Human amnion cells for the prevention of bronchopulmonary dysplasia: a protocol for a phase I dose escalation study

IntroductionBronchopulmonary dysplasia (BPD), an important sequela of preterm birth, is associated with long-term abnormalities of lung function and adverse neurodevelopmental outcomes. Inflammation, inhibition of secondary septation and vascular maldevelopment play key roles in the pathogenesis of BPD. Human amnion epithelial cells (hAECs), stem-like cells, derived from placental tissues are able to modulate the inflammatory milieu and, in preclinical studies of BPD-like injury, restore lung architecture and function. Allogeneic hAECs may present a new preventative and reparative therapy for BPD.Methods and analysisIn this two centre, phase I cell dose escalation study we will evaluate the safety of intravenous hAEC infusions in preterm infants at high risk of severe BPD. Twenty-four infants born at less than 29 weeks’ gestation will each receive intravenous hAECs beginning day 14 of life. We will escalate the dose of cells contained in a single intravenous hAEC infusion in increments from 2 million cells/kg to 10 million cells/kg. Further dose escalation will be achieved with repeat infusions given at 5 day intervals to a maximum total dose of 30 million cells/kg (three infusions). Safety is the primary outcome. Infants will be followed-up until 2 years corrected age. Additional outcome measures include a description of infants’ cytokine profile following hAEC infusion, respiratory outcomes including BPD and pulmonary hypertension and other neonatal morbidities including neurodevelopmental assessment at 2 years.Ethics and disseminationThis study was approved on the June12th, 2018 by the Human Research Ethics Committee of Monash Health and Monash University. Recruitment commenced in August 2018 and is expected to take 18 months. Accordingly, follow-up will be completed mid-2022. The findings of this study will be disseminated via peer-reviewed journals and at conferences.Protocol version5, 21 May 2018.Trial registration numberACTRN12618000920291; Pre-results.

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Human amnion epithelial cells for the prevention of bronchopulmonary dysplasia: a phase 1 dose escalation study

Cytotherapy ◽

10.1016/j.jcyt.2019.03.403 ◽

2019 ◽

Vol 21 (5) ◽

pp. S49

Author(s):

E.K. Baker ◽

R. Lim ◽

A. Malhotra ◽

S.E. Jacobs ◽

P.G. Davis ◽

...

Keyword(s):

Epithelial Cells ◽

Bronchopulmonary Dysplasia ◽

Dose Escalation ◽

Phase 1 ◽

Dose Escalation Study ◽

Human Amnion ◽

Amnion Epithelial Cells

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Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol

BMJ Open ◽

10.1136/bmjopen-2021-050725 ◽

2021 ◽

Vol 11 (11) ◽

pp. e050725

Author(s):

Jeroen H A Creemers ◽

Inka Pawlitzky ◽

Konstantina Grosios ◽

Uzi Gileadi ◽

Mark R Middleton ◽

...

Keyword(s):

Immune Responses ◽

Phase I ◽

Cancer Immunotherapy ◽

Dose Escalation ◽

Competent Authority ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Open Label ◽

Dose Escalation Study ◽

Registration Number

IntroductionThe undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers.Methods and analysisThis open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1.Ethics and disseminationThe Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal.Trial registration numberNCT04751786.

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