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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of medications, narazaciclib (an experimental treatment) and letrozole, to determine their safety and effectiveness in treating certain types of endometrial and gynecologic cancers. It targets individuals with recurrent or advanced endometrial cancer that persists or has spread. Eligible participants may include those with low-grade endometrial cancer who have not responded to other treatments. The study involves gradually increasing the dose of narazaciclib while maintaining a standard dose of letrozole to assess patient tolerance. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants the chance to contribute to groundbreaking cancer treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is examining the safety of using a combination of two drugs, narazaciclib and letrozole, to treat certain types of cancer. Letrozole is a well-known drug for some breast cancers, often used with other treatments, and much is known about its safety.

Narazaciclib, however, remains under study. Previous research has tested narazaciclib alone and with letrozole to assess patient tolerance and potential side effects. As the current study is in its early stages, researchers continue to gather important details about its safety and side effects.

Since this combination is being tested for a new purpose, ongoing trials are crucial for confirming its safety. Participants might experience side effects, so staying informed and maintaining contact with the study team is important for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of narazaciclib and letrozole for endometrial cancer because it offers a potentially new way to tackle the disease. Unlike standard treatments that mainly focus on hormone therapy alone, narazaciclib introduces a novel mechanism by targeting specific proteins involved in cancer cell growth, potentially enhancing the effectiveness of letrozole. This dual approach not only aims to inhibit tumor growth more effectively but also hopes to provide an option for patients who may not respond well to current treatments. By combining these two drugs, there's potential for improved outcomes and a new lifeline for patients with this type of cancer.

What evidence suggests that this trial's treatments could be effective for endometrial cancer?

Research has shown that using narazaciclib with letrozole might help treat low-grade endometrioid endometrial cancer. Letrozole is already known to fight cancer, especially when combined with drugs that block certain proteins (CDK 4/6) that promote cell growth. Narazaciclib is one of these blocking drugs. Early studies found that combining letrozole with these blockers can slow cancer growth. This trial will test the combination of narazaciclib and letrozole to target cancer cells more precisely, potentially leading to better patient outcomes. ^{1 3 6 7 8}

Who Is on the Research Team?

Victor Moyo, MD

Principal Investigator

Onconova Therapeutics

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05705505?term=NARAZACICLIB&rank=2

Study of Narazaciclib (ON 123300) Plus Letrozole in ... This study will assess the safety and efficacy of increasing doses of narazaciclib (ON 123300) in combination with the standard daily dose (2.5mg) of letrozole ...

2. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/391453

Study of Narazaciclib (ON 123300) Plus Letrozole in ... This study will assess the safety and efficacy of increasing doses of narazaciclib (ON 123300) in combination with the standard daily dose (2.5mg) of ...

3. clin.larvol.com clin.larvol.com/trial-detail/NCT05705505

Study of Narazaciclib (ON 123300) Plus Letrozole in ... Narazaciclib, evaluated as a monotherapy and in combination with letrozole in patients with recurrent metastatic low-grade endometrioid endometrial cancer and ...

4. biospace.com biospace.com/onconova-therapeutics-doses-first-patient-in-phase-1-2a-trial-of-narazaciclib-combined-with-letrozole-in-endometrial-cancer

Onconova Therapeutics Doses First Patient in Phase 1/2a ... Data from prior randomized and single-arm trials have demonstrated the anti-cancer activity of letrozole combined with CDK 4/6 inhibition in ...

5. onclive.com onclive.com/view/clinical-trials-in-endometrial-cancer-need-improved-diversity-to-address-rising-mortality-rates

Clinical Trials in Endometrial Cancer Need Improved ... Additionally, we have a [phase 1/2] trial [NCT05705505] evaluating a novel CDK4/6 inhibitor with narazaciclib [ON 123300] and letrozole in low- ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-02651

Study of Narazaciclib (ON 123300) Plus Letrozole in ... This study will assess the safety and efficacy of increasing doses of narazaciclib (ON 123300) in combination with the standard daily dose (2.5mg) of ...

7. firstwordpharma.com firstwordpharma.com/story/5738916

Onconova Therapeutics Doses First Patient in Phase 1/2a ... Data from prior randomized and single-arm trials have demonstrated the anti-cancer activity of letrozole combined with CDK 4/6 inhibition in ...

8. investor.onconova.com investor.onconova.com/node/14436/pdf

Onconova Therapeutics Announces Plans for a Phase 1/2a Trial ... trial of narazaciclib combined with letrozole in recurrent metastatic low-grade endometrioid endometrial cancer (LGEEC). In addition, the Company reported ...