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Reply to K. Masuda et al

Publication: Journal of Clinical Oncology
We thank Masuda et al1 for their valuable comments. They question the scientific and financial background of the recently reported COMMAND (ClinicalTrials.gov identifier: NCT01870609) trial in malignant pleural mesothelioma (MPM).2
At the time this study was conceived in 2013, there was (and remains) an unmet global need for improvement in the survival data in MPM. Few companies had drugs available for, or any interest in, treating this group of patients, and no second-line treatment was defined. Therefore new studies were welcomed by the research community. A global expert group was formed to discuss the possible value of this approach before the study was designed.
COMMAND was hypothesis driven and was based on a biologic rationale underpinned first by robust preclinical reports indicating a focal adhesion kinase (FAK)/moesin-ezrin-radixin-like protein (merlin) synthetic lethal interaction3,4 and preferential stem cell targeting.5 Second, clinical data from a phase I trial of the FAK inhibitor GSK2256098 in 29 patients with recurrent MPM reported a progression-free survival (PFS) correlation of 23.4 versus 11.3 weeks in merlin-negative versus merlin-positive MPM, respectively, lending support to the hypothesis that merlin loss might be predictive for FAK inhibition.6 The data presented and hypotheses of efficacy in MPM were considered to be sufficient to proceed to a clinical study. No concerns were noted by the global expert group. A randomized design was selected. Mesotheliomas exhibit considerable interpatient heterogeneity; thus, single-arm phase II data are prone to sampling bias and are less reliable in detecting a signal of efficacy compared with a placebo controlled, randomized design. The COMMAND trial therefore adopted a gold-standard approach for the evaluation of defactinib.
The COMMAND trial was a phase IIb, not a phase III, study. It was carefully designed with two planned interim analyses based on the co-primary end point, PFS. These steps were preplanned precisely because of the need to limit unnecessary patient accrual. The first of these interim analyses was scheduled after 128 PFS events, with the aim of determining whether to enrich for merlin-negative patients. However, the probability of observing a significant result was less than 0.1, implicating futility. On the basis of this initial analysis, further recruitment was halted. The fact that a higher number of grade 5 treatment-related adverse events occurred in the active arm is considered to be a random event, and because the study was double-blind and closely monitored, the reported relationship with death as a result of disease progression is merely a fact.
It is important to always carefully consider study proposals, especially in orphan disease settings. To echo the words of the English poet William Blake, “Hindsight is a wonderful thing, but foresight is better, especially when it comes to saving life.” The COMMAND trial sought to explore a hypothesis-driven novel therapy in a setting of unmet need. This trial remains one of the few reported molecularly stratified randomized trials aimed at personalizing therapy for MPM. To this day, there is still no approved second-line therapy for MPM despite many recent global efforts to change this.7-9 Due to the rarity of MPM, only a fraction of patients participate in clinical trials with the clear knowledge that doing so could be futile. We must commend these patients and their families who, with us, sought to improve outcomes through clinical investigation. On these grounds alone, this study was not a waste, but rather a robustly tested scientific hypothesis that proved negative.

Authors' Disclosures of Potential Conflicts of Interest and Data Availability Statement

Reply to K. Masuda et al

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Dean A. Fennell

Honoraria: Bristol-Myers Squibb, Bayer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, MSD, Inventiva, Paredox Therapeutics
Consulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, MSD Oncology, Roche, Clovis Oncology
Speakers' Bureau: Boehringer Ingelheim
Research Funding: Boehringer Ingelheim (Inst), Bayer, Astex Pharmaceuticals, Fuji Pharma (Inst), Lab 21 (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD Oncology

Paul Taylor

Stock and Other Ownership Interests: Genentech
Speakers' Bureau: AstraZeneca
Research Funding: Bayer, Celgene, Epizyme
Travel, Accommodations, Expenses: Boehringer Ingelheim, Bristol-Myers Squibb

David Gilligan

Stock and Other Ownership Interests: Genesis Healthcare (I)
Speakers' Bureau: Bristol-Myers Squibb, Pfizer, Roche, AstraZeneca
Travel, Accommodations, Expenses: Boehringer Ingelheim

Takashi Nakano

Honoraria: Ono Pharmaceutical
Consulting or Advisory Role: Boehringer Ingelheim, MSD, KYORIN Pharmaceutical

Arnaud Scherpereel

Consulting or Advisory Role: MSD Oncology, Roche, Bristol-Myers Squibb, AstraZeneca/MedImmune
Speakers' Bureau: Roche Pharma AG
Research Funding: Bristol-Myers Squibb (Inst), MSD Oncology (Inst)
Travel, Accommodations, Expenses: MSD Oncology, Bristol-Myers Squibb

Nick Pavlakis

Consulting or Advisory Role: Roche, Boehringer Ingelheim, Astra Zeneca, Merck KGaA, Merck Serono, Amgen, Merck Sharp & Dohme, Novartis, Ipsen, Pfizer, Takeda Pharmaceuticals, Bristol-Myers Squibb
Research Funding: Bayer (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: Boehringer Ingelheim, Roche, Bristol-Myers Squibb

