A Study to Investigate OQL011 on VEGFR Inhibitor-Associated Hand-Foot Skin Reaction in Cancer Patients

Study Overview
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Brief Summary
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Hand-Foot Skin Reaction (HFSR) is a common adverse event induced by Vascular Endothelial Growth Receptor Inhibitor (VEGFRi) treatment in cancer patients. The main purpose of this study is to evaluate the safety and efficacy of OQL011 compared to vehicle ointment in treating patients with moderate to severe VEGFRi-associated HFSR. This study will also identify an optimal dosage for Phase III study and explore the pharmacokinetics profile of OQL011 in HFSR patients.

Official Title
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A Phase II Study to Evaluate the Safety and Efficacy of OQL011 on VEGFR Inhibitor-Associated Hand-Foot Skin Reaction in Cancer Patients

Conditions
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Hand-Foot Skin Reaction (HFSR)

Intervention / Treatment
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* Drug: OQL011
* Drug: Vehicle Ointment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be age ≥ 18 years. Patient must have a confirmed cancer diagnosis for which VEGFRi treatment is indicated, and must be currently under VEGFRi-based anti-cancer therapy with stable dosage for ≥ 1 week. This treatment may be VEGFRi monotherapy or VEGFRi-based combination therapy, so long as it does not include prohibited therapies. Patient must have shown signs of HFSR that meet (for Part 1) the NCI CTCAE v5.0 - PPE grade 2 or higher OR (for Part 2) IGA-HFSR criteria of grade 3 or higher. Patient on pain medications is allowed provided they have been on stable dosage in the past 1 week and is going to continue at the same dosage. Patient is able to use topical medications and complete questionnaires reliably. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2. Patient must have the ability to understand and the willingness to sign a written informed consent prior to study entry. Exclusion Criteria: Patient with unresolved hand or foot skin disorders (NCI CTCAE v5.0 grade 2 or higher) due to other medications within 4 weeks prior to study entry. Patient who is using other topical medications in the hands or feet area and cannot stop such usage >7 days ahead of randomization. Patient who is using other concurrent cancer medications, such as capecitabine, pegylated liposomal doxorubicin, 5-fluorouracil, dabrafenib, vemurafenib, doxorubicin, docetaxel, cytarabine, ramucirumab and bevacizumab, which may result in hand-foot syndrome (HFS). Patient who is under uncontrolled intercurrent illness including, but not limited to, inadequately controlled nausea, vomiting, diarrhea or other conditions which may contribute to hypovolemia, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, recent myocardial infarction, uncontrolled hypotension or hypertension, cardiac arrhythmia, or psychiatric illness and social situations that would limit compliance with study requirements. Patient who has contraindication with the active compound, including severe anemia, increased intracranial pressure, known hypersensitivity. Patient who has other skin disorders that will affect the efficacy evaluation on hands and feet area, including but not limited to, tinea of feet and hands, hand/foot eczema, palmoplantar pustulosis, palmoplantar keratosis, acrodermatitis continua etc. Patient who used phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil within past 7 days. Patient with significantly abnormal lab test: Inadequate hematologic function as indicated by: Absolute neutrophil counts (ANC) ≤ 1,000 /mm^3 Hemoglobin (Hgb) ≤ 8.0 g/dL Platelet count ≤ 75,000 /mm^3 PT or PTT > 1.5 x ULN (if patients on anticoagulants: PT INR > 3.5 x ULN) Inadequate renal and liver function as indicated by: Albumin < 2.8 g/dL Total bilirubin ≥ 1.5 x ULN (or ≥ 2.5 x ULN for patients with Gilbert's syndrome) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≥ 3 x ULN (or ≥ 5 x ULN for patients with liver cancer) Creatinine > 2.0 x ULN. Pregnant or nursing women. Women of childbearing potential who are unwilling to comply with contraceptive requirements. Highly effective contraception which include two forms of birth control method (i.e., a hormonal method plus a barrier method) is advised for at least 2 weeks prior to study treatment and during study participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OQL011 Dose I<br>OQL011, Dose I, ointment, to be applied topically, three times a day, for up to six weeks (in Part 1) or four weeks (in Part 2) | Drug: OQL011<br>* OQL011 is an ointment containing active ingredient.<br>|
