A Simulated Phase I/II Clinical Trial of Ivermectin and Mebendazole in Advanced Solid Tumors: A Hybrid In Silico-In Vivo Approach (2025)

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.

Results: The Phase I simulation progressed through three dose levels. At Level 2 (Ivermectin 1 mg/kg, Mebendazole 400 mg/day), one DLT was observed in the initial three patients, but no further DLTs were noted in the expanded cohort. The in silico model successfully predicted the DLTs observed at Level 3, which was designated as the MTD. The dose from Level 2 was thus selected as the RP2D. In the Phase II simulation, a 20% objective response rate (ORR) and a 40% stable disease (SD) rate were observed, demonstrating a promising efficacy signal in the specified patient population.

Conclusion: This simulated hybrid trial successfully demonstrated the feasibility and efficiency of a combined in silico-in vivo approach. The results suggest that the ivermectin-mebendazole combination at the RP2D has a manageable safety profile and merits further investigation in a larger, randomized controlled trial for patients with KRAS G12C-mutated NSCLC.

1.0 Introduction

The development of novel oncology therapeutics is a high-risk, time-consuming, and expensive endeavor. Drug repurposing, the process of finding new clinical applications for existing drugs, presents a promising alternative, leveraging known safety and pharmacokinetic profiles. Ivermectin and mebendazole, two widely used antiparasitic agents, have demonstrated compelling antitumor activity in various preclinical models. However, the translation of these findings into clinical practice has been slow, largely due to a lack of well-designed clinical trials and funding.

Heavily pre-treated population with KRAS G12C-mutated NSCLC, a subgroup of NSCLC is known for its resistance to therapy. This is a population with a high unmet need, and their participation provides a strong ethical justification for exploring novel therapeutic combinations.

A key innovation of this hybrid design is the strategic use of biomarker-driven subgroups. The Phase II portion of the trial will focus on patients with KRAS G12C-mutated NSCLC. This subgroup is a rational choice for several reasons: it represents a significant patient population, there are approved targeted therapies (adagrasib, sotorasib) that demonstrate a clear response signal, and ivermectin's known ability to overcome drug resistance and enhance immunogenicity provides a strong mechanistic hypothesis for its use as a combinatorial agent in this specific context. Patients will be required to have comprehensive biomarker testing on their tumors before enrollment.

This report describes a simulation of a hybrid Phase I/II clinical trial designed to expedite the evaluation of a combination therapy using ivermectin and mebendazole for advanced solid tumors. The trial design integrates in silico (computational) modeling with a standard clinical methodology to optimize dose-finding and cohort selection. The primary objectives of the simulated trial were to:

1. Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of the combination therapy in a pulsed, concurrent regimen using a hybrid in silico-in vivo approach.

2. Evaluate the preliminary efficacy of the RP2D in a biomarker-selected patient population.

2.0 Methods

2.1 Trial Design

This was a simulated, single-arm, open-label, Phase I/II clinical trial. The Phase I portion followed a standard "3+3" dose-escalation design, guided by an in silico computational model. The Phase II portion enrolled a single cohort of patients at the RP2D determined in Phase I.

2.2 Patient Eligibility (Simulated)

Patients with histologically or cytologically confirmed advanced solid tumors, who had failed or were intolerant to standard therapies, were enrolled. Key simulated inclusion criteria included:

• Age $\ge$ 18 years.

• ECOG performance status 0-2.

• Adequate hematologic, renal, and hepatic function.

• Measurable disease per RECIST 1.1.

• Phase II cohort was restricted to patients with documented KRAS G12C-mutated NSCLC.

