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
5472 - Early response evaluation and CEA response in patients treated in a Danish randomized study comparing trifluridine/tipiracil (TAS-102) with or without bevazicumab in patients with chemorefractory metastatic colorectal cancer (mCRC)
Presenter: Camilla Qvortrup
Session: Poster Display session 2
Resources:
Abstract
2037 - Updated survival analysis of the randomized phase III trial comparing S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer (SALTO) by the Dutch Colorectal Cancer Group.
Presenter: Johannes Kwakman
Session: Poster Display session 2
Resources:
Abstract
3053 - JFMC51-1702-C7: Phase II study investigating efficacy and safety of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) in patients (pts) with metastatic colorectal cancer (mCRC) refractory or intolerant to standard chemotherapies.
Presenter: Keisuke Kazama
Session: Poster Display session 2
Resources:
Abstract
3183 - Bevacizumab plus trifluridine/tipiracil in elderly patients with previously untreated metastatic colorectal cancer (KSCC 1602): A single-arm, Phase 2 study
Presenter: Akitaka Makiyama
Session: Poster Display session 2
Resources:
Abstract
3233 - Biweekly TAS-102 and Bevacizumab as a Third-Line Chemotherapy for metastatic colorectal cancer: A Phase II Multicenter Clinical Trial (TAS-CC4 study)
Presenter: Yoichiro Yoshida
Session: Poster Display session 2
Resources:
Abstract
5907 - Liquid biopsy concordance based on clonality and timing of testing in patients with metastatic colorectal cancer
Presenter: Pashtoon Kasi
Session: Poster Display session 2
Resources:
Abstract
1866 - Plasma clearance of RAS mutation under therapeutic pressure is a rare event in metastatic colorectal cancer
Presenter: Emilie Moati
Session: Poster Display session 2
Resources:
Abstract
2312 - High Circulating miR-1247 is a marker for poor prognosis in patients with metastatic colorectal cancer treated with chemotherapy and cetuximab
Presenter: Jakob Schou
Session: Poster Display session 2
Resources:
Abstract
5602 - Clinical relevance of circulating tumor (ct)DNA genotyping for first line cetuximab-based treatment monitoring in metastatic colorectal cancer (mCRC): a prospective multicentric study
Presenter: JOANA Vidal Barrull
Session: Poster Display session 2
Resources:
Abstract
3182 - Clonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer
Presenter: Beili Wang
Session: Poster Display session 2
Resources:
Abstract