Background: Hand-foot skin reaction (HFSR) is associated with the use of multi-targeted tyrosine kinase inhibitors sharing vascular endothelial growth factor receptor inhibitor (VEGFRi) activity (e.g., cabozantinib, regorafenib, sorafenib, sunitinib). HFSR results from impaired vascular repair mechanisms from inhibition of VEGF signaling and is characterized by painful palmoplantar lesions that may impact the quality of life and consistent dosing of anticancer agents. NOVA-II is a two-part, double-blind, randomized controlled trial evaluating OQL011, a nitroglycerin (NTG) topical ointment. Part 1 enrolled 31 subjects and studied OQL011 0.2% NTG for Grade ≥2 NCI CTCAE v5.0 palmar-plantar erythrodysesthesia (PPE). Part 1 safety and pharmacokinetic data support the continuance of NOVA-II, Part 2 dose-ranging study. The Part 1 inclusion criteria and primary endpoint were based on NCI CTCAE PPE. A unique investigator global assessment (IGA) was evaluated in Part 1 for HFSR severity (Grades 0-4) and has been revised utilizing Part 1 data for use as the primary endpoint for Part 2. We hypothesize that OQL011 containing NTG, a nitric oxide donor releasing free nitric oxide and activating guanylate cyclase in skin vessels, will mitigate HFSR symptoms and disease severity via local upregulation of the VEGF/VEGFR signaling pathways. Methods: NOVA-II Part 2 is a global, dose-ranging phase 2, double-blind, randomized controlled trial to evaluate the safety and efficacy of 3 doses of OQL011 (0.1%, 0.2%, and 0.5% NTG) compared to vehicle control for the treatment of moderate to severe VEGFRi associated HFSR. Part 2 will enroll up to 140 patients (randomized 1:1:1:1; vehicle: OQL011@ 0.1%: 0.2%: 0.5% NTG) with IGA Grade ≥3 (IGA scale 0-4). Subjects will apply the study drug (i.e., OQL011 or vehicle) to palmar and plantar surfaces TID and will be evaluated at Visit 1 (Day 0), Visit 2 (Day 14), and Visit 3 (Day 28). The primary endpoint is the proportion of patients achieving an IGA Grade ≤1 at Visit 2 (Day 14). A superiority test will be performed to compare each of the OQL011 doses to the vehicle, and the study drug exposure-response relationship will be explored. The correlation between IGA and NCI CTCAE v5.0 PPE, patient-reported outcomes including a numerical pain rating scale (NPRS), and Hand-foot Quality of Life (HF-QoL) questionnaire will be measured. Pharmacokinetics will be evaluated in a subset of subjects randomized 2:2:2:1, with 6 patients in each of the 3 OQL011 dose level groups and 3 patients in the vehicle group. PK samples will be collected on Day 0 at pre-dose, 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, and 8 h, after the first application of investigational drugs. Study enrollment for Part 2 is currently ongoing in the United States, India, and China. (NCT04088318) Clinical trial information: NCT04088318.