Trametinib for Ovarian Cancer

Recruiting at 584 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to progression

260 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back (recurrent), become worse (progressive), or spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.

Will I have to stop taking my current medications?

The trial requires that any hormonal therapy directed at the tumor be stopped at least one week before joining, and any other cancer treatments, including chemotherapy and radiation, must be stopped at least four weeks before joining. Herbal supplements are also not allowed during the study.

What data supports the effectiveness of the drug Trametinib for ovarian cancer?

Research shows that Trametinib, a MEK1/2 inhibitor, increases progression-free survival from 7.2 months to 13 months in women with recurrent low-grade serous ovarian cancer and boosts the overall response rate from 6% to 26%. ^{1 2 3 4 5}

Is trametinib safe for use in humans?

Trametinib has been studied in various trials and is generally considered safe, with safety results aligning with its known profile. In one study, no serious adverse events led to withdrawal, and in another, some patients experienced severe treatment-related side effects, but these were managed with dose adjustments. ^{1 6 7 8 9}

How is the drug trametinib unique for treating ovarian cancer?

Trametinib is unique for treating low-grade serous ovarian cancer because it targets the MEK1/2 proteins in the MAPK pathway, which is often altered in these tumors, and it has shown to significantly increase progression-free survival compared to standard treatments. ^{1 2 10 11 12}

Research Team

David M Gershenson

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for patients with recurrent or progressive low-grade ovarian cancer or peritoneal cavity cancer who have previously undergone at least one platinum-based chemotherapy. They must not have received certain inhibitor therapies, be able to swallow oral medication, and meet specific health criteria including organ function tests. Pregnant women, nursing mothers, and those with serious medical risks are excluded.

Inclusion Criteria

I stopped my cancer hormone therapy at least a week ago.

I stopped any cancer treatments like chemo or radiation 4 weeks ago.

I am following the birth control and pregnancy guidelines for Trametinib.

Exclusion Criteria

I have not been treated with MEK, KRAS, or BRAF inhibitors.

I need medication that can affect my heart's rhythm.

Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients, or to DMSO, or to Cremophor EL

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either trametinib or a clinician's choice of standard therapy. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle, up to progression

Multiple visits per cycle for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

2 years every 3 months, 3 years every 6 months, then annually for 5 years

Regular follow-up visits

Treatment Details

Interventions

• Trametinib

Trial Overview The effectiveness of trametinib is being compared to standard treatments (letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin hydrochloride or topotecan) in this phase II/III trial. Trametinib aims to inhibit enzymes needed for tumor cell growth and its performance will be measured against existing therapies.

Participant Groups

Group I: Arm B (trametinib) Experimental Treatment 2 Interventions

Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (letrozole, tamoxifen, paclitaxel, PLD, topotecan) Active Control 7 Interventions

Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

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

Approved in European Union as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in United States as Mekinist for:

• Melanoma
• Non-small cell lung cancer
• Thyroid cancer

Approved in Canada as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in Japan as Mekinist for:

• Melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Findings from Research

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

In a phase 3 trial involving 36 patients with untreated BRAF V600-mutant metastatic melanoma, the combination of spartalizumab, dabrafenib, and trametinib resulted in a high objective response rate of 78%, with 44% achieving complete responses.

While the treatment showed promising efficacy, 72% of patients experienced severe treatment-related adverse events, and 17% had to permanently discontinue the therapy due to these side effects, highlighting the need for careful monitoring and management of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Dummer, R., Lebbé, C., Atkinson, V., et al.[2022]

References

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

Rare Ovarian Cancer's First Positive Trial. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Impressive and durable clinical responses obtained with dabrafenib and trametinib in low-grade serous ovarian cancer harbouring a BRAF V600E mutation. [2022]

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

Differences in MEK inhibitor efficacy in molecularly characterized low-grade serous ovarian cancer cell lines. [2022]

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

Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. [2022]

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

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors. [2021]

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

Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Dual Fulvestrant-Trametinib Therapy in Recurrent Low-Grade Serous Ovarian Cancer. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. [2023]

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

Imatinib mesylate in combination with docetaxel for the treatment of patients with advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis : a Hoosier Oncology Group trial. [2020]