This paper presents an optimization of a thorium-plutonium (Th-Pu) fuel cycle by screening various design options for the Integral Inherently Safe Light Water Reactor (I²S-LWR). The I²S-LWR is an advanced 2850 MWt integral pressurized water reactor with enhanced safety beyond that of Gen-III+ reactors. The features of this reactor, such as material choice, make it attractive for alternative fuel cycles including the use of thorium. Recently, the feasibility of the Th-Pu cycle was studied and the benefits associated with it were demonstrated. More specifically, the Pu incineration performance was enhanced by adopting multi-batch (i.e. more than 3-batch) schemes and extended burnup (above 100 MWd/kg). The optimized design with the most favorable loading pattern was obtained by applying the Simulated Annealing optimization technique. This paper demonstrates further plausible modifications to the Th-Pu cycle design that may enhance its performance considerably. The paper seeks to identify the contributory factors, such as cladding types, plutonium vectors and initial plutonium loadings, with major impact on the incineration performance. The postirradiation characteristics are also analyzed and suggest that such a cycle may simplify the design and operation of the waste repository.