Public awareness of ivermectin's purported anticancer properties has led to widespread off-label use. In a 2023 cross-sectional study in Loja, Ecuador, 19% of respondents reported using ivermectin as an adjunct to cancer treatment. However, clinical data remain virtually absent. To date, only one partially reported human study has investigated ivermectin in combination with anti-PD-1 therapy in patients with metastatic triple-negative breast cancer. Among the first nine treated patients, no treatment-related serious adverse events were observed, and the study remains ongoing.

Despite this growing interest, ivermectin's off-label use carries risks. For instance, Gilene et al. described a case of severe neurotoxicity in a patient with metastatic osteosarcoma receiving regorafenib, likely due to a pharmacokinetic interaction through CYP3A49. Moreover, the potential impact of ivermectin on the gut microbiome-a key modulator of immune checkpoint inhibitor (ICI) immunotherapy success or failure efficacy-remains poorly understood. As antibiotic exposure has been linked to diminished immunotherapy outcomes, ivermectin's antibiotic properties raise legitimate concerns about possible microbiome disruption. However, variables such as ivermectin dose, the duration of exposure, and the type of immunotherapy are each variables that remain poorly studied.

Taken together, these data underscore the urgency to prospectively evaluate ivermectin's immunologic effects in patients with cancer treated ICIs. Given ivermectin's wide availability, affordability, and public interest, rigorous clinical testing is crucial to determine whether it enhances-or potentially compromises-anticancer immunity while simultaneously assessing its safety to provide guidance for clinicians and patients.

This study will investigate the safety, pharmacodynamic effects, and potential for dose-responsive immune modulation of ivermectin given concurrently with immune checkpoint inhibitor therapy in adult subjects with solid tumors.

Inclusion Criteria:

• Histologically or clinically confirmed solid tumor malignancy for which the patient has been receiving an immune checkpoint inhibitor (ICI) as part of standard of care for ≥21 days prior to the first ivermectin dose, either alone or in combination with other systemic therapies. Both metastatic and (neo)adjuvant treatment settings are permitted.
• Adults ≥ 18 years of age.
• ECOG Performance Status of 0-2.
• Subjects must be able to swallow oral medication.
• Subjects must not have any known and active gastrointestinal disorders that impact absorption (e.g., inflammatory bowel disease, short bowel syndrome, severe diarrhea, prior major GI surgery [e.g., gastric bypass], or chronic vomiting) as determined by the investigator.
• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
• Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 weeks after the last dose of study drug to minimize the risk of pregnancy. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.
• Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 4 weeks following the last dose of study drug.

Exclusion Criteria:

• Subjects who are currently taking, or have taken, ivermectin without a washout period prior to first treatment on study.

  a. Subjects can become eligible for study participation if they do a 2-week wash-out period prior to first treatment on study.

• Subjects who have received their first dose of ICI therapy <21 days before the baseline visit.

  a. Subjects can become eligible for study participation after ≥21 days have passed following Cycle 1 of ICI.

• Subjects of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug.

• Subjects who are confirmed to be pregnant or breastfeeding.

• History of any other disease, metabolic dysfunction, clinical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.

• Administration of all vaccines within 30 days prior to the first dose of trial treatment and while on treatment.

• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

• Rental function: Creatinine clearance ≤ 30 mL/min

• Hepatic function:

  1. Total bilirubin > 1.5 x ULN unless patients with Gilbert Syndrome (total bilirubin > 3 x ULN)
  2. Liver metastasis: AST/ALT > 5 x ULN

• Concomitant use of Strong CYP3A4 inhibitor for 7 days or 5 half-lives, whichever is longer

• Concomitant use of Strong CYP3A4 inducer for 14 days or 5 half-lives, whichever is longer

• QTc > 480 msec