Panitumumab Skin Toxicity Prevention Trial

Study Overview
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Brief Summary
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Background and rationale: EGFR represents the main and more studied signal activation pathway in the development of colorectal carcinoma. KRAS, NRAS, BRAF and PI3KA mutations and ERBB2 and MET amplification are responsible for most of the cases of primary resistance to anti-EGFR antibody treatments. Despite the identification of these resistance mechanisms, a primary resistance to the therapy was detected in a certain percentage of cases, in which tumour bio-molecular characteristics would suggest a possible response to anti-EGFR antibody treatment. In these cases, pathway activation mechanisms should exist, which act in an alternative, complementary or parallel way than the EGFR one, allowing tumour progression despite of EGFR pharmacological deactivation. Skin toxicity is a characteristic of drugs having EGFR as a target and it shows itself mainly as a sterile acneiform folliculitis together with neutrophils perifollicular infiltrates but also as skin xerosis and paronychia starting from the earliest cycles of treatment. This skin toxicity seems to be closely related to EGFR activation of pro-inflammatory cytokines able to activate specific inflammatory activators, which induce neutrophils granulocytes chemotaxis. Lycopene is a compound belonging to carotenoid group, largely contained in tomatoes and their derivatives, which has an extreme antioxidant activity. In Dermatology, prolonged use of β-carotenoids in general and of lycopene in particular in the diet showed to be effective in skin protection from ageing, sunlight and radiotherapy damages because these compounds may accumulate in skin and thus contribute to reduce free radicals and inflammation effects. Moreover, lycopene ability to induce apoptosis and to inhibit cell cycle progression in some types of tumour cells, both in vitro and in vivo, has already been described. Lycopene seems to be able to suppress significantly PCNA (Proliferating cell nuclear antigen, cofactor of DNA polymerase-β) and β-catenin nuclear expression in neoplastic cells, essential substrate of WNT/β-catenin pathway, which is itself closely connected to activating pathways often involved in carcinogenesis of some kinds of tumours, in particular of colorectal carcinoma, like Akt/GSK3β/β-catenin and Hippo pathways. For its proved skin anti-inflammatory activity as powerful free radicals scavenger, lycopene, which accumulates itself specifically in skin, could be effective in reducing anti-EGFR drugs toxicity. Contemporary use of lycopene could have a positive effect on anti-EGFR drugs treatment effectiveness in patients with metastatic colorectal carcinoma due to its ability to interfere with pathways involved in neoplastic cells proliferation. Estimated population:100 patients (50 for each of the two groups of treatment) Study Framework: In this study, patients suffering from metastatic colorectal cancer and submitted to therapy with panitumumab would be enrolled. According to indications, panitumumab would be used: in first line combined with Folfox or Folfiri; in second line combined with Folfiri or treatments containing Irinotecan in monotherapy in any therapeutic line in patients resistant to Fluoropyrimidines, Oxaliplatin and Irinotecan or intolerant to these drugs. Standard schedules of these treatments would be used. This is a phase-II, randomized, double-blind study between experimental prophylactic treatment with Lycopene vs placebo: Treatment A - lycopene tablets 20 mg Treatment B - placebo tablets Patients should take orally Lycopene/placebo after dinner (to promote its absorption), starting the day before the beginning of treatment with panitumumab for the entire duration of the therapy, until progression of the disease or definitive drug suspension for toxicity. Objectives of the study Primary objective: to assess the effectiveness of lycopene versus placebo in reducing skin toxicity induced by panitumumab in patients treated for metastatic colorectal carcinoma. Secondary objective: to assess lycopene pharmacokinetics Exploratory objectives: to assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Disease Control (DC), Objective Response (OR) and Stabilisation of the Disease (SD). To assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Progression Free Survival (PFS). As far as randomization is concerned, the two groups will be balanced according to sex, therapeutic line and institution in which patients will be treated.

Official Title
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Double-blind, Phase II Study to Assess the Effectiveness of Lycopene vs Placebo to Reduce Skin Toxicity in Patients With Colorectal Carcinoma Treated With Panitumumab

Conditions
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Colorectal Cancer Metastatic, Skin Toxicity

Intervention / Treatment
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* Drug: Lycopene
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Standard schedules of these treatments would be used. Inclusion and exclusion criteria would be the following: Inclusion criteria: Age ≥ 18 years; Patients suffering from colorectal adenocarcinoma at stage-IV, for which a treatment with panitumumab is required; No previous treatment with anti-EGFR drugs; Presence of at least one neoplastic lesion one-dimensionally measurable; No systemic anti-neoplastic therapy, nor experimental therapy or radiotherapy during the three weeks before randomization; Proper contraceptive treatment by patient and his/her partner; Written informed consent for participating to the study; Performance Status (under ECOG scale) 0, 1. 2. Exclusion criteria PS > 2 Poor patient compliance; Dermatological ongoing pathologies which contraindicate the treatment or made skin toxicity assessment difficult; Presence of clinical conditions which could alter lycopene absorption (altered intestinal transit, malabsorption); Pregnancy; Absence of measurable lesions; Previous treatment with anti-EGFR drugs; Intolerance/allergy to tomato or milk.

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: Lycopene 20mg cpr/die<br>Lycopene is a compound belonging to carotenoid group, largely contained in tomatoes and their derivatives, which has an extreme antioxidant activity. In Dermatology, prolonged use of β-carotenoids in general and of lycopene in particular in the diet showed to be effective in skin protection from ageing, sunlight and radiotherapy damages because these compounds may accumulate in skin and thus contribute to reduce free radicals and inflammation effects. | Drug: Lycopene<br> <br> |
| Placebo Comparator: Placebo<br>Containing same excipients than the experimental Lycopene 20 mg but not active principle (Lycopene) | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin toxicity reduction | Reduction of grade 2/4 skin toxicity of 30% in the experimental group. Toxicity will be evaluated as: worst toxicity for each patient during the treatment; grade 3 or grade 4 toxicity duration related to the treatment duration for each patient in the two arms; number and duration of tetracyclines and antibiotic treatment related to the treatment duration for each patient in the two arms; toxicity in difference time points (G15, G29, .....) for each clinical skin features (rash papular, pustular - xerosis skin - paronychia) in the two arms | Skin toxicity will be verified every two weeks assessed up to 12 weeks, from date of randomization until the date of first documented progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lycopene, Anti EGFR therapy