Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies
Open accessAbstract
Purpose: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. Methods: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. Results: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. Conclusion: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The PK/PD model-based approach was gaining acceptance for FIH dose selection.
“while the PK/PD model‐based approach was gaining acceptance.71”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
A TMDD/PKPD model for TAM-163 identified an efficacy threshold to achieve significant weight gain in monkeys.
“a TMDD/PKPD model was developed for TAM‐163, an agonist antibody targeting tyrosine receptor kinase‐B (TrkB). The integration of exposure, target coverage, and pharmacological activity identified an efficacy threshold to achieve significant weight gain in monkeys.71”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
The usefulness of toxicity as the criterion to guide dose escalation was limited in FIH trials of mAbs.
“and the usefulness of toxicity as the criterion to guide dose escalation was limited.71, 72”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
Approximately 58% of studies used NHPs only and nearly 80% used both NHPs and rodents to determine FIH dose.
“Based on literature, approximately 58% of studies used NHPs only and nearly 80% used both NHPs and rodents to determine FiH dose.71”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
Severe mAb-related toxicities in FIH trials between 2000 and 2013 were infrequent.
“Recent surveys on the strategies and outcomes of mAbs tested in FIH trials between 2000 and 2013 found that severe mAb‐related toxicities were infrequent”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
The recommended FIH dose for TAM-163 based on the MABEL approach was projected to achieve <10% target coverage at Cmax.
“The recommended FIH dose for TAM‐163 based on the MABEL approach was projected to achieve <10% target coverage at Cmax.”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
Surveys on FIH dose selection showed that guidance based on NOAEL was the most frequently used method.
“Surveys on FIH dose selection showed that guidance based on no observed adverse effects levels (NOAEL) was the most frequently used method”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [71]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Continual Reassessment Method: A Practical Design for Phase 1 Clinical Trials in Cancer
O’Quigley, J., PEPE, M. S., & Fisher, L. D. (1990) · Biometrics · doi:10.2307/2531628 · Cited by 1,586 · see citing works
Dose Escalation Methods in Phase I Cancer Clinical Trials
Le Tourneau, C., Lee, J. J., & Siu, L. L. (2009) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djp079 · Cited by 867 · see citing works
Duncan, J. S., Whittle, M. C., Nakamura, K., Abell, A. N., Midland, A. A., Zawistowski, J. S., Johnson, N. L., Granger, D. A., Jordan, N. V., Darr, D. B., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.053 · Cited by 732 · see citing works
Accelerated Titration Designs for Phase I Clinical Trials in Oncology
Simon, R. M., Rubinstein, L., Arbuck, S. G., Christian, M. C., Freidlin, B., & Collins, J. M. (1997) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/89.15.1138 · Cited by 634 · see citing works
Continual Reassessment Method: A Likelihood Approach
O’Quigley, J., & Shen, L. Z. (1996) · Biometrics · doi:10.2307/2532905 · Cited by 382 · see citing works
Phase I Clinical Trial Design in Cancer Drug Development
Eisenhauer, E. A., O'Dwyer, P. J., Christian, M. C., & Humphrey, J. S. (2000) · Journal of Clinical Oncology · doi:10.1200/jco.2000.18.3.684 · Cited by 239 · see citing works
Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice
Parulekar, W. R., & Eisenhauer, E. A. (2004) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djh182 · Cited by 225 · see citing works
Muller, P. Y., Milton, M., Lloyd, P. M., Sims, J., & Brennan, F. R. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.10.013 · Cited by 146 · see citing works
Cutsem, E. V., Tejpar, S., Vanbeckevoort, D., Peeters, M., Humblet, Y., Gelderblom, H. A. J., Vermorken, J. B., Viret, F., Glimelius, B. L. G., Gallerani, E., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.40.9243 · Cited by 130 · see citing works
Postel-Vinay, S. C., Collette, L., Paolettí, X., et al. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.04.031 · Cited by 123 · see citing works
Preclinical safety testing of monoclonal antibodies: the significance of species relevance
Chapman, K., Pullen, N., Graham, M., & Ragan, I. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2242 · Cited by 121 · see citing works
Normolle, D. P., & Lawrence, T. S. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.3844 · Cited by 111 · see citing works
Paolettí, X., Tourneau, C. L., Verweij, J., et al. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.04.030 · Cited by 79 · see citing works
Safety of biologics, lessons learnt from TGN1412
Stebbings, R., Poole, S., & Thorpe, R. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.10.002 · Cited by 70 · see citing works
Dose Selection in Phase I Studies: Why We Should Always Go for the Top
Sleijfer, S., & Wiemer, E. A. C. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.5192 · Cited by 70 · see citing works
Generalizing the TITE‐CRM to adapt for early‐ and late‐onset toxicities
Braun, T. (2005) · Statistics in Medicine · doi:10.1002/sim.2337 · Cited by 69 · see citing works
Tourneau, C. L., Stathis, A., Vidal, L., Moore, M. J., & Siu, L. L. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.25.9606 · Cited by 60 · see citing works
Tourneau, C. L., Razak, A. R. A., Gan, H. K., et al. (2011) · European Journal of Cancer · doi:10.1016/j.ejca.2011.03.016 · Cited by 58 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development
Ovacik, M., & Lin, K. (2018) · Clinical and Translational Science · doi:10.1111/cts.12567 · Cited by 299 · see citing works
Suh, H. Y., Peck, C., Yu, K.-S., & Lee, H. (2016) · Drug Design, Development and Therapy · doi:10.2147/dddt.s121520 · Cited by 51 · see citing works
- Authors
- Tosi, D., Laghzali, Y., Vinches, M., Alexandre, M., Homicsko, K., Fasolo, A., Del Conte, G., Durigova, A., Hayaoui, N., Gourgou, S., Gianni, L., & Mollevi, C.
- Affiliations
- Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier–Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele–Scientific Institute, Milan, Italy.
- Centre Hospitalier Universitaire Vaudois (CH)
- Venue
- Journal of Clinical Oncology
- Published
- 2015-07-01
- Volume
- 33
- Issue
- 19
- Pages
- 2158-2165
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2131730234
- Cited by
- 33
- References
- 18
- Citations by year
- 2025: 3 · 2023: 2 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 2 · 2017: 2 · 2016: 7 · 2015: 1
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion)
- HAL (submittedVersion)
- IRIS (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR‐10‐LABX‐53‐01, ANR-10, ANR‐10‐LABX‐53)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- monoclonal antibodies, clinical trial design, dose escalation, maximum tolerated dose, dose-limiting toxicity
- MeSH terms
- Antibodies, Monoclonal, Antineoplastic Agents, Clinical Trials as Topic, Dose-Response Relationship, Drug, Humans, Neoplasms, Research Design, Maximum Tolerated Dose
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
