Narazaciclib + Letrozole for Endometrial Cancer

Recruiting at 7 trial locations

Overseen By Victor Moyo, MD

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Traws Pharma, Inc.

Must be taking: Letrozole

Must not be taking: CDK 4/6 inhibitors

Disqualifiers: Other cancers, Heart disease, Infections, others

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

Compensation: Varies

Number of Visits: 1

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests narazaciclib with letrozole in patients with recurring and spreading gynecologic cancers. It aims to find the safest and most effective dose of narazaciclib. The combination works by directly attacking cancer cells and reducing hormone levels that help these cells grow.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take strong inducers and inhibitors of certain liver enzymes (CYP2C8 and CYP3A4) within 5 half-lives before starting the trial.

What data supports the effectiveness of the drug combination Narazaciclib and Letrozole for endometrial cancer?

Research shows that letrozole, an aromatase inhibitor, has been effective in treating endometrial cancer by affecting hormone levels. Additionally, a study combining letrozole with another drug, ribociclib, showed positive results in patients with relapsed estrogen receptor-positive endometrial cancer, suggesting potential benefits of combining letrozole with other drugs. ^{1 2 3 4 5}

What safety data exists for the treatment with Narazaciclib and Letrozole?

Letrozole, also known as Femara, has been studied for safety in various conditions, including endometrial cancer and endometriosis. It has been used in combination with other treatments and generally shows a safety profile that is acceptable for clinical use, although specific safety data for Narazaciclib is not provided in the available research. ^{1 2 4 5 6}

How is the drug Narazaciclib + Letrozole unique for treating endometrial cancer?

This treatment combines Narazaciclib with Letrozole, an aromatase inhibitor that reduces estrogen levels, which can help slow the growth of endometrial cancer. The combination is novel as it may enhance the effectiveness of Letrozole by targeting cancer cells in a new way, potentially offering a more effective option compared to Letrozole alone. ^{1 2 5 7 8}

Research Team

Victor Moyo, MD

Principal Investigator

Onconova Therapeutics

Eligibility Criteria

This trial is for adults with recurrent metastatic low-grade endometrioid endometrial cancer who can swallow pills, have had up to two prior systemic treatments (excluding certain therapies), and whose major organs function well. They must not be pregnant, agree to use contraception if applicable, and have a life expectancy of at least 12 weeks.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My endometrial cancer is low-grade and mostly endometrioid.

I have previously received immunotherapy for my cancer, if it was available and not advised against for me.

Exclusion Criteria

My cancer is not related to the uterus or other female reproductive organs.

My cancer is not a low-grade or early-stage type.

I do not have any serious heart conditions that are not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase 1 Treatment

Eligible patients are enrolled in escalating dose cohorts of narazaciclib in combination with letrozole in 28-day cycles to determine the maximum tolerated dose and recommended phase 2 dose.

28 days per cycle

Multiple visits per cycle for dose escalation and monitoring

Phase 2a Treatment

Patients receive narazaciclib and letrozole at the recommended phase 2 dose in 28-day cycles until disease progression, withdrawal, or unacceptable toxicity.

Until disease progression or withdrawal

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival assessments.

Up to 2 years after end of treatment

Periodic visits for follow-up assessments

Treatment Details

Interventions

• Letrozole
• Narazaciclib

Trial Overview The study tests increasing doses of narazaciclib combined with a standard dose of letrozole in patients with specific gynecologic cancers. It aims to determine the safety and effectiveness of this combination treatment.

Participant Groups

Group I: Escalating daily doses of narazaciclib in combination with letrozole (2.5mg day) Experimental Treatment 2 Interventions

Phase 1: Initiating at 160mg per day of narazaciclib, patients will receive escalating doses of narazaciclib (oral tablets/once daily) in combination with 2.5mg of letrozole (oral tablet/once daily). Phase 2: All patients will receive the recommended phase 2 dose (RP2D) of the combination of narazaciclib (oral tablets) and letrozole (oral tablet/QD)

Letrozole is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Femara for:

• Breast cancer in postmenopausal women
• Increasing the chance of ovulation in women with polycystic ovary syndrome

Approved in European Union as Letrozole for:

• Early breast cancer in postmenopausal women
• Advanced breast cancer in postmenopausal women

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?

