Abstract 2656: Ethical considerations in evaluating targeted anticancer drug candidates in healthy volunteers – safety and risk assessments
Authors: Xiong Hao , Pradhan Rajendra , Nada Adel , Krivoshik Andrew , Holen Kyle , Gordon Gary , Awni Walid , Humerickhouse Rod 
Published: June 2012

Abstract
Background: Biopharmaceutical and clinical pharmacology studies are typically conducted in healthy volunteers with few exceptions, such as for anti-cancer drugs. Traditional chemotherapies are too toxic to be studied in healthy volunteers. However, even for targeted anti-cancer drugs that often have mild to moderate toxicity profiles that don't expose healthy volunteers to extra risks, studies have rarely been conducted in the population. Navitoclax (ABT-263) is an orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in several Phase 1 studies in cancer patients. The need to evaluate multiple formulations and the difficulty in recruiting patients made it critical to evaluate the possibility of recruiting healthy volunteers to support formulation development.
Methods: Nonclinical safety data and clinical data from Phase 1 studies in cancer patients were evaluated extensively by a multi-functional team to determine the subject inclusion criteria, the maximally recommended dose, and a risk management plan. The protocol, safety evaluation and recommendations were reviewed and approved by the Drug Safety Evaluation Committee at Abbott.
Results: In nonclinical studies, navitoclax was not genotoxic; it caused testicular toxicity, and dose-dependent thrombocytopenia (TCP) and lymphopenia, which are all expected from inhibition of Bcl-2 targets. In Phase 1 single-agent studies in cancer patients, the most frequent, dose-limiting toxicity was TCP. Nonclinical safety data supported a single dose ≤30 mg navitoclax in healthy volunteers. Furthermore, evaluation of clinical safety data, TCP dose-response and lymphopenia data supported administration of a navitoclax dose ≤100 mg in a single-dose, multiple-period crossover study in healthy female volunteers of non-childbearing potential. Two relative bioavailability (BA) studies in healthy female subjects with non-child bearing potential (N=12 each) were conducted sequentially and successfully, the first at a 25 mg dose and the second at a 100 mg dose. Compared to similar studies in cancer patients, on average, each study in healthy volunteers saved 3.5 months. A well-informed decision to select a Phase 2 formulation was made on the basis of limited data in patients and high-quality data in healthy volunteers.
Conclusion: The case study illustrated that targeted anti-cancer drugs can be studied in healthy volunteers with careful assessment of both clinical/nonclinical data and by putting appropriate risk management plan in place. When feasible, BA studies in healthy volunteers avoid delaying potentially active treatments to cancer patients. Such studies also provide high-quality bioavailability data in a timelier and inexpensive fashion compared to similar studies in cancer patients, and they don't impose risks beyond the minimal levels that are standard in healthy volunteer studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2656. doi:10.1158/1538-7445.AM2011-2656