A bootstrapping method to optimize go/no-go decisions from single-arm, signal-finding studies in oncology.

Phase Ib trials are common in oncology development but often are not powered for statistical significance. Go/no-go decisions are largely driven by observed trends in response data. We applied a bootstrapping method to systematically compare tumor dynamic end points to historical control data to identify drugs with clinically meaningful efficacy. A proprietary mathematical model calibrated to phase Ib anti-PD-1 therapy trial data (KEYNOTE-001) was used to simulate thousands of phase Ib trials (n = 30) with a combination of anti-PD-1 therapy and four novel agents with varying efficacy. A redacted bootstrapping method compared these results to a simulated phase III control arm (N = 511) while adjusting for differences in trial duration and cohort size to determine the probability that the novel agent provides clinically meaningful efficacy. Receiver operating characteristic (ROC) analysis showed strong ability to separate drugs with modest (area under ROC [AUROC] = 83%), moderate (AUROC = 96%), and considerable efficacy (AUROC = 99%) from placebo in early-phase trials (n = 30). The method was shown to effectively move drugs with a range of efficacy through an in silico pipeline with an overall success rate of 93% and false-positive rate of 7.5% from phase I to phase III. This model allows for effective comparisons of tumor dynamics from early clinical trials with more mature historical control data and provides a framework to predict drug efficacy in early-phase trials. We suggest this method should be employed to improve decision making in early oncology trials.

Rad51-mediated interhomolog recombination during budding yeast meiosis is promoted by the meiotic recombination checkpoint and the conserved Pif1 helicase.

During meiosis, recombination between homologous chromosomes (homologs) generates crossovers that promote proper segregation at the first meiotic division. Recombination is initiated by Spo11-catalyzed DNA double strand breaks (DSBs). 5' end resection of the DSBs creates 3' single strand tails that two recombinases, Rad51 and Dmc1, bind to form presynaptic filaments that search for homology, mediate strand invasion and generate displacement loops (D-loops). D-loop processing then forms crossover and non-crossover recombinants. Meiotic recombination occurs in two temporally distinct phases. During Phase 1, Rad51 is inhibited and Dmc1 mediates the interhomolog recombination that promotes homolog synapsis. In Phase 2, Rad51 becomes active and functions with Rad54 to repair residual DSBs, making increasing use of sister chromatids. The transition from Phase 1 to Phase 2 is controlled by the meiotic recombination checkpoint through the meiosis-specific effector kinase Mek1. This work shows that constitutive activation of Rad51 in Phase 1 results in a subset of DSBs being repaired by a Rad51-mediated interhomolog recombination pathway that is distinct from that of Dmc1. Strand invasion intermediates generated by Rad51 require more time to be processed into recombinants, resulting in a meiotic recombination checkpoint delay in prophase I. Without the checkpoint, Rad51-generated intermediates are more likely to involve a sister chromatid, thereby increasing Meiosis I chromosome nondisjunction. This Rad51 interhomolog recombination pathway is specifically promoted by the conserved 5'-3' helicase PIF1 and its paralog, RRM3 and requires Pif1 helicase activity and its interaction with PCNA. This work demonstrates that (1) inhibition of Rad51 during Phase 1 is important to prevent competition with Dmc1 for DSB repair, (2) Rad51-mediated meiotic recombination intermediates are initially processed differently than those made by Dmc1, and (3) the meiotic recombination checkpoint provides time during prophase 1 for processing of Rad51-generated recombination intermediates.