Safety and Efficacy Placebo Controlled Study of ATH008 Cream in PPES Patients Secondary to Capecitabine

• Efficacy of ATH008 cream in reducing the number of subjects presenting PPES grade 2/3 secondary to capecitabine therapy [ Time Frame: minimum every 21 days, maximum of 4 capecitabine cycles, followed by a safety observation period of 14 days ] [ Designated as safety issue: No ]
  percentage of subjects that develop PPES grade 2 or 3 according to the NCI CTCAE v4.03 criteria
  
  
• Safety of ATH008 cream in patients presenting PPES secondary to capecitabine therapy [ Time Frame: minimum every 21 days, maximum of 4 capecitabine cycles, followed by a safety observation period of 14 days ] [ Designated as safety issue: Yes ]
  adverse events and serious adverse events (incidence, causality, and severity) related to treatment with ATH008 cream
  
  
• Plasmatic levels of ATH008 cream when given topically [ Time Frame: blood sampling at specific timepoints (Pre-dose, Day 1 and Day 21) ] [ Designated as safety issue: Yes ]
  plasmatic levels of the active ingredient and its metabolite when given topically
  
  

• Efficacy of ATH008 cream in improving the quality of life of patients presenting PPES [ Time Frame: minimum every 21 days, maximum of 4 capecitabine cycles, followed by a safety observation period of 14 days ] [ Designated as safety issue: No ]
  quality of life compared to baseline
  
  
• Efficacy of ATH008 cream in improving signs and symptoms of PPES [ Time Frame: minimum every 21 days, maximum of 4 capecitabine cycles, followed by a safety observation period of 14 days ] [ Designated as safety issue: No ]
  proportion of subjects that present no PPES signs or symptoms, time to progression and time to improvement of PPES grades,assessment from photographs of erythema, desquamation, existence of blisters, fissures and ulcers; percentage of palms and soles affected by PPES
  
  
• Assessment of patient reported pain [ Time Frame: minimum every 21 days, maximum of 4 capecitabine cycles, followed by a safety observation period of 14 days ] [ Designated as safety issue: No ]
  assessment of pain, using a 0-10 score, analysed comparing the values measured during the study treatment period with the baseline pain value
  
  
• Accumulated dose intensity of capecitabine before and during ATH008 cream treatment [ Time Frame: minimum every 21 days, maximum of 4 capecitabine cycles, followed by a safety observation period of 14 days ] [ Designated as safety issue: No ]
  accumulated capecitabine dose during study treatment (mg / m2) from the starting of ATH008 cream treatment
  
  

This is a Phase II Placebo Controlled, Multicenter Study that will involve up to 114 patients with Palmar-Plantar Erythrodysesthesia Syndrome (PPES) secondary to capecitabine therapy. Eligible patients will be enrolled into Part I or Part II of the study.

The first part of the study (Part I) is designed

• to demonstrate the safety of ATH008 cream 1%, 3% and 8% and ATH008 cream placebo,
• to determine the plasmatic levels of the active ingredient and its metabolite after repeated doses of ATH008 cream 1%, 3% and 8%, and
• to determine the grade of PPES at Day 1 and Day 21 of ATH008 cream treatment Part I will have four different arms; patients will receive one of the three different doses of drug product (ATH008 cream 1%, ATH008 cream 3% or ATH008 cream 8%) or placebo (ATH008 cream placebo) in repeated doses (twice daily) during a period of 21 days.

Patients will continue to be assessed for safety and pharmacokinetics of active ingredient and its metabolite (Pre-dose, Day 1 and Day 21). Results of Part I will determine the most appropriate and beneficial dose for the second part of the study.

The second part of the study (Part II) is aimed at demonstrating the safety and efficacy of ATH008 cream in reducing the number of patients presenting PPES grade 2/3 secondary to capecitabine therapy following a four times daily application.

Part II will have three different arms; patients will receive ATH008 cream 3%, 8% or placebo in repeated doses (four times per day) since appearance of PPES grade 1 until appearance of grade 2-3 or a maximum of 4 cycles. Patients will continue to be assessed for safety. The clinical signs will be reported by iconographic register of lesions and pain will be evaluated using a pain scale. Patient will fill a questionnaire reporting QoL.