Topical Tretinoin for Colon Cancer

(FACE Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Christopher D. Nevala-Plagemann

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Utah

Disqualifiers: Prior anti-EGFR, Facial rash, Others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn if using topical tretinoin will help patients with colorectal cancer 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.

Do I need to stop my current medications for the trial?

The trial requires a washout period (time without taking certain medications) for any prohibited medications, lasting at least five half-lives or as clinically indicated, before starting treatment. The specific medications that are prohibited are not listed in the provided information.

What evidence supports the effectiveness of the drug Topical Tretinoin for colon cancer?

Research shows that all-trans retinoic acid (ATRA), a component of Topical Tretinoin, can reduce the invasiveness of colon cancer cells and decrease the number of liver metastases in animal models. Additionally, ATRA has been found to inhibit the growth of colon cancer cells by targeting specific receptors involved in cancer cell growth. ^{1 2 3 4 5}

Is topical tretinoin generally safe for humans?

Topical tretinoin (all-trans-retinoic acid) has been used in various treatments and is generally well-tolerated, but it can cause skin irritation and dryness. In some cases, it has been associated with more serious side effects like hypercalcemia (high calcium levels in the blood) and genital ulcers, especially when used in combination with other medications. ^{4 6 7 8 9}

How is the drug Topical Tretinoin unique for treating colon cancer?

Topical Tretinoin is unique for colon cancer treatment because it is applied directly to the skin, unlike most cancer treatments that are taken orally or intravenously. This method may help reduce systemic side effects, which are common with oral formulations of tretinoin used for other conditions. ^{1 4 10 11 12}

Research Team

Christopher D. Nevala-Plagemann

Principal Investigator

Huntsman Cancer Institute

Eligibility Criteria

Adults over 18 with metastatic colorectal cancer, who are about to start or are currently receiving panitumumab or cetuximab treatment. They must have good organ function and performance status, not be pregnant, agree to use contraception if applicable, and have recovered from previous cancer treatments.

Inclusion Criteria

My colorectal cancer diagnosis was confirmed through tissue examination.

I am willing to receive treatment with panitumumab or cetuximab.

I am 18 years old or older.

Exclusion Criteria

I am not taking any medications that are not allowed in the study.

I do not have an active infection like TB, hepatitis B, or C.

Known prior severe hypersensitivity to investigational product or any component in its formulations

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive topical tretinoin on one side of the face and placebo on the other side to assess the impact on anti-EGFR induced acneiform rash

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Topical Tretinoin (Retinoid)

Trial Overview The trial is testing whether topical tretinoin can prevent or reduce skin rash side effects in patients treated with anti-EGFR drugs for colorectal cancer. One side of the face will receive tretinoin while the other side gets a placebo to compare results.

Participant Groups

Group I: Tretinoin half of face (right) and Placebo/Moisturizer other half of the face (left) Experimental Treatment 1 Intervention

Randomized, double-blind, split-face. Randomization will determine which side of the face Tretinoin will be applied to (left or right). The other side of the face (left or right) will have placebo applied. All participants will receive both treatment and placebo.

Group II: Tretinoin half of face (left) and Placebo/Moisturizer other half of the face (right) Experimental Treatment 1 Intervention

Randomized, double-blind, split-face. Randomization will determine which side of the face Tretinoin will be applied to (left or right). The other side of the face (left or right) will have placebo applied. All participants will receive both treatment and placebo.

Topical Tretinoin is already approved in Canada for the following indications:

Approved in Canada as Tretinoin for:

• Acne
• Psoriasis

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Jeffrey Wilkins

University of Utah

Chief Medical Officer since 2022

MD from Meharry Medical College

Stephen Tullman

University of Utah

Chief Executive Officer since 2022

BS in Accounting from Rutgers University

Findings from Research

In a study involving 28 female nude mice, dietary vitamin A supplementation significantly reduced the number of liver metastases from ATRA-resistant colon cancer cells to 17% of the control group, suggesting its potential as a therapeutic strategy.

The vitamin A supplementation did not cause any adverse effects, such as weight loss or toxicity, indicating it is a safe option for potentially reducing cancer metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic vitamin A preloading reduces colorectal cancer metastatic multiplicity in a mouse xenograft model. Park, EY., Pinali, D., Lindley, K., et al.[2021]

All three tested retinoids (ATRA, 9-cis, and 13-cis retinoic acid) effectively reduced the expression of matrilysin, an enzyme linked to the invasion of colon cancer cells, in both laboratory and mouse models.

The retinoids suppressed the invasiveness of colon cancer cell lines and reduced tumor invasion in mice without affecting overall tumor growth, suggesting their potential as therapeutic agents in managing colorectal carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinoic acids reduce matrilysin (matrix metalloproteinase 7) and inhibit tumor cell invasion in human colon cancer. Adachi, Y., Itoh, F., Yamamoto, H., et al.[2018]

Topical tretinoin, a form of vitamin A, has demonstrated antitumor effects in various studies, effectively removing premalignant actinic keratoses and showing potential in treating skin lesions when combined with 5-fluorouracil.

Importantly, after over a decade of use, tretinoin has not been found to cause or promote cancer in humans, indicating its safety in long-term topical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

All-trans-retinoic acid and cutaneous cancers. Epstein, JH.[2019]

The review of nine retinoids for cancer prevention found that all-trans-retinoic acid, 13-cis-retinoic acid, and N-ethylretinamide are not suitable for human use due to toxicity, potential to enhance cancer, or ineffectiveness.

