Jonathan Kish
Session: Poster Display session 2
Resources:
Abstract
5876 - Palbociclib-Fulvestrant (PALBO-FUL) and Everolimus -Exemestane (EVE-EXE) for Second line Hormonal Treatment (HT) of Metastatic Breast Cancer (MBC) with Lobular Histology: a Propensity Score Matched Analysis of a Multicenter ‘Real-World’ Patients (pts) Series.
Presenter: Armando Orlandi
Session: Poster Display session 2
Resources:
Abstract
3587 - Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)
Presenter: E Dees
Session: Poster Display session 2
Resources:
Abstract
5696 - Final results of the STEM trial: SFX-01 in the Treatment and Evaluation of ER+ Her2- Metastatic breast cancer (mBC)
Presenter: Sacha Howell
Session: Poster Display session 2
Resources:
Abstract
1475 - Alpelisib (ALP) + Fulvestrant (FUL) in Hormone-Receptor Positive (HR+), Human Epidermal Growth Factor Receptor-2–Negative (HER2–) Advanced Breast Cancer (ABC): Subgroup Analysis by Presence of Visceral Metastasis (VM) in the SOLAR-1 Trial
Presenter: Mario Campone
Session: Poster Display session 2
Resources:
Abstract
2549 - Phase 1 Dose Escalation Study of a Selective Androgen Receptor Modulator RAD140 in Estrogen Receptor Positive (ER+), HER2 Negative (HER2-) Breast Cancer (BC)
Presenter: Erika Hamilton
Session: Poster Display session 2
Resources:
Abstract
3787 - A Phase I study of XZP-3287, a novel oral CDK4/6 Inhibitor, administered on a continuous dosing schedule, in patients with advanced solid tumours
Presenter: Binghe Xu
Session: Poster Display session 2
Resources:
Abstract
4835 - Phase-I dose-escalation and expansion study of the PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors
Presenter: Huiping Li
Session: Poster Display session 2
Resources:
Abstract
5083 - Phase 2 study of DHP107 (Liporaxel®, oral paclitaxel) in first-line, HER2 negative recurrent/metastatic breast cancer (OPTIMAL study, NCT03315364)
Presenter: Jin-Hee Ahn
Session: Poster Display session 2
Resources:
Abstract