Traws Pharma, Inc.

Lead Sponsor

Trials

34

Recruited

1,800+

Onconova Therapeutics, Inc.

Lead Sponsor

Trials

32

Recruited

1,700+

Findings from Research

In a study of 10 post-menopausal patients with endometrial cancer, short-term treatment with letrozole was well-tolerated and led to a significant 37.8% reduction in blood estradiol levels, indicating its effectiveness in lowering estrogen levels.

The treatment also resulted in notable clinical improvements, such as pain relief and a 31.1% decrease in endometrial ultrasound signal, suggesting potential benefits in managing endometrial cancer before surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant therapy of endometrial cancer with the aromatase inhibitor letrozole: endocrine and clinical effects. Berstein, L., Maximov, S., Gershfeld, E., et al.[2019]

In a study of 29 young women with early endometrial carcinoma (EC) and complex atypical hyperplasia (CAH), 88.2% of EC patients and 100% of CAH patients achieved complete response after treatment with gonadotropin-releasing hormone agonist (GnRHa) combined with either a levonorgestrel-releasing intrauterine system or letrozole.

Both treatment combinations were effective for fertility preservation, with a median time to complete response of around 4.5 to 5 months, suggesting they are viable options for young women with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women. Zhou, H., Cao, D., Yang, J., et al.[2018]

The phase III RUBY and NRG-GY018 trials demonstrated that women with newly diagnosed or first-recurrent advanced endometrial cancer benefit from combining a PD-1 inhibitor (dostarlimab or pembrolizumab) with standard chemotherapy.

This combination treatment significantly prolonged progression-free survival, and there was a positive trend in overall survival, indicating its potential effectiveness in managing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ICI-Chemo New Standard for Endometrial Cancer. [2023]

In a phase II clinical trial involving 40 patients with relapsed ER-positive ovarian and endometrial cancer, the combination of ribociclib and letrozole showed promising efficacy, with a progression-free survival (PFS) rate of 55% at 12 weeks for endometrial cancer and 50% for ovarian cancer.

The treatment was particularly effective in low-grade serous ovarian cancer, where all three patients experienced a PFS of 24 weeks or more, highlighting the potential of this combination therapy for specific cancer subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers. Colon-Otero, G., Zanfagnin, V., Hou, X., et al.[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]

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]

Anastrozole treatment in endometrial cancer patients led to the most frequent pain relief and significant reductions in endometrial wall thickness in 60% of patients, indicating its potential efficacy as a neoadjuvant therapy.

Both anastrozole and letrozole resulted in substantial decreases in intratumoral aromatase and blood estradiol levels, while exemestane was associated with lower progesterone receptor levels, suggesting different mechanisms of action among the aromatase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma]. Bershteĭn, LM., Danilova, MA., Kovalevskiĭ, AIu., et al.[2018]

In a study of 179 women with endometrial carcinoma or atypical endometrial hyperplasia, 94.4% achieved complete remission using gonadotropin-releasing hormone agonist (GnRHa) combined with either a levonorgestrel-releasing intrauterine device (LNG-IUD) or letrozole, demonstrating high efficacy in preserving fertility.

The median time to complete remission was 6 months, and among those who achieved remission, 32.3% became pregnant, indicating that this treatment not only effectively addresses cancer but also supports reproductive goals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncological and reproductive outcomes for gonadotropin-releasing hormone agonist combined with aromatase inhibitors or levonorgestrel-releasing intra-uterine system in women with endometrial cancer or atypical endometrial hyperplasia. Chen, J., Cao, D., Yang, J., et al.[2023]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant therapy of endometrial cancer with the aromatase inhibitor letrozole: endocrine and clinical effects. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women. [2018]

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

ICI-Chemo New Standard for Endometrial Cancer. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers. [2021]

5. Brazil pubmed.ncbi.nlm.nih.gov

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

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. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma]. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Oncological and reproductive outcomes for gonadotropin-releasing hormone agonist combined with aromatase inhibitors or levonorgestrel-releasing intra-uterine system in women with endometrial cancer or atypical endometrial hyperplasia. [2023]