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- Title
Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials.
- Authors
Hansen, Aaron R.; Cook, Natalie; Ricci, M. Stacey; Razak, Albiruni; Le Tourneau, Christophe; McKeever, Kathleen; Roskos, Lorin; Dixit, Rakesh; Siu, Lillian L.; Hinrichs, Mary Jane
- Abstract
Background. First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). Materials and Methods. A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. Results. The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8-500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5-55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD. Conclusion. One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials.
- Subjects
ANIMAL experimentation; ANTINEOPLASTIC agents; BIOTECHNOLOGY; DRUG side effects; DRUG toxicity; MONOCLONAL antibodies; PHARMACEUTICAL arithmetic; SYSTEMATIC reviews; DECISION making in clinical medicine; TREATMENT effectiveness
- Publication
Oncologist, 2015, Vol 20, Issue 6, p653
- ISSN
1083-7159
- Publication type
Article
- DOI
10.1634/theoncologist.2015-0008