Letrozole for Uterine Fibroids

(PLUM Trial)

Recruiting at 2 trial locations

Overseen by Alison Huang, MD, MAS, MPhil

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: University of California, San Francisco

Must not be taking: Aromatase inhibitors, SERMs, Estrogens, Methadone

Disqualifiers: Pregnancy, Breast cancer, Osteoporosis, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The PLUM Study is a randomized, double-blinded, 2-arm, parallel-group, placebo-controlled trial is designed to compare the efficacy of letrozole versus placebo on leiomyoma-related symptoms and quality of life as well as leiomyoma and uterine size.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as letrozole, other aromatase inhibitors, selective estrogen receptor modulators (SERMs), and certain hormone therapies, at least 4 weeks before starting the study. Additionally, you should not use medications that might interact unsafely with letrozole, like methadone or thalidomide, in the 4 weeks before the trial.

What data supports the effectiveness of the drug Letrozole for treating uterine fibroids?

Letrozole is known to be effective in reducing or shrinking tumors in postmenopausal women with hormone-sensitive breast cancer, suggesting it may have potential in treating other hormone-related conditions like uterine fibroids. ^{1 2 3 4 5}

Is letrozole generally safe for humans?

Letrozole, also known as Femara, is generally considered safe for humans, with most side effects being mild, such as hot flashes, joint pain, nausea, and fatigue. It has been used in many countries for treating breast cancer in postmenopausal women, and its safety profile is well-documented in these studies. ^{2 6 7 8 9}

How does the drug Letrozole differ from other treatments for uterine fibroids?

Letrozole is unique because it is a non-steroidal aromatase inhibitor that reduces estrogen levels, which can help shrink uterine fibroids. Unlike some other treatments, it is taken orally and specifically targets the hormonal aspect of fibroid growth. ^{1 3 8 9 10}

Research Team

Vanessa Jacoby, MD, MAS

Principal Investigator

University of California, San Francisco

Alison Huang, MD, MAS, MPhil

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for premenopausal women aged 21-54 who have confirmed uterine fibroids with symptoms like heavy bleeding, pelvic discomfort, or urinary issues. Participants must have regular menstrual cycles and agree to use non-hormonal contraception if sexually active.

Inclusion Criteria

If you are at risk of getting pregnant, you agree to use a non-hormonal barrier method of birth control during the study.

I experience heavy bleeding, pelvic discomfort, or pain during sex due to fibroids.

My menstrual cycles are regular, lasting 21 to 38 days and no longer than 14 days for the last 3 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either oral letrozole 2.5mg/day or placebo for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Letrozole (Hormone Therapy)

Trial Overview The PLUM Study is testing the effectiveness of Letrozole (2.5mg) compared to a placebo in reducing symptoms related to uterine fibroids and improving quality of life, as well as decreasing the size of leiomyoma and the uterus itself.

Participant Groups

Group I: Letrozole Experimental Treatment 1 Intervention

Oral letrozole 2.5mg/day

Group II: Placebo and Letrozole Placebo Group 2 Interventions

Placebo capsule for 12 weeks; Oral letrozole 2.5mg/day for 12 weeks

Letrozole is already approved in Canada for the following indications:

Approved in Canada as Letrozole for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

Letrozole is more effective than tamoxifen for adjuvant therapy in postmenopausal women with hormone-responsive early breast cancer, and it is well tolerated by patients.

Extended therapy with letrozole after tamoxifen treatment is more effective than placebo, making it a valuable treatment option while ongoing trials investigate the best duration and comparison with other aromatase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer. Keating, GM.[2021]

In a study involving BALB/c female mice, letrozole (Ltz) did not demonstrate antiestrogenic effects in preventing endometrial hyperplasia induced by carcinogen and estrogen, as both Ltz and estrogen treatments resulted in higher incidences of hyperplasia compared to the control group.

The combination of medroxyprogesterone acetate (MPA) showed a protective effect against endometrial hyperplasia, indicating that Ltz may not be effective in this context, as it did not reduce the severity of lesions compared to MPA treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of letrozole in carcinogen-plus-estrogen-induced endometrial hyperplasia in mice. Lara, AC., Cândido, EB., Vidigal, PV., et al.[2019]

In a study of 39 patients undergoing HIFU ablation for uterine fibroids, letrozole pretreatment showed improved energy and treatment efficiency compared to no medication and GnRHa, particularly for larger fibroids over 10 cm.

