Background: Tasquinimod is a small molecule with immunomodulatory, antiangiogenic and anti-metastatic properties that targets the tumor microenvironment.Objective: This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors.Patients and Methods: This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38) and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment.Results: Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort)found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell and gastric cancer cohorts. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%). The safety profile of tasquinimod across the four cancer patient cohorts was consistent with that previously reported in previous studies and no new safety concerns were identified.