High Dose Vitamin A for Stem Cell Transplant Recipients

Overseen By Rachel Dalton

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Ohio State University Comprehensive Cancer Center

Disqualifiers: Vitamin A allergy, Abnormal liver enzymes, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 2 weeks

130 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and how well high dose vitamin A works in preventing gastrointestinal graft versus host disease (GVHD) in participants undergoing donor stem cell transplant. Vitamin A deficiency is associated with increased risk of gastrointestinal GVHD. Vitamin A regulates growth and differentiation of intestinal cells and may reduce risk of gastrointestinal GVHD.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have a history of allergic reactions to Vitamin A or similar issues, it might affect your participation.

What data supports the effectiveness of the drug Vitamin A Compound for stem cell transplant recipients?

Research shows that Vitamin A, particularly its derivatives called retinoids, can enhance immune functions and may help in cancer treatment by affecting cell growth and survival. This suggests potential benefits for stem cell transplant recipients, as these processes are crucial for recovery and engraftment. ^{1 2 3 4 5}

Is high dose Vitamin A generally safe for humans?

High doses of Vitamin A can cause several side effects, including changes in mood and behavior, liver enlargement, increased blood fat levels, and skin dryness. In infants, excessive Vitamin A can lead to severe anemia and low platelet counts. Most side effects are reversible, but liver and bone issues may persist. ^{2 6 7 8 9}

How does the drug Vitamin A Compound differ from other treatments for stem cell transplant recipients?

The use of high-dose Vitamin A, specifically all-trans retinoic acid, is unique because it enhances the maintenance and self-renewal of stem cells, which may improve the success of stem cell transplants. This approach is different from standard treatments as it focuses on promoting the engraftment and long-term repopulating activity of stem cells. ^{3 6 10 11 12}

Research Team

Hannah Choe, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults set to have a stem cell transplant from a donor who matches their human leukocyte antigen (HLA) or is slightly mismatched. They should be undergoing this procedure due to blood cancers and can have either intense or less intense pre-transplant treatments.

Inclusion Criteria

Adult patients planned to undergo an allogeneic stem cell transplant (SCT) with an human leukocyte antigen (HLA)-matched (unrelated or related) or 1 allele mismatched (7/8) donor or haploidentical donor who received either myeloablative or nonmyeloablative conditioning for hematologic malignancies are eligible

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single, high dose of vitamin A orally or enterally prior to stem cell transplant. A second dose may be administered two weeks after transplant if vitamin A levels have not improved.

2 weeks

1 visit (in-person) for initial dose, potential follow-up for second dose

Follow-up

Participants are monitored for safety, effectiveness, and incidence of gastrointestinal GVHD after treatment. Stool samples are collected for microbiome analysis.

28 days

Periodic follow-up visits

Long-term follow-up

Participants are monitored for the incidence of gastrointestinal GVHD up to 180 days after stem cell transplant.

180 days

Treatment Details

Interventions

• Vitamin A Compound

Trial Overview The study tests if high doses of vitamin A can prevent gastrointestinal problems after receiving a stem cell transplant from a donor. It's in the early stages, focusing on safety and how well it works to stop these complications.

Participant Groups

Group I: Treatment Cohort (vitamin A compound) Experimental Treatment 1 Intervention

Participants receive vitamin A compound PO or enterally once prior to stem cell transplant. once over a given 24 hour period with or without food. We will re-dose at 2000 IU/kg (maximum 120,000 IU) if Week 2 Vitamin A levels remain within 10% of baseline Vitamin A.

Group II: Control Cohort (usual care) Active Control 1 Intervention

Patients receive usual care.

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Findings from Research

In a study of 100 patients with metastatic breast carcinoma undergoing chemotherapy, high doses of Vitamin A (350,000 to 500,000 IU) significantly increased the complete response rate, particularly in post-menopausal women.

Post-menopausal patients showed a notable increase in serum retinol levels and improved response rates, duration of response, and projected survival, highlighting the potential benefits of Vitamin A in this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients]. Israël, L., Hajji, O., Grefft-Alami, A., et al.[2007]

Intravenous liposomal all-trans-retinoic acid (L-ATRA) maintains significantly higher and stable plasma concentrations compared to oral ATRA, with 13- and 22-fold greater AUC values on days 1 and 9, respectively, indicating a more effective delivery method.

Despite higher plasma levels of L-ATRA, the side effects were similar to those of oral ATRA, although L-ATRA was associated with dermal exfoliation in 31% of subjects, while oral ATRA led to abnormal liver function tests in 23% of subjects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. Ozpolat, B., Lopez-Berestein, G., Adamson, P., et al.[2022]

All-trans retinoic acid (RA) significantly enhances the engraftment of unrelated umbilical cord blood stem/progenitor cells in a murine model, leading to faster hematopoiesis and immune recovery compared to untreated controls.

Mice treated with RA showed improved survival rates after transplantation, with 30 and 60-day survival rates increasing from 41.67% to 72.23% and 70.83% respectively for higher cell doses, indicating RA's potential as a supportive treatment in clinical umbilical cord blood transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Experimental study on promoting the engraftment of hematopoietic stem/progenitor cell by all-trans retinoic acid]. Mai, HR., Huang, SL., Xu, HG., et al.[2013]

In a study involving 248 patients with early-stage melanoma, oral vitamin A (100,000 IU/d for 18 months) did not improve disease-free survival or overall survival compared to observation, indicating it may not be an effective adjuvant therapy.

