Designing combination drug phase I trials has become increasingly complex, due to the increasing diversity in classes of agents, mechanisms of action, safety profiles and drug-administration schedules. With approximately 850 agents currently in development for cancer treatment, it is evident that combination development must be prioritised, as based on a specific hypothesis, as well as a projected development path for the involved combination. In this manuscript the most relevant issues and pitfalls for combination drug phase I trial design are discussed. Several phase I study designs that incorporate controls to circumvent bias due to imbalances in observed background toxicity are discussed.

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Keywords Bayesian, Bayesian learning, Combination, Controls, Dose-escalation, Phase I, Trial design, alkylating agent, carboplatin, cardiotoxicity, clinical research, clinical trial, combination drug phase 1 trial, docetaxel, dose response, doxorubicin, drug dose escalation, drug mechanism, drug potentiation, etoposide, feasibility study, febrile neutropenia, human, leukemogenesis, maximum tolerated dose, methodology, model, neuropathy, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor, oncology, oxaliplatin, paclitaxel, phase 1 clinical trial, priority journal, radiation dose, review, taxane derivative, treatment duration
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Journal European Journal of Cancer
Hamberg, A.P, Ratain, M.J, Lesaffre, E.M.E.H, & Verweij, J. (2010). Dose-escalation models for combination phase i trials in oncology. European Journal of Cancer (Vol. 46, pp. 2870–2878). doi:10.1016/j.ejca.2010.07.002