| Experimental: OQL011 Dose II<br>OQL011, Dose II, ointment, to be applied topically, three times a day, for up to six weeks (in Part 1) or four weeks (in Part 2) | Drug: OQL011<br>* OQL011 is an ointment containing active ingredient.<br>|
| Experimental: OQL011 Dose III<br>OQL011, Dose III, ointment, to be applied topically, three times a day, for up to six weeks (in Part 1) or four weeks (in Part 2) | Drug: OQL011<br>* OQL011 is an ointment containing active ingredient.<br>|
| Other: Vehicle Ointment<br>Vehicle ointment, to be applied topically, three times a day, for up to six weeks (in Part 1) or four weeks (in Part 2) | Drug: Vehicle Ointment<br>* Vehicle ointment is an ointment containing no active ingredient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (For Part 1) Proportion of patients who achieve NCI CTCAE v5.0 - Palmar-Plantar Erythrodysesthesia (PPE) grade 0 or 1 OR (for Part 2) The proportion of patients achieving IGA-HFSR grade 0 or 1 |  | 3 weeks (Part 1) OR 2 weeks (Part 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (For Part 1) Proportion of patients who have improvement in HFSR severity and achieve clear (0) or almost clear (1) as measured by IGA-i (Investigator-assessed Investigator's Global Assessment) scale | The IGA scale ranges from grade 0 (clear) to 4 (severe), the higher the score, the worse the condition. | 3 weeks and 6 weeks | 
| (For Part 2) Proportion of patients achieving IGA-HFSR grade 0 or 1 | The IGA scale ranges from grade 0 (clear) to 4 (severe), the higher the score, the worse the condition. | 4 weeks | 
| (For Part 2) Proportion of patients achieving at least two-grade improvement in IGA-HFSR | The IGA scale ranges from grade 0 (clear) to 4 (severe), the higher the score, the worse the condition. | 2 weeks and 4 weeks | 
| (For Part 1) Proportion of patients who achieve NCI CTCAE v5.0 - PPE grade 0 or 1 |  | 6 weeks | 
| (For Part 2) Change from baseline in NCI CTCAE v5.0 - PPE grade |  | 2 weeks and 4 weeks | 
| Change from baseline in HF-QoL (Hand-Foot Skin Reaction and Quality of Life) Questionnaire total score | HF-QoL questionnaire is comprised of a 20-item symptom domain and an 18-item daily activity domain. Each item is rated on a 5-point scale from 0 (not at all) to 4 (always or extremely) during the previous week. The HF-QoL symptom and daily activity total scores are transformed to a scale of 0 to 100, based on the sum of each unit-weighted item score divided by the maximum score. Higher scores on the HF-QoL indicate worse quality of life or greater symptom burden. (refer to R. T. Anderson et al., The Oncologist 2015;20:831-838) | 3 weeks and 6 weeks (Part 1) OR 2 weeks and 4 weeks (Part 2) | 
| (For Part 1) Change from baseline in patient reported pain using VAS (Visual Analog Scale) | The subject records pain associated with HFSR using 100 mm VAS ranging from no pain at 0 mm to unbearable pain at 100 mm on the paper VAS. | 3 weeks and 6 weeks | 
| (For Part 2) Change from baseline in patient reported pain using NPRS (Numerical Pain Rating Scale) | The subject records pain associated with HFSR using score 0 to 10 ranging from no pain for Score 0 to unbearable pain for Score 10. | 2 weeks and 4 weeks | 
| (For Part 1) Proportion of patients who have improvement in HFSR severity and achieve clear (0) or almost clear (1) as measured by IGA-c (Centrally-assessed Investigator's Global Assessment) scale | The IGA scale ranges from grade 0 (clear) to 4 (severe), the higher the score, the worse the condition. | 3 weeks and 6 weeks | 
| Safety assessment by type, incidence and intensity of adverse events |  | 6 weeks (Part 1) and 4 weeks (Part 2) | 
| Plasma concentration of active compound and its derivatives |  | 1 day | 
| (For Part 2) The exposure-response relationship of different dose level OQL011 |  | 4 weeks |