Avutometinib + Defactinib + Letrozole for Ovarian Cancer

(CHAMELEON Trial)

Recruiting at 7 trial locations

Overseen By Chrisann Kyi, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Warfarin, Strong CYP3A4, others

Disqualifiers: Prior systemic therapy, Major surgery, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

20 Participants Needed

Trial Summary

What is the purpose of this trial?

The researchers are doing this study to find out whether the combination of avutometinib, defactinib, and letrozole is an effective treatment for people with low-grade serous ovarian cancer (LGSOC). The researchers will also look at the safety of this combination.

Will I have to stop taking my current medications?

The trial requires that you avoid certain medications, supplements, and foods that can interact with the study drugs, specifically those that are strong CYP3A4 or CYP2C9 inhibitors or inducers, and P-glycoprotein inhibitors or inducers. You should discuss your current medications with the study team to determine if any changes are needed.

What data supports the effectiveness of the drug combination Avutometinib, Defactinib, and Letrozole for ovarian cancer?

Research shows that Letrozole, one of the drugs in the combination, has been effective in treating certain types of ovarian cancer, especially in patients with estrogen receptor-positive cancer. It has been shown to help control the disease and extend the time before the cancer returns. ^{1 2 3 4 5}

What safety information is available for the drugs Avutometinib, Defactinib, and Letrozole?

Letrozole has been studied for safety in various conditions, including breast and ovarian cancer. It may increase the risk of bone fractures and osteoporosis (weakening of bones), and there is a higher chance of heart attacks compared to some other treatments. Lipid-lowering medications were needed for some patients on letrozole. ^{2 5 6 7 8}

What makes the drug combination Avutometinib, Defactinib, and Letrozole unique for ovarian cancer?

This drug combination is unique because it includes Letrozole, which is not a standard treatment for ovarian cancer but has shown promise in prolonging disease control in certain cases. Letrozole is typically used for hormone-sensitive breast cancer, and its use in ovarian cancer is still being explored, making this combination a novel approach. ^{2 3 5 7 9}

Research Team

Rachel Grisham, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for individuals with low-grade serous ovarian cancer. Participants should meet specific health criteria set by the researchers, but these details are not provided here.

Inclusion Criteria

A specialist decided surgery isn't my first treatment option, or surgery didn't remove all my cancer.

I am HIV positive, on treatment, and my viral load is undetectable.

I have another cancer, but it won't affect this cancer treatment's safety or results.

Exclusion Criteria

I am allergic to ingredients in the trial medication.

I am currently breastfeeding.

I have had rhabdomyolysis in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avutometinib, defactinib, and letrozole. Avutometinib is administered 3.2 mg PO twice weekly, defactinib 200 mg PO BID for 3 weeks followed by a 1-week rest period in each 4-week cycle, and letrozole 2.5 mg PO daily. Pre/perimenopausal patients receive leuprolide acetate for ovarian suppression.

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Avutometinib
• Defactinib
• Letrozole

Trial Overview The study tests a combination of three drugs: Avutometinib, Defactinib, and Letrozole to see if they're effective in treating low-grade serous ovarian cancer.

Participant Groups

Group I: Avutometinib, Defactinib, and Letrozole Experimental Treatment 3 Interventions

Enrolled patients will be treated with avutometinib 3.2 mg PO, twice weekly (e.g. M/Th,Tu/F, or W/Sa) + defactinib 200 mg PO BID for 3 weeks, followed by a 1 week rest period, in each 4-week (28 day) cycle. Patients will also be treated with letrozole 2.5 mg PO daily, and pre/perimenopausal patients will also receive leuprolide acetate 3.75 mg subcutaneously every 4 weeks or 11.25 mg every 3 months for ovarian suppression while an ovary remains in situ.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Findings from Research

In a phase II study of 42 ER-positive ovarian cancer patients treated with letrozole, 17% showed a significant response in CA125 levels, indicating some efficacy of the drug in this specific patient group.