Jan P. van Meerbeeck

Travel, Accommodations, Expenses: Roche Belgium

Joachim G.J.V. Aerts

Stock and Other Ownership Interests: Amphera
Consulting or Advisory Role: Eli Lilly, Boehringer Ingelheim, MSD Oncology, Roche, Bristol-Myers Squibb, Amphera, AstraZeneca, Takeda Pharmaceuticals
Patents, Royalties, Other Intellectual Property: Dendritic cell–based immunotherapy (Inst); proteomics in non–small-cell lung cancer (Inst)

Anna K. Nowak

Consulting or Advisory Role: Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer Ingelheim, Epizyme, Roche, Merck Sharp & Dohme, Douglas Pharmaceuticals, Bristol-Myers Squibb
Research Funding: AstraZeneca (Inst), Douglas Pharmaceuticals (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Boehringer Ingelheim

Hedy Kindler

Consulting or Advisory Role: AstraZeneca, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Ipsen, Erytech Pharma, Five Prime Therapeutics, Paredox Therapeutics, Aldeyra Therapeutics, Kyowa Hakko Kirin, Astellas Pharma
Research Funding: Aduro BioTech (Inst), AstraZeneca (Inst), Bayer (Inst), GlaxoSmithKline (Inst), Merck (Inst), MedImmune (Inst), Verastem (Inst), Bristol-Myers Squibb (Inst), Eli Lilly (Inst), Polaris Pharmaceuticals (Inst), Deciphera Pharmaceuticals (Inst), Inhibrx (Inst), Genentech (Inst)

Paul Baas

Honoraria: AstraZeneca, Bristol-Myers Squibb
Consulting or Advisory Role: Merck Sharp & Dohme (Inst), Bristol-Myers Squibb (Inst), Aduro BioTech (Inst), Aldeyra Therapeutics (Inst), Pfizer (Inst)
Research Funding: Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst)
Travel, Accommodations, Expenses: Merck Sharp & Dohme
Other Relationship: Bristol-Myers Squibb
No other potential conflicts of interest were reported.

References

1.
Masuda K, Ishiki H, Oyamada S, et al: Questions regarding the randomized phase II trial of defactinib as maintenance therapy in malignant pleural mesothelioma. J Clin Oncol 37:2293-2294, 2019
2.
Fennell DA, Baas P, Taylor P, et al: Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND–A double-blind, randomized, phase II study. J Clin Oncol 37:790-798, 2019
3.
Shapiro IM, Kolev VN, Vidal CM, et al: Merlin deficiency predicts FAK inhibitor sensitivity: A synthetic lethal relationship. Sci Transl Med 6:237ra68, 2014
4.
Poulikakos PI, Xiao GH, Gallagher R, et al: Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 25:5960-5968, 2006
5.
Kaiser J: The cancer stem cell gamble. Science 347:226-229, 2015
6.
Soria JC, Plummer R, Ranson M, et al.; Loss of the tumor suppressor merlin as a potential predictive biomarker of clinical activity for the oral, focal adhesion kinase (FAK) inhibitor GSK2256098 in Pts with recurrent mesothelioma. Eur J Cancer 48:188, 2012 (abstr 610)
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Maio M, Scherpereel A, Calabrò L, et al: Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): A multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Lancet Oncol 18:1261-1273, 2017
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Fennell DA: Targeting the tumour vasculature in mesothelioma. Lancet Oncol 19:723-724, 2018
9.
Krug LM, Kindler HL, Calvert H, et al: Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol 16:447-456, 2015

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Published In

Journal of Clinical Oncology
Pages: 2294 - 2295
PubMed: 31329517

History

Published online: July 22, 2019
Published in print: September 01, 2019

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Dean A. Fennell, PhD, MD [email protected]
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Paul Taylor, MD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
David Gilligan, MD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Takashi Nakano, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Arnaud Scherpereel, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Nick Pavlakis, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Jan P. van Meerbeeck, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Joachim G.J.V. Aerts, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Anna K. Nowak, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Hedy Kindler, MD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands
Paul Baas, MD, PhD
Dean A. Fennell, PhD, MD, University of Leicester and University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom; Paul Taylor, MD, Wythenshawe Hospital, Manchester, United Kingdom; David Gilligan, MD, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; Takashi Nakano, MD, PhD, Hyogo College of Medicine, Nishinomiya, Japan; Arnaud Scherpereel, MD, PhD, Calmette Hospital, Regional University Hospital of Lille, Lille, France; Nick Pavlakis, MD, PhD, Northern Cancer Institute, St Leonards, NSW, Australia; Jan P. van Meerbeeck, MD, PhD, Universitair Ziekenuis, Antwerp, Belgium; Joachim G.J.V. Aerts, MD, PhD, Erasmus Medical College, Rotterdam, the Netherlands; Anna K. Nowak, MD, PhD, University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia; Hedy Kindler, MD, University of Chicago Medical Center, Chicago, IL; and Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands

Notes

Corresponding author: Dean A. Fennell, PhD, MD, University of Leicester, Mesothelioma Research Programme, Robert Kirkpatrick Clinical Sciences Building, Leicester LE1 5WW, United Kingdom; e-mail: [email protected].

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Dean A. Fennell, Paul Taylor, David Gilligan, Takashi Nakano, Arnaud Scherpereel, Nick Pavlakis, Jan P. van Meerbeeck, Joachim G.J.V. Aerts, Anna K. Nowak, Hedy Kindler, Paul Baas
Journal of Clinical Oncology 2019 37:25, 2294-2295

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