This report describes, to our knowledge, results from the first phase 0 trial of a candidate chemopreventive agent in oncology. Participant accrual was accomplished over a relatively short time period (five months from activation to closure) and a lead formulation for SR13668 was rapidly identified using pharmacokinetic data as the primary endpoint. Our study provides strong support for expanding the phase 0 trial paradigm beyond chemotherapy drug development.
SR13668 was developed utilizing a computer-assisted structural analysis of four active I3C metabolites. The resulting compound exhibited antitumor activity, but very low water solubility. (7
) As expected for Biopharmaceutics Drug Classification Class II drugs(11
) that demonstrate dissolution rate limited absorption in vivo
, SR13668 bioavailability was extremely low in preclinical species, but was improved substantially by the surfactant-based formulation PEG400 Labrosol®
(1:1 v/v oral solution).(9
) Formulation approaches to achieve the highest oral bioavailability of SR13668 in humans focused on suitable carriers for dissolved drug or increasing the dissolution rate. Formulation approaches further focused on the use of SEDDS, Generally Recommended as Safe (GRAS) that have been used in approved drug products to expedite advancement of the preferred formulation into subsequent phase I and II clinical trials. Of note, four SEDDS evaluated in our phase 0 trial all demonstrated SR13668 release and apparent solubility that were well in excess of the solid drug substance and were acceptable for in vivo
evaluation. These results are remarkable in light of the poor solubility in water and limited solubility in traditional organic solvents.
The FDA guidance for exploratory IND studies explores examples of clinical trials used to study drug pharmacokinetics, pharmacologic effects and mechanism of action related to efficacy, and further notes that other applications may be proposed.2
The recent report from Kummar, et al, describes a phase 0 trial of a potential chemotherapy agent (ABT-888) among subjects with advanced malignancies, with pharmacodynamic modulation over a specified dose range defined as the primary endpoint.(15
) In contrast, our trial was designed to evaluate a candidate chemoprevention agent (SR13668) in healthy adult volunteers, with pharmacokinetic comparison across formulations defined as the primary endpoint. These two reports represent substantially different and complementary applications of the phase 0 trial design.
Statistical challenges for the design and analysis of phase 0 chemoprevention trials are similar to those encountered in phase 0 chemotherapeutic trials.(16
) Application and interpretation of pharmacokinetics and/or pharmacodynamics data that are based on a relatively small number of study participants require careful planning and appropriate caution. In addition, biologically and statistically “significant” responses must be rigorously defined. In our phase 0 trial, pharmacokinetics data were chosen as the primary endpoint for investigating SR13668 bioavailability, since the major objective was to identify a preferred formulation for further development as a candidate chemoprevention agent. We adopted a flexible combination of biologic and statistical criteria for the selection of formulations to make this study not only scientifically sound but also clinically feasible in a phase 0 setting. The use of two-stage design over factorial design for food effect and agent formulation also improved efficiency by reducing the necessary sample size.
Given that tobacco carcinogens have been shown to stimulate upregulation of the P13K/Akt pathway,(18
) coupled with the finding that SR13668 concentration was enhanced in pulmonary tissue following oral administration to rats,(9
) further development of this compound as a potential lung cancer chemoprevention agent may be worth pursuing. However, while formulation of SR13668 in a SEDDS vehicle greatly improved its solubility and bioavailability, administration of a 38 mg dose (1/50th
of the rat NOAEL) still required ingestion of 8 capsules, which could adversely affect compliance with repeat or prolonged administration, particularly if substantially higher dosing is needed to achieve a pharmacologic response. Thus, additional data regarding the pharmacologic activity in humans would be important to fully evaluate the feasibility of successfully advancing SR13668 as a candidate chemoprevention agent. Alternatively, other approaches may be considered to enhance SR13668 bioavailability including assessment of vehicles that are not yet GRAS and/or consideration of water-soluble prodrugs. Additional computer-assisted structural analysis might also identify water-soluble analogs of SR13668 that maintain pharmacologic activity, while providing more efficient delivery.
In summary, based on our experience in this first-ever, phase 0 chemoprevention trial, pharmacokinetic analyses of different formulations represents an effective strategy to rapidly inform subsequent clinical testing. The inherent ethical issue of providing a microdose intervention with no anticipated clinical benefits is much less challenging in chemoprevention trials, which generally exclude patients with cancer or other unstable medical conditions. As noted by Murgo, et al,(19
) phase 0 trials can be designed to address several different pharmacologic endpoints, which should permit broad opportunities to accelerate chemoprevention agent development under this novel paradigm.