Panitumumab Skin Toxicity Prevention Trial

Colorectal Cancer Metastatic Clinical Trial

— PaSTo  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03167268
• Other study ID #: PaSTo
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 3, 2016
• Est. completion date: November 30, 2021

Study information

• Verified date: September 2021
• Source: Ospedale San Carlo Borromeo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 28
• Est. completion date: November 30, 2021
• Est. primary completion date: January 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Standard schedules of these treatments would be used.

Inclusion and exclusion criteria would be the following:

Inclusion criteria:

1. Age = 18 years;

2. Patients suffering from colorectal adenocarcinoma at stage-IV, for which a treatment with panitumumab is required;

3. No previous treatment with anti-EGFR drugs;

4. Presence of at least one neoplastic lesion one-dimensionally measurable;

5. No systemic anti-neoplastic therapy, nor experimental therapy or radiotherapy during the three weeks before randomization;

6. Proper contraceptive treatment by patient and his/her partner;

7. Written informed consent for participating to the study;

8. Performance Status (under ECOG scale) 0, 1. 2.

Exclusion criteria

1. PS > 2

2. Poor patient compliance;

3. Dermatological ongoing pathologies which contraindicate the treatment or made skin toxicity assessment difficult;

4. Presence of clinical conditions which could alter lycopene absorption (altered intestinal transit, malabsorption);

5. Pregnancy;

6. Absence of measurable lesions;

7. Previous treatment with anti-EGFR drugs;

8. Intolerance/allergy to tomato or milk.

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms
• Skin Toxicity

Intervention

Drug:
• Lycopene

Other:
• Placebo

Locations

Country	Name	City	State
Italy	Marco Pirovano	Milano

Sponsors (1)

Lead Sponsor	Collaborator
Ospedale San Carlo Borromeo

Country where clinical trial is conducted

Italy, 

References & Publications (22)

Chen J, Song Y, Zhang L. Effect of lycopene supplementation on oxidative stress: an exploratory systematic review and meta-analysis of randomized controlled trials. J Med Food. 2013 May;16(5):361-74. doi: 10.1089/jmf.2012.2682. Epub 2013 Apr 30. Review. — View Citation

Di Franco R, Calvanese M, Murino P, Manzo R, Guida C, Di Gennaro D, Anania C, Ravo V. Skin toxicity from external beam radiation therapy in breast cancer patients: protective effects of Resveratrol, Lycopene, Vitamin C and anthocianin (Ixor®). Radiat Onco — View Citation

Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Blasinska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: — View Citation

Galimont-Collen AF, Vos LE, Lavrijsen AP, Ouwerkerk J, Gelderblom H. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007 Mar;43(5):845-51. Epub 2007 Feb 7. Re — View Citation

Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW. Cutaneous side effects of epidermal growth factor receptor inhibitors: clinical presentation, pathogenesis, and management. J Am Acad Dermatol. 2007 Feb;56(2):317-26. Epub 2006 Dec 1. Review. — View Citation

Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014 Jul;13(7):513-32. doi: 10.1038/nrd4233. Review. — View Citation

Kasdagly M, Radhakrishnan S, Reddivari L, Veeramachaneni DN, Vanamala J. Colon carcinogenesis: influence of Western diet-induced obesity and targeting stem cells using dietary bioactive compounds. Nutrition. 2014 Nov-Dec;30(11-12):1242-56. doi: 10.1016/j. — View Citation

Khuda-Bukhsh AR, Das S, Saha SK. Molecular approaches toward targeted cancer prevention with some food plants and their products: inflammatory and other signal pathways. Nutr Cancer. 2014;66(2):194-205. doi: 10.1080/01635581.2014.864420. Epub 2013 Dec 30. — View Citation

Kim M, Jho EH. Cross-talk between Wnt/ß-catenin and Hippo signaling pathways: a brief review. BMB Rep. 2014 Oct;47(10):540-5. Review. — View Citation

Lacouture ME, Maitland ML, Segaert S, Setser A, Baran R, Fox LP, Epstein JB, Barasch A, Einhorn L, Wagner L, West DP, Rapoport BL, Kris MG, Basch E, Eaby B, Kurtin S, Olsen EA, Chen A, Dancey JE, Trotti A. A proposed EGFR inhibitor dermatologic adverse ev — View Citation

Lemieux E, Cagnol S, Beaudry K, Carrier J, Rivard N. Oncogenic KRAS signalling promotes the Wnt/ß-catenin pathway through LRP6 in colorectal cancer. Oncogene. 2015 Sep 17;34(38):4914-27. doi: 10.1038/onc.2014.416. Epub 2014 Dec 15. — View Citation

Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem. 2011 Sep;22(9):799-806. doi: 10.1016/j.jnutbio.2010.11.001. Epub 2011 Feb 4. Review. — View Citation

Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014 Nov;4(11):1269-80. doi: 10.1158/2159-8290.CD-14-0462. Epub 2014 Oct — View Citation

Pastore S, Mascia F, Mariani V, Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol. 2008 Jun;128(6):1365-74. Epub 2007 Nov 29. Review. — View Citation

Preet R, Mohapatra P, Das D, Satapathy SR, Choudhuri T, Wyatt MD, Kundu CN. Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC. Carcinogenesis. 2013 Feb;34(2):277-86. doi: 10.1093/carcin/bgs — View Citation

Requena C, Llombart B, Sanmartín O. Acneiform eruptions induced by epidermal growth factor receptor inhibitors: treatment with oral isotretinoin. Cutis. 2012 Aug;90(2):77-80. — View Citation

Rodeck U. Skin toxicity caused by EGFR antagonists-an autoinflammatory condition triggered by deregulated IL-1 signaling? J Cell Physiol. 2009 Jan;218(1):32-4. doi: 10.1002/jcp.21585. Review. — View Citation

Sarkar FH, Li Y, Wang Z, Kong D. The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metastasis Rev. 2010 Sep;29(3):383-94. doi: 10.1007/s10555-010-9233-4. Review. — View Citation

Shao A, Hathcock JN. Risk assessment for the carotenoids lutein and lycopene. Regul Toxicol Pharmacol. 2006 Aug;45(3):289-98. Epub 2006 Jun 30. Review. — View Citation

Stahl W, Sies H. ß-Carotene and other carotenoids in protection from sunlight. Am J Clin Nutr. 2012 Nov;96(5):1179S-84S. doi: 10.3945/ajcn.112.034819. Epub 2012 Oct 10. Review. — View Citation

Tang FY, Pai MH, Wang XD. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model. J Agric Food Chem. 2011 Aug 24;59(16):9011-21. doi: 10.1021/jf2017644. Epub 2011 Jul 25. — View Citation

Tang FY, Shih CJ, Cheng LH, Ho HJ, Chen HJ. Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Mol Nutr Food Res. 2008 Jun;52(6):646-54. doi: 10.1002/mnfr.200700272. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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