The Medical Advisor

The Food and Drug Administration (FDA) has approved the combination of two immunotherapy drugs for the initial treatment of some people with advanced colorectal cancer. The approval is for the use of   nivolumab (Opdivo)   and   ipilimumab (Yervoy)   for people whose tumors are classified as   MSI -H or   dMMR . For DNA damage that involves mispaired DNA bases (lightning bolt), specific proteins help repair that damage (orange, blue, green). Mismatch repair-deficient, or dMMR, tumors are full of cancer cells in which this repair process doesn't work properly.  Credit: Cancer Cell International. May 2021. https://doi.org/10.1186/s12935-021-01976-y. CC BY 4.0. About 5% of people with advanced colorectal cancer have MSI-H or dMMR tumors, which means the tumors are unable to properly repair certain types of DNA damage that can occur during cell division . Several colorectal cancer experts said the approval should immediately make the combination the prefe...

Abstract Background: Repurposed drugs like ivermectin and mebendazole have shown preclinical anticancer activity but lack robust clinical trial data. The traditional linear, time-intensive clinical trial process is a significant barrier to their rapid evaluation. This report outlines a simulated hybrid Phase I/II clinical trial combining an in silico model with a traditional dose-escalation design, followed by an efficacy evaluation in a biomarker-defined population. Methods: A Phase I, open-label, 3+3 dose-escalation study was simulated to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of a pulsed, concurrent regimen of ivermectin and mebendazole. The simulation integrated an in silico model to predict dose-limiting toxicities (DLTs) and guide dose escalation decisions. Subsequently, a Phase II cohort of 25 patients with KRAS G12C -mutated non-small cell lung cancer (NSCLC) received the RP2D to assess preliminary efficacy using RECIST 1.1 criteria. ...