In oncology clinical development, phase II has the widest range of possible goals which can be addressed at this stage. In contrast, there is general agreement for what is to be done at phase I and phase III. Phase I generates the initial data used to select a dose which can be used relatively safely in a larger population. Likewise, phase III studies aim to establish evidence justifying efficacy and safety enabling health authority approval. Generally, these designs focus on clinically relevant survival and event-time endpoints. Phase II trials, on the other hand, have the simple but ill-defined mission of providing evidence for one or more of the many possible strategic paths between these two phases. Specifically, the phase II programme must bridge between the current knowledge about the initially established dosing regimen and the phase III design to support registration. There are many possible paths, representing the many approaches to learning about how to use a compound to treat cancer. The diversity of clinical development paths can also be deduced from the range of clinical trial designs described in this book. This chapter will focus on selecting phase II designs originating in response to strategies embodied in a commercially oriented clinical development plan (CDP).

Commercially sponsored trials are a component of a pre-specified, evolving, comprehensive CDP. A CDP can be formally thought of as a document which frames the development of a compound in terms of medical indications, staging of activities and collection of data for justifying registration across possible indications. This contains justification for components which the development team considers essential to develop the compound. The choice of trial designs should address the CDP’s objectives, conditional on previous results. The goal of the CDP is to provide a roadmap of activities to efficiently either deliver a commercially viable product or terminate development early for futility and/or safety issues. A commercially viable product requires both regulatory approval and agreement by payers to reimburse.

The selection process described in this chapter takes into account pharmaceutical drug development challenges and drivers. These frame the constraints and requirements which inform the selection of the phase II design(s). The source for these challenges arise both internally and externally and relate to both scientific and operational considerations. Internal clinical development decisions which impact phase II include timing and prioritisation of the compound in relation to other compounds in the portfolio. External clinical constraints and drivers include current medical practice, payer approaches and competition from external compounds. Constraints include both financial resources and shared internal specialised employee skills which are in limited supply and required for more sophisticated designs. Some parts of this chapter are forward looking and represent practices which are not yet incorporated. Other parts are retrospective and may be suboptimal or obsolete due to recent statistical, clinical or regulatory landscape changes. This chapter just reflects a snapshot in time of current thinking.

Multiple options often exist for clinical development strategies at the planning stage for the phase II programme, with acceleration and hesitation pressure coming from both the development team and the external environment. The selection of one or more strategies in the face of uncertainty informs the choice of phase II design(s) to be implemented. The range of strategic goals that are addressed in this chapter consists of those for potential registration, establishing exploratory activity, regimen selection, prediction of phase III success, safety trials and prospective identification of targeted populations. We next describe some of the commercial challenges and drivers before discussing strategic considerations and how they can inform study design selection.

The environment for commercial clinical drug development can change frequently, making fixed as well as long-term planning difficult. New information arises regarding science, competitors, regulators and payer organisation; payer organisation can cause an extreme change in plans, from rapid acceleration to a complete halt of the programme. In addition, corporate philosophy and goals, as well as organisational structure, can also impact a development programme’s strategy.

Competition, both internal and external, is a difficult factor to manage. Competition can take the form of internal competition between indications for a compound’s resources, as well as between compounds which address the same family of indications. The CDP should outline how to address this.

The approach in this chapter naturally emphasises strategic goals based on commercial experience. These strategic goals reflect both common, clinical and scientific goals and relevant corporate financial opportunities and challenges, since maintaining positive cash flow, and the extent of that income source, will dictate potential opportunities and risks. For any publicly traded company, the value of the investigational portfolio is intrinsically incorporated into the value of the stock price. A failed phase III trial can strongly influence the stock price of a company if this compound reflects a sizable portion of the stock price as well as an erosion of confidence in the company to register drugs. Decisions which benefit the company are at the level of the clinical trial, such as minimising patients who are exposed to toxic drugs via careful sample size determination and interim analyses. Other decisions at the strategic level, including selection of drugs with most appropriate benefit/risk balance, and the efficient development of viable therapies also benefit both patients and society as a whole. While this could be done formally using a decision-theoretic framework, it is often informally managed.

The CDP provides guidance in terms of overall goals and approaches for clinical development. Since it has a strategic focus for approaching clinical development, a selection of trial designs based on strategic deliverables is simpler for teams to use. We first give some examples of overall programme-level strategies that could be under consideration, before moving forward with how a few common phase II strategies are addressed.

Overall programme strategies are described differently from, and yet contain, the phase II strategies which are being considered. For example, one increasingly popular development strategy is to target a rare but well-characterised oncological indication, register the compound for treatment in that setting and then construct a series of interrelated development programmes to expand into different indications. These expanded indications are selected by considering the targets which represent a component of the tumour, unlike the original indication where the target is found more homogenously across the whole tumour. Another strategy is to leverage chemical synergies and initially target a medium-sized indication based on initial pre-clinical and phase I results, combined with how they may relate to existing medical practice and needs. Other common strategies include pairing new treatments with existing ones for combination therapies, as well as including in the initial plans a focus on setting up a possible diagnostic/compound combination.

Phase II studies address the middle stage of these strategies. For each example given above, multiple questions could be addressed depending on the specific tactical implementation of the global CDP strategy. The rest of this section focuses on the phase II-specific strategic aspects.