title: Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies.
abstract: BACKGROUND
  Immunostimulatory monoclonal antibodies (imAbs) targeting immune checkpoint molecules are revolutionizing oncology not only regarding cancer therapeutics and clinical care, but also from a drug development point of view. A handful of first-generation molecules have been approved so far based on their tremendous efficacy, after an expedited development phase that has challenged most paradigms established in the era of conventional cytotoxic therapy and to some extent molecularly targeted agents. A huge wave of second-generation imAbs is just entering into phase 1 trials now, in monotherapy or in combination. In order to maximize their chances of success in early phase trials, and eventually for patients' benefit, their clinical development has to benefit from lessons learnt from previous imAbs phase 1 trials.
  
  
  METHODS
  We reviewed the early clinical development of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed death-1 receptor/ligand. Particularities of each agent, including safety, dose--toxicity and dose--efficacy relationships, scheduling, pharmacokinetics (PK), pharmacodynamics (PD), trial design, biomarkers, response assessment and overall drug development strategies, are described and challenged.
  
  
  RESULTS
  As opposed to conventional cytotoxic agents, dose of imAbs is not linearly associated with efficacy and toxicity. Therefore, the definition of a minimal immunologically active dose could be proposed. Traditional patient eligibility criteria might also be revisited as the toxicity profile and mechanism of toxicity--immune-related adverse events--are mostly known and their physiopathology somehow less unexpected than with molecularly targeted small molecules. Most challenging are the comprehensive investigation of complex PK and PD characteristics as well as the definition of patient selection biomarkers. Finally, the early focus on efficacy (and not only dose confirmation) in expansion cohorts challenges the traditional phase 1/2/3 drug development process.
  
  
  CONCLUSIONS
  Several drug development paradigms have been challenged by imAbs. Here, we discuss novel approaches for an efficient and successful drug development of these agents.
authors.affiliation: DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif Faculty of Medicine, Université Paris Saclay, Université Paris-Sud, Paris Inserm Unit U981, Gustave Roussy, Villejuif sophie.postel-vinay@gustaveroussy.fr.
authors.forename: S
authors.initials: S
authors.lastname: Postel-Vinay
authors.affiliation: DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif.
authors.forename: S
authors.initials: S
authors.lastname: Aspeslagh
authors.affiliation: Biostatistics and Epidemiology Unit, Gustave-Roussy, Villejuif Inserm Unit U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif.
authors.forename: E
authors.initials: E
authors.lastname: Lanoy
authors.affiliation: Faculty of Medicine, Université Paris Saclay, Université Paris-Sud, Paris Inserm Unit U981, Gustave Roussy, Villejuif Department of Medical Oncology, Gustave Roussy, Villejuif.
authors.forename: C
authors.initials: C
authors.lastname: Robert
authors.affiliation: DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif Faculty of Medicine, Université Paris Saclay, Université Paris-Sud, Paris Inserm Unit U981, Gustave Roussy, Villejuif.
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, Villejuif Inserm Unit U1015, Gustave Roussy, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Marabelle
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004306:Dose-Response Relationship, Immunologic; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy*; D018579:Patient Selection
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen
keywords: adaptive designs; drug development; immune checkpoint inhibitors; immunostimulatory monoclonal antibodies; phase 1; toxicity