The study identified predictive markers, such as low HER2 expression, that may help determine which patients are more likely to respond to letrozole treatment, highlighting the potential for personalized therapy in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. Smyth, JF., Gourley, C., Walker, G., et al.[2022]

In a phase II study involving 33 women with recurrent estrogen receptor-positive ovarian cancer, letrozole showed a clinical benefit in 26% of patients, with one achieving a partial response and seven having stable disease.

Letrozole was well-tolerated, with no severe toxicities reported, and the most common side effects were mild, such as fatigue and sweating, indicating a favorable safety profile for this treatment in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum. Ramirez, PT., Schmeler, KM., Milam, MR., et al.[2018]

Letrozole shows promise in managing ovarian cancer, particularly in low-grade serous ovarian cancer, by prolonging recurrence-free intervals and providing disease control in recurrent cases.

The drug has a favorable toxicity profile, but further research is needed to identify the best patient populations and treatment settings for its use in ovarian cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole in the management of advanced ovarian cancer: an old drug as a new targeted therapy. Marchetti, C., De Felice, F., Ergasti, R., et al.[2021]

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 phase II trial involving 27 women with relapsed or recurrent epithelial ovarian cancer, oral letrozole showed some activity, achieving a 15% objective response rate with one complete and two partial responses among patients with measurable disease.

Letrozole was generally well tolerated, indicating limited toxicity; however, there was no correlation between treatment response and the presence of estrogen or progesterone receptors, suggesting that its mechanism of action needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study. Papadimitriou, CA., Markaki, S., Siapkaras, J., et al.[2018]

In a Phase II trial involving 60 patients with relapsed ovarian cancer, letrozole treatment led to disease stabilization in 10 patients for at least 12 weeks, although no complete or partial responses were observed.

Higher levels of estrogen and progesterone receptors in tumors were significantly associated with stable disease, suggesting that letrozole may be effective for a subset of patients with endocrine-sensitive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup. Bowman, A., Gabra, H., Langdon, SP., et al.[2018]

Letrozole has been fully approved by the FDA for treating postmenopausal women with hormone receptor-positive early breast cancer, showing a significant improvement in disease-free survival compared to tamoxifen, with a hazard ratio of 0.87 in the adjuvant trial.

While letrozole is effective, it is associated with a higher risk of bone fractures and myocardial infarction compared to tamoxifen, which has its own risks such as endometrial cancer and thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. Cohen, MH., Johnson, JR., Justice, R., et al.[2021]

The FACE trial is a large-scale study involving 4000 postmenopausal women with hormone receptor-positive, node-positive breast cancer, comparing the efficacy and safety of letrozole and anastrozole over a treatment period of up to 5 years.

The primary goal of the trial is to assess disease-free survival (DFS), while secondary objectives include evaluating overall survival (OS) and the time to distant metastases, which will provide comprehensive insights into the effectiveness of both treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FACE trial: letrozole or anastrozole as initial adjuvant therapy? Jonat, W., Mundhenke, C.[2018]

Letrozole is an effective treatment for postmenopausal women with early-stage or advanced hormone-sensitive breast cancer, showing a 43% reduction in disease recurrences when used as extended adjuvant therapy beyond standard tamoxifen treatment.

In advanced breast cancer, letrozole outperformed tamoxifen in terms of time to disease progression (9.4 months vs. 6.0 months) and has a similar tolerability profile, making it a recommended first-line therapy according to treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. Simpson, D., Curran, MP., Perry, CM.[2018]

References

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

Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. [2022]

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

Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Letrozole in the management of advanced ovarian cancer: an old drug as a new targeted therapy. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study. [2018]

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

CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. [2021]

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

The FACE trial: letrozole or anastrozole as initial adjuvant therapy? [2018]

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

Letrozole: a review of its use in postmenopausal women with breast cancer. [2018]