Immunotherapy + Radiation + Chemotherapy for Endometrial Cancer

(FIERCE Trial)

Not currently recruiting at 1 trial location

Overseen By Lead Gyn Nurse

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: University of Oklahoma

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Recurrent disease, Prior radiation, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for endometrial cancer, which affects the lining of the uterus. The goal is to determine if combining the immunotherapy drug pembrolizumab with radiation and chemotherapy (carboplatin and paclitaxel) is safe and practical. It targets individuals who have had a hysterectomy and have specific types of endometrial cancer confined to the uterus or nearby areas. Participants should not have recurrent disease or previous pelvic radiation therapy. This trial may suit those recently diagnosed and seeking new treatment options. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain treatments like systemic anti-cancer therapy, immunosuppressive therapy, or have received a live vaccine recently, you may need to stop or adjust those before joining. It's best to discuss your specific medications with the trial team.

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

Research has shown that pembrolizumab is usually well-tolerated. In studies with patients who have endometrial cancer, it demonstrated side effects that are generally mild to moderate and manageable, whether used alone or with other treatments.

Vaginal cuff brachytherapy, a type of targeted radiation therapy, effectively controls early-stage cancer with minimal side effects. It helps reduce the risk of cancer returning in the treated area.

Carboplatin and paclitaxel, chemotherapy drugs with a strong safety record, are often used to treat various cancers, including endometrial cancer. Most patients tolerate these drugs well, and any side effects are usually manageable.

This trial is in its early stages, so detailed safety data from this specific trial might not be available yet. However, the treatments used here have a history of being generally safe when administered under medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for endometrial cancer because it combines immunotherapy, radiation, and chemotherapy in a novel way. Pembrolizumab, a key player in this regimen, is an immunotherapy that helps the immune system recognize and attack cancer cells more effectively. This approach is different from standard treatments, which typically involve only chemotherapy and radiation, by potentially boosting the effectiveness of each component through their combined action. By administering pembrolizumab before and during chemotherapy and radiation, the treatment aims to enhance the overall response and control of the cancer, which could lead to improved outcomes for patients.

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

In this trial, participants will receive a combination of treatments, including pembrolizumab, a type of immunotherapy that has shown promising results for advanced endometrial cancer. Research indicates that combining pembrolizumab with chemotherapy can extend the time patients live without their cancer worsening from 8.7 months to 13.1 months. Additionally, vaginal cuff brachytherapy, a targeted form of radiation, has proven effective in early-stage endometrial cancer, improving survival rates with few side effects. The chemotherapy drugs carboplatin and paclitaxel, also included in this trial, have been shown to shrink tumors in 50% of patients with recurring endometrial cancer. Together, these treatments offer a comprehensive approach to fighting endometrial cancer and provide a strong foundation for ongoing research and trials. ^{1 3 5 6 7}

Who Is on the Research Team?

Christina Washington, MD

Principal Investigator

Stephenson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with high-risk endometrial cancer, who've had a hysterectomy (removal of the uterus), and possibly other surgeries like removal of ovaries or lymph nodes. They should not have received recent cancer treatments, live vaccines, or have active infections. People with certain serious health conditions or those pregnant are excluded.

Inclusion Criteria

My condition is Stage II endometrial cancer with cervical involvement.

My nerve damage is mild or not noticeable.

The participant (or legally acceptable representative if applicable) provides written informed consent for the trial and authorization permitting release of personal health information.

Exclusion Criteria

I have had or currently have lung inflammation treated with steroids.

Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

You have a severe allergic reaction (Grade 3 or higher) to pembrolizumab or any of its ingredients.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Pembrolizumab is given 7 days prior to radiation therapy (vaginal cuff brachytherapy)

1 week

Chemotherapy

Three cycles of pembrolizumab combined with Carboplatin/Paclitaxel chemotherapy

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Paclitaxel
• Pembrolizumab
• Vaginal cuff brachytherapy (VCB)

Trial Overview The study tests pembrolizumab (an immunotherapy drug) combined with vaginal cuff brachytherapy (targeted radiation therapy) followed by chemotherapy using paclitaxel and carboplatin in patients with high-risk endometrial cancer to see if this approach is effective.

How Is the Trial Designed?

Group I: Pembrolizumab + Radiation Therapy + Pembrolizumab/Chemotherapy Experimental Treatment 4 Interventions

Pembrolizumab given 7 days prior to radiation therapy (e.g., vaginal cuff brachytherapy) followed by three cycles pembrolizumab combined with Carboplatin/Paclitaxel chemotherapy

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a study of 25 patients with stage I-II serous endometrial cancer, the combination of surgery, intravaginal radiation therapy (IVRT), and chemotherapy (carboplatin/paclitaxel) was well tolerated, with 88% completing all 6 cycles of chemotherapy and only 4% experiencing severe toxicity.

The treatment resulted in a high 5-year progression-free and overall survival rate of 88%, with no cases of vaginal recurrence reported, suggesting that this approach is effective for early-stage serous endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent carboplatin/paclitaxel and intravaginal radiation in surgical stage I-II serous endometrial cancer. Alektiar, KM., Makker, V., Abu-Rustum, NR., et al.[2021]

In a study of 37 patients with advanced or recurrent endometrial carcinoma, the combination of paclitaxel and carboplatin resulted in a 61% objective response rate, including one complete response and ten partial responses, indicating its efficacy in treating this cancer.