2.3 Treatment Regimen (Simulated)

The combination therapy consisted of oral ivermectin and oral mebendazole. A pulsed, concurrent schedule was employed, with a 21-day cycle. Dosing was escalated in Phase I as follows:

• Level 1: Ivermectin 0.5 mg/kg + Mebendazole 200 mg/day

• Level 2: Ivermectin 1 mg/kg + Mebendazole 400 mg/day

• Level 3: Ivermectin 1.5 mg/kg + Mebendazole 1000 mg/day

2.4 In Silico Modeling

A mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed prior to trial initiation. The model incorporated known drug metabolism pathways, off-target effects, and preclinical toxicity data. The model simulated the predicted plasma concentrations and potential tissue-level toxicity at each dose level. This model served as a predictive tool to inform dose escalation decisions and to confirm the safety rationale for progressing to the next cohort.

2.5 Safety and Efficacy Assessments (Simulated)

Safety was evaluated based on the incidence and severity of adverse events (AEs) graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. DLTs were defined as any Grade 3 or higher non-hematologic toxicity or Grade 4 hematologic toxicity. Efficacy in Phase II was assessed every six weeks via CT scans. Objective tumor response was classified according to RECIST 1.1 criteria into Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD).

3.0 Results

3.1 Phase I: Dose-Finding

Cohort 1 (Level 1): Three patients were enrolled. All patients completed the first cycle without experiencing any DLTs. The most common adverse events were Grade 1 fatigue and nausea, which were manageable. The in silico model accurately predicted this favorable safety profile.

Cohort 2 (Level 2): Three new patients were enrolled. One patient experienced a Grade 3 DLT (nausea and vomiting) within the first cycle. This necessitated the enrollment of an additional three patients. The expanded cohort of three patients completed the cycle with no further DLTs. The RP2D was therefore set at this dose level.

Cohort 3 (Level 3): Three patients were enrolled. Two out of three patients experienced DLTs, including Grade 3 dizziness and Grade 4 neutropenia. Based on the "3+3" design rules, the trial was stopped at this level, and the MTD was determined to have been exceeded. The in silico model's prediction of a high risk of DLTs at this dose was confirmed.

3.2 Phase II: Efficacy

The RP2D from Phase I (Ivermectin 1 mg/kg + Mebendazole 400 mg/day) was evaluated in 25 patients with KRAS G12C-mutated NSCLC. The simulated outcomes were:

• Partial Response (PR): 5 patients (20%)

• Stable Disease (SD): 10 patients (40%)

• Progressive Disease (PD): 10 patients (40%)

The objective response rate (ORR) was 20%, and the disease control rate (DCR = PR + SD) was 60%.

4.0 Discussion

This simulated trial demonstrates a method for the efficient clinical investigation of repurposed drug combinations. The hybrid in silico-in vivo model proved valuable in providing a predictive framework that mirrored the actual clinical outcomes, particularly in identifying the point at which the MTD was exceeded. This approach has the potential to reduce the number of patients exposed to potentially toxic doses and shorten the overall timeline of early-phase trials.

The preliminary efficacy signal observed in the Phase II cohort is particularly encouraging. A 20% ORR in a heavily pre-treated population with KRAS G12C-mutated NSCLC, a subgroup known for its resistance to therapy, suggests a genuine anti-tumor effect of the combination. The high rate of stable disease further supports the hypothesis that this regimen can provide meaningful disease control.

This simulation provides a compelling rationale for a definitive Phase III randomized controlled trial comparing the ivermectin-mebendazole combination against a standard of care in this specific patient population. The successful application of a hybrid design highlights a potential new paradigm for the clinical development of low-cost, repurposed drugs.

5.0 Conclusion

This simulated clinical trial provides a strong conceptual framework and promising simulated data to support the continued investigation of the ivermectin-mebendazole combination in oncology. The results suggest a favorable safety profile at the RP2D (recommended phase 2 dose) and a clinically meaningful efficacy signal in a biomarker-defined patient population.

Future drug repurposing and combination studies, particularly for agents like ivermectin and mebendazole, should leverage in silico and computational modeling. These technologies can be used to simulate patient responses and optimize trial design, creating more efficient, biomarker-driven clinical studies that reduce the time, cost, and number of patients needed to obtain a definitive answer.

Acknowledgments: This study was supported by computational resources. No external funding was received.

Disclaimer: Hypothetical simulation for education and research; not medical advice. Consult professionals.