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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of three drugs—avutometinib (VS-6766), defactinib (VS-6063), and letrozole (Femara)—can effectively treat low-grade serous ovarian cancer, a type of ovarian cancer with slow-growing tumors. Researchers are also assessing the safety of this treatment mix for patients. Women diagnosed with low-grade serous ovarian cancer who are not candidates for primary surgery might be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

A previous study found the combination of avutometinib and defactinib to be safe for patients with recurring ovarian cancer, meaning most patients tolerated the treatment well. While some side effects occurred, they were generally manageable. Research shows that this combination is effective for many patients, indicating it is both effective and reasonably safe.

Letrozole, a medicine often used for breast cancer, is part of this combination. It is well-known and generally considered safe, with common side effects like hot flashes and joint pain.

Overall, the available data suggest that the combination treatment is safe for most patients, with manageable side effects. However, individual experiences may vary, and discussing any concerns with the study team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of avutometinib, defactinib, and letrozole for treating ovarian cancer because it offers a novel approach compared to standard chemotherapy and hormone therapy. Avutometinib and defactinib work together to target specific pathways that help cancer cells survive and spread, potentially enhancing the effectiveness of letrozole, a hormone therapy. This combination aims to attack the cancer on multiple fronts, possibly leading to better outcomes than current treatments that often focus on a single pathway. By suppressing ovarian function in pre/perimenopausal patients, this regimen is tailored to maximize the treatment's effectiveness, offering hope for improved results.

What evidence suggests that this combination treatment could be effective for low-grade serous ovarian cancer?

Research has shown that combining the drugs avutometinib and defactinib may effectively treat low-grade serous ovarian cancer. One study found that nearly half of the patients (46%) experienced a positive and lasting response to this treatment. In this trial, participants will receive a combination of avutometinib, defactinib, and letrozole, a drug often used in hormone therapies, which might enhance the treatment's effectiveness. While these results are encouraging, further research is needed to fully understand the efficacy of this combination. ^{2 3 6 7 8}

Who Is on the Research Team?

Rachel Grisham, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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