While the treatment was effective, it was associated with significant hematologic toxicity, with 59% of patients experiencing grade 3 or 4 leukopenia and 86% experiencing neutropenia, highlighting the need for monitoring and potential supportive care during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. Arimoto, T., Nakagawa, S., Yasugi, T., et al.[2015]

In a phase 3 trial involving 816 patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy (paclitaxel plus carboplatin) significantly improved progression-free survival, especially in patients with mismatch repair-deficient (dMMR) tumors, showing a 70% reduction in the risk of progression or death.

For patients with mismatch repair-proficient (pMMR) tumors, pembrolizumab also enhanced progression-free survival compared to placebo, indicating its efficacy across different tumor types, while the safety profile was consistent with known effects of pembrolizumab and chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. Eskander, RN., Sill, MW., Beffa, L., et al.[2023]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a study of 122 patients with high and intermediate-high risk endometrial cancer, those treated with a dose dense regimen of paclitaxel plus carboplatin showed a significantly higher three-year progression-free survival (79.5%) compared to those on the standard three-weekly protocol (57.4%).

The dose dense protocol also resulted in fewer progression events and distant metastases, along with improved overall survival in advanced stage cases, while experiencing fewer complaints of musculoskeletal pain compared to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose dense carboplatin paclitaxel improves progression free survival in patients with endometrial cancer. Kogan, L., Laskov, I., Amajoud, Z., et al.[2022]

In a review of three studies involving 1,431 patients, the addition of PD-1/PD-L1 inhibitors to standard chemotherapy (carboplatin and paclitaxel) significantly improved progression-free survival (PFS) and overall survival (OS) in patients with mismatch repair-deficient endometrial cancer.

However, this benefit was not observed in patients with mismatch repair-proficient tumors, indicating that the effectiveness of the combination therapy may depend on the specific genetic characteristics of the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1/PD-L1 inhibitors plus carboplatin and paclitaxel compared with carboplatin and paclitaxel in primary advanced or recurrent endometrial cancer: a systematic review and meta-analysis of randomized clinical trials. de Moraes, FCA., Pasqualotto, E., Lopes, LM., et al.[2023]

In a phase 2 trial involving 125 women with advanced or recurrent endometrial cancer, adding avelumab to standard chemotherapy (carboplatin and paclitaxel) showed a similar median progression-free survival of 9.6 months compared to 9.9 months for chemotherapy alone, suggesting no significant improvement in efficacy.

However, the experimental group receiving avelumab experienced more serious adverse events, indicating potential safety concerns that need to be addressed in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial. Pignata, S., Scambia, G., Schettino, C., et al.[2023]

The combination of paclitaxel and carboplatin showed promising activity in treating endometrial cancer resistant to standard therapies, with 63% of evaluable patients experiencing a significant reduction in tumor size.

While the treatment had acceptable toxicity levels, with some patients experiencing grade 3 or 4 hematologic issues, further follow-up is needed to assess long-term survival outcomes and the overall effectiveness of this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A trial of outpatient paclitaxel and carboplatin for advanced, recurrent, and histologic high-risk endometrial carcinoma: preliminary report. Price, FV., Edwards, RP., Kelley, JL., et al.[2016]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7676887/

Carboplatin and Paclitaxel for Advanced Endometrial Cancer This was the first trial to show a survival advantage for combination chemotherapy in patients with measurable advanced or recurrent endometrial cancer. For ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2352578919300414

Retreatment with carboplatin and paclitaxel for recurrent ... Re-exposure to paclitaxel and carboplatin chemotherapy resulted in tumor shrinkage in 50% of women with endometrial cancer. 15% of patients with recurrent ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00584909

A Phase II Study of Paclitaxel and Carboplatin in Patients ... The safety of this combination is well established in a number of phase III trials and currently is used in the primary setting for patients with ovarian cancer ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)00721-X/fulltext

Overall survival in patients with endometrial cancer treated ... An improvement of 13.9 months in median PFS2 was observed in patients receiving dostarlimab plus carboplatin–paclitaxel (median PFS2 of 32.3 ...

5. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11654-z

PD-1/PD-L1 inhibitors plus carboplatin and paclitaxel ... Immunotherapy plus carboplatin-paclitaxel increased significantly PFS and OS among patients with advanced or recurrent endometrial cancer.

6. asco.org asco.org/abstracts-presentations/ABSTRACT183754

Adjuvant carboplatin and paclitaxel chemotherapy followed ... Conclusions: Our data suggests that adjuvant carboplatin and paclitaxel, followed by RT, in high-risk endometrial cancer is safe and effective.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1048891X25001811

Real-world treatment patterns and clinical outcomes in ... The median real-world progression-free survival from initiation of second-line therapy was 8.1 months (95% CI 7.6 to 10.0) overall and 7.6 (95% CI 5.3 to 19.8) ...