While GnRHa resulted in a greater volume reduction of fibroids (38.6% vs. 16.4% for letrozole), it also led to more hypoestrogenic symptoms and longer treatment times, suggesting letrozole may be a safer and more efficient option for certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole as premedication of high intensity focused ultrasound treatment of uterine fibroids: A retrospective observation study. Chen, WC., Hsu, CC., Huang, HJ., et al.[2022]

Letrozole is an effective aromatase inhibitor for postmenopausal women with hormone-sensitive breast cancer, showing significant tumor reduction and well-tolerated at low daily doses, as confirmed by recent phase III clinical studies.

It has demonstrated superior efficacy and lower toxicity compared to tamoxifen in first-line therapy for advanced breast cancer, and is also a viable option for second-line treatment after tamoxifen failure, with potential benefits in early breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of letrozole (Femara(R)) in breast cancer therapy: A clinical review. Crucitta, E., Locopo, N., Silvestris, N., et al.[2019]

Letrozole, a type 2 aromatase inhibitor, effectively reduces estrogen levels in postmenopausal women, leading to improved disease-free survival in breast cancer patients compared to other treatments like tamoxifen.

The drug is generally well-tolerated, though it may cause side effects such as hot flushes, joint pain, and a potential increased risk of fractures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: advancing hormone therapy in breast cancer. Lee, RJ., Armstrong, AC., Wardley, AM.[2018]

Letrozole and anastrozole significantly increased apoptosis in epithelial endometrial cells from patients with endometriosis, particularly at higher concentrations (10 nM for Letrozole and 100-500 nM for Anastrozole).

Both drugs also reduced cell proliferation in these cells, indicating their potential as effective treatments for endometriosis by promoting cell death and inhibiting growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of aromatase inhibitors on proliferation and apoptosis in eutopic endometrial cell cultures from patients with endometriosis. Meresman, GF., Bilotas, M., Abello, V., et al.[2006]

Letrozole is a new non-steroidal aromatase inhibitor approved in Japan for treating postmenopausal women with breast cancer, particularly effective for those with steroid receptor positive or receptor-unknown locally advanced or metastatic cases.

The drug is generally well-tolerated, with mostly mild side effects such as hot flashes and fatigue, and has shown beneficial results in large international studies for post-surgical endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. Tsukagoshi, S.[2018]

Letrozole, a non-steroidal aromatase inhibitor, significantly reduced the size of uterine leiomyomas in 16 premenopausal women over a 3-month treatment period, improving symptoms like heavy menstrual bleeding.

The treatment did not negatively impact bone mineral density, suggesting that letrozole may be a safe option for managing uterine leiomyomas, although further research with larger trials is necessary to confirm its overall safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of symptomatic uterine leiomyoma with letrozole. Gurates, B., Parmaksiz, C., Kilic, G., et al.[2022]

Letrozole, an aromatase inhibitor, was effective in treating endometrial hyperplasia in a small case series of five premenopausal women, with no evidence of hyperplasia or atypia after 3 months of treatment.

All patients showed low serum levels of estradiol, suggesting that letrozole effectively reduces estrogen levels, which may contribute to its therapeutic action; however, further studies are necessary to confirm its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole as primary therapy for endometrial hyperplasia in young women. Li, HZ., Chen, XN., Qiao, J.[2018]

In a small randomized phase II study involving 9 patients with newly diagnosed uterine leiomyosarcoma, letrozole showed promising results, with a median progression-free survival (PFS) not reached compared to 17.3 months in the observation group.

Patients receiving letrozole had a 100% progression-free rate at 12 months and maintained a significant advantage over the observation group, suggesting that letrozole may be a potential adjuvant therapy for early-stage uLMS, although further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of letrozole vs. observation in patients with newly diagnosed uterine leiomyosarcoma (uLMS). Slomovitz, BM., Taub, MC., Huang, M., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer. [2021]

2. Brazil pubmed.ncbi.nlm.nih.gov

Effect of letrozole in carcinogen-plus-estrogen-induced endometrial hyperplasia in mice. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Letrozole as premedication of high intensity focused ultrasound treatment of uterine fibroids: A retrospective observation study. [2022]

4. Spain pubmed.ncbi.nlm.nih.gov

The role of letrozole (Femara(R)) in breast cancer therapy: A clinical review. [2019]

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

Letrozole: advancing hormone therapy in breast cancer. [2018]

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

Effects of aromatase inhibitors on proliferation and apoptosis in eutopic endometrial cell cultures from patients with endometriosis. [2006]

7. Japan pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of symptomatic uterine leiomyoma with letrozole. [2022]

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

Letrozole as primary therapy for endometrial hyperplasia in young women. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A randomized phase II study of letrozole vs. observation in patients with newly diagnosed uterine leiomyosarcoma (uLMS). [2022]