Topical Tretinoin Prophylaxis for Anti-EGFR Induced Skin Toxicity in Patients With Solid Tumors

Official title

A Phase II, Randomized, Double-Blind, Split-Face of Topical Tretinoin Prophylaxis for Anti-EGFR Induced Skin Toxicity in Patients With Solid Tumors

Overview

The goal of this clinical trial is to learn if using topical tretinoin will help patients with solid tumors who are experiencing an acneiform rash as a side effect of their treatment. Researchers will compare the use of tretinoin on one side of the face to the use of a placebo on the other side of the face to see if there is an impact.

Detailed description

The anti-epidermal growth factor receptor (anti-EGFR) agents cetuximab and panitumumab have been shown in numerous trials to be active in patients with metastatic colorectal cancer (mCRC). Current American Society of Clinical Oncology guidelines strongly recommend offering an antiEGFR therapy in combination with chemotherapy to patients with treatment-naïve, left-sided, RAS wild-type mCRC. In addition to colorectal cancer, anti-EGFR agents are also approved for use in the management of head and neck, cutaneous squamous cell, and penile cancers. Novel prophylactic approaches are needed so that more patients can benefit from the survival advantage provided by these drugs without a sacrificing quality of life.

Tretinoin is a vitamin A derivative (all-trans retinoic acid) that has been used by dermatology for more than five decades and is currently approved for the management of moderate to severe acne vulgaris. Initially, tretinoin was recognized as a potential treatment for acne vulgaris based on its comedolytic properties. However, over the past decade tretinoin has been increasingly recognized for its immunomodulatory properties raising the potential for use in dermatologic disorders other than acne vulgaris.

Although the pathogenesis of anti-EGFR associated skin toxicity is still not entirely understood, the clinical presentation shares many similarities with acne vulgaris, and inflammation is felt to play a major role. For this reason, there is interest in the use of tretinoin in the management of anti-EGFR associated rash. Topical tretinoin is associated with minimal transdermal absorption thus making it a viable option for investigation into its use as a prophylactic agent for anti-EGFR associated rash.

This split-face study will utilize a topical moisturizer as a placebo applied to the opposite half of the face as the topical tretinoin. Eucerin, a topical emollient will be used as the placebo in this study. Eucerin is not associated with any significant adverse reactions.

This is a randomized, double-blind, split-face, phase II study of topical tretinoin prophylaxis for anti-EGFR treatment-induced skin toxicity in patients with locally advanced or metastatic solid tumors. Patients will apply topical tretinoin to one half of the face and topical moisturizer (placebo) to the other half of the face daily, starting the day that anti-EGFR treatment is initiated. The sides of the face tretinoin and moisturizer are applied to will be randomized. Standardized photographs of the face will be obtained at screening and every two weeks from Week 1 Day 1 until after six weeks of treatment. Photographs will be graded by a dermatologist who will be blinded to treatment sidedness. Facial rash severity will be graded using a modified Investigators Global Assessment (IGA) score.

Interventions

• Drug Topical Tretinoin
  Topical tretinoin will be applied to one half of the face, either left or right side. The side the topical tretinoin will be applied to will be randomized.
• Other Placebo
  A placebo (topical moisturizer) will be applied to the other half of the face, either left or right side. The side the topical tretinoin will be applied to will be randomized.

Primary outcome measures

• The maximum difference in modified Investigators Global Assessment (IGA) score between the treated and untreated sides of the face at any assessment. [Time frame: up to 6 weeks from the initiation of study therapy]

Secondary outcome measures (2)

• Frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE version 5.0 and the modified IGA), seriousness, duration, and relationship to study treatment. [Time frame: up to 6 weeks from the initiation of study therapy]
• Proportion of acneiform rash per CTCAE v5.0 [Time frame: up to 6 weeks from the initiation of study therapy]

Eligibility criteria

Inclusion criteria

• Participant aged ≥ 18 years
• Histologically confirmed solid tumor.
• Radiologically confirmed locally advanced or metastatic disease.
• Eligible for and willing to receive treatment with panitumumab or cetuximab as standard-of-care.
• ECOG Performance Status ≤ 2.
• Adequate organ function as defined as:

--Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN ----Participants with liver metastases will be allowed to enroll with AST and ALT levels ≤ 5 x ULN.
• Negative pregnancy test for participants who have not undergone surgical sterilization or shown evidence of post-menopausal status. The following age-specific requirements apply:

--< 50 years of age:

• Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
• Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
• Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

--≥ 50 years of age:

• Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
• Had radiation-induced menopause with last menses >1 year ago; or
• Had chemotherapy-induced menopause with last menses >1 year ago; or
• Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
• Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.4.2.
• Must have recovered from adverse effects of any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy). CTCAE adverse events less than or equal to grade 1 are acceptable. CTCAE adverse events grade 2 or greater may be acceptable as determined by an investigator with appropriate documentation.
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion criteria

• Treatment with an anti-EGFR agent within 90 days of registration.
• Pre-existing facial rash that per the treating investigator would preclude the ability to assess response to topical tretinoin.
• The diagnosis of another malignancy within ≤ 2 years before study enrollment, except for those considered to be adequately treated with no evidence of disease or symptoms and/or will not require therapy during the study duration (i.e., basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix, or low-grade prostate cancer with Gleason Score ≤ 6).
• Any other condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
• Systemic active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.

--Note: Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Participants positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.
• Known prior severe hypersensitivity to investigational product or any component in its formulations (CTCAE v5.0 Grade ≥ 3).
• Participants taking prohibited medications as described in Section 6.8.2. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Huntsman Cancer Institute at University of Utah — Salt Lake City

Publications

• Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20 PMID 21502544
• Berlin J, Posey J, Tchekmedyian S, Hu E, Chan D, Malik I, Yang L, Amado RG, Hecht JR. Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer. 2007 Mar;6(6):427-32. doi: 10.3816/CCC.2007.n.011. PMID 17531105
• Kohne CH, Hofheinz R, Mineur L, Letocha H, Greil R, Thaler J, Fernebro E, Gamelin E, Decosta L, Karthaus M. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol. 2012 Jan;138(1):65-72. doi: 10.1007/s00432-011-1061-6. Epub 2011 Sep 30. PMID 21960318
• Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wi PMID 37071094
• Nevala-Plagemann C, Iyengar S, Trunk AD, Pappas L, Haaland B, Garrido-Laguna I. Treatment Trends and Clinical Outcomes of Left-Sided RAS/RAF Wild-Type Metastatic Colorectal Cancer in the United States. J Natl Compr Canc Netw. 2022 Feb 4;20(3):268-275. doi: 10.6004/jnccn.2021.7079. PMID 35120306
• Ciliberto D, Staropoli N, Caglioti F, Chiellino S, Ierardi A, Ingargiola R, Botta C, Arbitrio M, Correale P, Tassone P, Tagliaferri P. The best strategy for RAS wild-type metastatic colorectal cancer patients in first-line treatment: A classic and Bayesian meta-analysis. Crit Rev Oncol Hematol. 2018 May;125:69-77. doi: 10.1016/j.critrevonc.2018.03.003. Epub 2018 Mar 9. PMID 29650279
• Morris VK, Kennedy EB, Baxter NN, Benson AB 3rd, Cercek A, Cho M, Ciombor KK, Cremolini C, Davis A, Deming DA, Fakih MG, Gholami S, Hong TS, Jaiyesimi I, Klute K, Lieu C, Sanoff H, Strickler JH, White S, Willis JA, Eng C. Treatment of Metastatic Colorectal Cancer: ASCO Guideline. J Clin Oncol. 2023 Jan 20;41(3):678-700. doi: 10.1200/JCO.22.01690. Epub 2022 Oct 17. PMID 36252154
• Lacouture ME, Anadkat M, Jatoi A, Garawin T, Bohac C, Mitchell E. Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review. Clin Colorectal Cancer. 2018 Jun;17(2):85-96. doi: 10.1016/j.clcc.2017.12.004. Epub 2017 Dec 13. PMID 29576427

Identifiers

NCT: NCT06358677 · HCI171997

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