Optimal treatments depend on numerous factors such as drug chemical properties, disease biology, and patient characteristics to which the treatment is applied. To realize the promise of AI in healthcare, there is a need for designing systems that can capture patient heterogeneity and relevant biomedical knowledge. Here we present PlaNet, a geometric deep learning framework that reasons over population variability, disease biology, and drug chemistry by representing knowledge in the form of a massive clinical knowledge graph that can be enhanced by language models. Our framework is applicable to any sub-population, any drug as well drug combinations, any disease, and to a wide range of pharmacological tasks. We apply the PlaNet framework to reason about outcomes of clinical trials: PlaNet predicts drug efficacy and adverse events, even for experimental drugs and their combinations that have never been seen by the model. Furthermore, PlaNet can estimate the effect of changing population on the trial outcome with direct implications on patient stratification in clinical trials. PlaNet takes fundamental steps towards AI-guided clinical trials design, offering valuable guidance for realizing the vision of precision medicine using AI.