New Drug Development and Clinical Pharmacology Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials

Background. First-in-human (FIH) trials of low-molecular-weight anticanceragentsconventionallyderiveasafestartdose(SD)from one-tenth the severely toxic dose in 10% of rodents or one-sixth thehighestnonseverely toxicdose (HNSTD) innonrodent species. No consensushasbeen reachedonwhether this paradigmcanbe 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 toassess the safetyof 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 theMTDorMAD 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. The Oncologist 2015;20:653–659 Implications for Practice: Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamicmarkerswasuseful in confirming thehypothetical SD, andattempts shouldbeexplored in futureanimal studies to identify such parameters.