PMID- 36106110
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220917
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 12
DP  - 2022
TI  - Integration of healthy volunteers in early phase clinical trials with 
      immuno-oncological compounds.
PG  - 954806
LID - 10.3389/fonc.2022.954806 [doi]
LID - 954806
AB  - AIM: Traditionally, early phase clinical trials in oncology have been performed 
      in patients based on safety risk-benefit assessment. Therapeutic transition to 
      immuno-oncology may open new opportunities for studies in healthy volunteers, 
      which are conducted faster and are less susceptible to confounders. Aim of this 
      study was to investigate to what extent this approach is utilized and whether 
      pharmacodynamic endpoints are evaluated in these early phase trials. We conducted 
      a comprehensive review of clinical trials with healthy volunteers using 
      immunotherapies potentially relevant for oncology. METHODS: Literature searches 
      according to PRISMA guidelines and after registration in PROSPERO were conducted 
      in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 
      October 2020, using search terms of relevant targets in immuno-oncology. Articles 
      describing clinical trials with immunotherapeutics in healthy volunteers with a 
      mechanism relevant for oncology were included. "Immunotherapeutic" was defined as 
      compounds exhibiting effects through immunological targets. Data including study 
      design and endpoints were extracted, with specific attention to pharmacodynamic 
      endpoints and safety. RESULTS: In total, we found 38 relevant immunotherapeutic 
      compounds tested in HVs, with 86% of studies investigating safety, 82% 
      investigating the pharmacokinetics (PK) and 57% including at least one 
      pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were 
      Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like 
      symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like 
      reaction and liver enzymes increase. PD endpoints investigated comprised of 
      cytokines, immune and inflammatory biomarkers, cell counts, phenotyping 
      circulating immune cells and ex vivo challenge assays. DISCUSSION: Healthy 
      volunteer studies with immuno-oncology compounds have been performed, although 
      not to a large extent. The integration of healthy volunteers in well-designed 
      proof-of-mechanism oriented drug development programs has advantages and could be 
      pursued more in the future, since integrative clinical trial protocols may 
      facilitate early dose selection and prevent cancer patients to be exposed to 
      non-therapeutic dosing regimens. SYSTEMATIC REVIEW REGISTRATION: 
      https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, 
      identifier CRD42020210861.
CI  - Copyright (c) 2022 Radanovic, Klarenbeek, Rissmann, Groeneveld, van Brummelen, 
      Moerland and Bosch.
FAU - Radanovic, Igor
AU  - Radanovic I
AD  - Centre for Human Drug Research, Leiden, Netherlands.
AD  - Leiden University Medical Center, Leiden, Netherlands.
FAU - Klarenbeek, Naomi
AU  - Klarenbeek N
AD  - Centre for Human Drug Research, Leiden, Netherlands.
FAU - Rissmann, Robert
AU  - Rissmann R
AD  - Centre for Human Drug Research, Leiden, Netherlands.
AD  - Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden 
      University, Leiden, Netherlands.
FAU - Groeneveld, Geert Jan
AU  - Groeneveld GJ
AD  - Centre for Human Drug Research, Leiden, Netherlands.
AD  - Leiden University Medical Center, Leiden, Netherlands.
FAU - van Brummelen, Emilie M J
AU  - van Brummelen EMJ
AD  - Centre for Human Drug Research, Leiden, Netherlands.
FAU - Moerland, Matthijs
AU  - Moerland M
AD  - Centre for Human Drug Research, Leiden, Netherlands.
AD  - Leiden University Medical Center, Leiden, Netherlands.
FAU - Bosch, Jacobus J
AU  - Bosch JJ
AD  - Centre for Human Drug Research, Leiden, Netherlands.
AD  - Leiden University Medical Center, Leiden, Netherlands.
LA  - eng
PT  - Systematic Review
DEP - 20220829
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC9465458
OTO - NOTNLM
OT  - clinical trials
OT  - healthy volunteers
OT  - immunotherapy
OT  - oncology
OT  - pharmacology
OT  - phase I
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/09/16 06:00
MHDA- 2022/09/16 06:01
PMCR- 2022/01/01
CRDT- 2022/09/15 02:38
PHST- 2022/05/27 00:00 [received]
PHST- 2022/08/09 00:00 [accepted]
PHST- 2022/09/15 02:38 [entrez]
PHST- 2022/09/16 06:00 [pubmed]
PHST- 2022/09/16 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2022.954806 [doi]
PST - epublish
SO  - Front Oncol. 2022 Aug 29;12:954806. doi: 10.3389/fonc.2022.954806. eCollection 
      2022.