Conversely, 9-cis-retinoic acid, etretinate, and acitretin show some potential for cancer prevention, but further research is needed, while all-trans N-(4-hydroxyphenyl)retinamide appears particularly promising.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An International Evaluation of the Cancer-Preventive Potential of Nine Retinoids. Miller, AB., Nettesheim, P., Stewart, BW.[2019]

All-trans retinoic acid (ATRA) significantly inhibits the growth of HT29 colon carcinoma cells in a way that does not induce differentiation, suggesting a unique mechanism of action against cancer cell proliferation.

The growth-inhibiting effects of ATRA are primarily mediated through the retinoic acid receptor alpha (RARalpha), as shown by the ability of a selective RARalpha agonist to replicate ATRA's effects and the complete blockage of these effects by a RARalpha antagonist.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinoic acid receptor alpha mediates growth inhibition by retinoids in human colon carcinoma HT29 cells. Nicke, B., Kaiser, A., Wiedenmann, B., et al.[2013]

All-trans-retinoic acid (ATRA) is an effective treatment for acute promyelocytic leukemia, but it can cause side effects such as retinoic acid syndrome and Sweet's syndrome.

This report highlights a rare case of hypercalcemia in a patient treated with ATRA, potentially linked to the interaction with voriconazole, which inhibits cytochrome P450 function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. Bennett, MT., Sirrs, S., Yeung, JK., et al.[2019]

All-trans-retinoic acid (ATRA) is an effective treatment for acute promyelocytic leukemia, with most side effects being minor except for differentiation syndromes.

The study highlights genital ulcers as an underreported adverse effect of ATRA, emphasizing the need for awareness to prevent serious complications in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genital ulcers following all-trans-retinoic acid therapy: A case series with review of literature. Saraswat, N., Kumar, S., Prem, R., et al.[2023]

In a multi-institutional study in Japan, tretinoin (ATRA) was highly effective for treating refractory and relapsed acute promyelocytic leukemia, achieving complete remission in 81.5% of previously untreated patients who could not tolerate chemotherapy.

While side effects were common (87.8% of patients experienced issues like skin dryness and headaches), they were generally well tolerated, and serious complications like retinoic acid syndrome were managed effectively, allowing for continued treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Co-operative study of all-trans retinoic acid as a differentiation induction therapy of acute promyelocytic leukemia]. Yamada, O., Hatake, K., Tanimoto, M., et al.[2013]

In a study involving 84 patients with facial hyperpigmented lesions, a new nano-atRA gel formulation improved hyperpigmentation in 95.5% of cases after an average treatment duration of 14.3 weeks, with nearly complete elimination in 59.1% of lesions.

The nano-atRA gel caused similar exfoliation and scaling effects as conventional atRA gel but resulted in less erythema, indicating a potentially safer option for patients prone to irritant dermatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical trial of topical bleaching treatment with nanoscale tretinoin particles and hydroquinone for hyperpigmented skin lesions. Sato, K., Matsumoto, D., Iizuka, F., et al.[2017]

ATRA microspheres (MS) effectively reduced disease symptoms in murine models of inflammatory bowel disease (IBD), suggesting a promising treatment option with fewer systemic side effects compared to traditional oral ATRA.

The ATRA MS formulation demonstrated superior efficacy and better pharmacokinetics than soluble ATRA, indicating that targeted delivery to the gut may enhance therapeutic outcomes for IBD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis. Nicoletti, F., Hammer, L., Furtado, S., et al.[2022]

The study demonstrated that incorporating all-trans-retinoic acid (ATRA) into 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) significantly enhances its aqueous solubility and photostability, which are crucial for developing effective formulations.

These findings suggest that a parenteral or aqueous oral formulation of ATRA could be feasible, but further evaluation of its biopharmaceutical properties is needed before clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

2-hydroxypropyl-beta-cyclodextrin increases aqueous solubility and photostability of all-trans-retinoic acid. Lin, HS., Chean, CS., Ng, YY., et al.[2019]

Topical all-trans retinoic acid (tretinoin) 0.1% showed improvement in symptoms and signs for all eight patients with various ocular surface disorders, including those following Stevens-Johnson syndrome and chronic kerato conjunctivitis.

While the treatment was effective, some patients experienced local irritation, and challenges with formulation and stability need to be addressed before broader use of topical retinoids can be implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical retinoic acid therapy for disorders of the outer eye. Wright, P.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Hepatic vitamin A preloading reduces colorectal cancer metastatic multiplicity in a mouse xenograft model. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Retinoic acids reduce matrilysin (matrix metalloproteinase 7) and inhibit tumor cell invasion in human colon cancer. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

All-trans-retinoic acid and cutaneous cancers. [2019]

4. Thailand pubmed.ncbi.nlm.nih.gov

An International Evaluation of the Cancer-Preventive Potential of Nine Retinoids. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Retinoic acid receptor alpha mediates growth inhibition by retinoids in human colon carcinoma HT29 cells. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. [2019]

7. India pubmed.ncbi.nlm.nih.gov

Genital ulcers following all-trans-retinoic acid therapy: A case series with review of literature. [2023]

8. Japan pubmed.ncbi.nlm.nih.gov

[Co-operative study of all-trans retinoic acid as a differentiation induction therapy of acute promyelocytic leukemia]. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

A clinical trial of topical bleaching treatment with nanoscale tretinoin particles and hydroquinone for hyperpigmented skin lesions. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis. [2022]

11. England pubmed.ncbi.nlm.nih.gov

2-hydroxypropyl-beta-cyclodextrin increases aqueous solubility and photostability of all-trans-retinoic acid. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Topical retinoic acid therapy for disorders of the outer eye. [2013]