While 12% of patients receiving vitamin A experienced significant toxicities (grade 3 or 4), the lack of survival benefits suggests that further research on vitamin A for melanoma treatment is not justified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. Meyskens, FL., Liu, PY., Tuthill, RJ., et al.[2017]

Retinoids, which are derivatives of vitamin A, play a crucial role in regulating immune functions and cancer development by interacting with nuclear receptors, specifically retinoic acid receptors (RARs) and retinoid X receptors (RXRs).

These compounds have shown promise in treating certain cancers, such as acute promyelocytic leukemia and cutaneous T cell lymphomas, and ongoing clinical trials are exploring their effectiveness against solid tumors and B-cell malignancies, highlighting their potential to enhance immune responses in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinoids as critical modulators of immune functions: new therapeutic perspectives for old compounds. Montrone, M., Martorelli, D., Rosato, A., et al.[2021]

In a phase I trial involving 13 cancer patients, daily doses of retinol (vitamin A) showed dose-limiting toxicities, particularly neuropsychiatric changes and hepatomegaly, at higher doses (above 240,000 U/m2).

Due to observed toxicities, a maximum safe dose of 200,000 U/m2/day of retinol is recommended for future studies, highlighting the need for careful monitoring of side effects in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of retinol in cancer patients. Goodman, GE., Alberts, DS., Earnst, DL., et al.[2017]

An infant experienced severe anemia and thrombocytopenia after being given an excessive dose of 62,000 IU/day of vitamin A for 80 days, indicating the dangers of hypervitaminosis A.

The study found that high levels of vitamin A directly inhibited the proliferation of bone marrow cells, likely through the up-regulation of specific cell cycle inhibitors, suggesting that excessive vitamin A intake can lead to significant bone marrow dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. Perrotta, S., Nobili, B., Rossi, F., et al.[2021]

Oral retinoids have a well-established safety profile, but rare side effects can still occur, highlighting the importance of careful patient selection and monitoring.

The main concern with oral retinoids is their potential teratogenicity, which can be effectively managed by adhering to recommended precautions during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects of systemic retinoids and their clinical management. Saurat, JH.[2019]

Synthetic retinoids, developed from vitamin A, aim to treat skin disorders with abnormal keratinization while having a better therapeutic-toxicity ratio than retinol, but they still require high doses that can lead to side effects.

Most side effects from retinoids resemble those from excessive vitamin A intake, affecting various body systems, and while many are reversible, there is still uncertainty about the long-term effects and reversibility of toxicity after stopping the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side effects and long-term toxicity of synthetic retinoids. Yob, EH., Pochi, PE.[2016]

In a study involving 135 patients, the addition of calcipotriol ointment to systemic treatment with acitretin significantly improved psoriasis outcomes, with 67% of patients in the calcipotriol group achieving clearance or marked improvement compared to 41% in the placebo group.

The combination therapy allowed patients to achieve these results with a lower cumulative dose of acitretin, indicating that calcipotriol not only enhances efficacy but also helps reduce the amount of acitretin needed, while maintaining a good safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of addition of calcipotriol ointment (50 micrograms/g) to acitretin therapy in psoriasis. van de Kerkhof, PC., Cambazard, F., Hutchinson, PE., et al.[2019]

Retinol at a concentration of 1 µmol/L significantly enhances the expression of stem cell factor (SCF) and colony-stimulating factor 1 (CSF1) in cultured human umbilical-derived mesenchymal stem cells (UCMSCs).

The study confirmed that while retinol positively affects SCF and CSF1 levels, it does not alter the expressions of epidermal growth factor (EGF) or leukemia inhibitory factor (LIF) in these cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of retinol on expressions of epidermal growth factor, stem cell factor, colony-stimulating factor 1 and leukemia inhibitory factor in human umbilical cord-derived mesenchymal stem cells]. Zhuo, HL., Bai, LP., Liu, D., et al.[2020]

All-trans retinoic acid (ATRA) significantly enhances the maintenance and production of short-term and long-term repopulating stem cells from murine hematopoietic precursors, indicating its potential as a therapeutic agent in stem cell biology.

In contrast, the RAR antagonist AGN 193109 reduces the repopulating ability of these stem cells by promoting their differentiation into more mature cells, highlighting the critical role of retinoids in regulating hematopoietic stem cell differentiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells. Purton, LE., Bernstein, ID., Collins, SJ.[2021]

References

1. France pubmed.ncbi.nlm.nih.gov

[Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients]. [2007]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Experimental study on promoting the engraftment of hematopoietic stem/progenitor cell by all-trans retinoic acid]. [2013]

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

Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. [2017]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Retinoids as critical modulators of immune functions: new therapeutic perspectives for old compounds. [2021]

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

Phase I trial of retinol in cancer patients. [2017]

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

Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition. [2021]

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

Side effects of systemic retinoids and their clinical management. [2019]

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

Side effects and long-term toxicity of synthetic retinoids. [2016]

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

The effect of addition of calcipotriol ointment (50 micrograms/g) to acitretin therapy in psoriasis. [2019]

11. China pubmed.ncbi.nlm.nih.gov

[Effects of retinol on expressions of epidermal growth factor, stem cell factor, colony-stimulating factor 1 and leukemia inhibitory factor in human umbilical cord-derived mesenchymal stem cells]. [2020]

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

All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells. [2021]