Immunotherapy + Radiation + Chemotherapy for Endometrial Cancer

(FIERCE Trial)

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

45 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this single arm, open label study is to evaluate the feasibility of pembrolizumab combined with radiation administered to the upper part of the vagina (vaginal cuff brachytherapy) followed by three cycles of pembrolizumab and chemotherapy in patients with endometrial cancer.

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.

What data supports the effectiveness of the drugs used in the Immunotherapy + Radiation + Chemotherapy for Endometrial Cancer trial?

Pembrolizumab (Keytruda) is approved for treating advanced endometrial cancer with specific genetic features, and paclitaxel plus carboplatin is the standard chemotherapy for advanced or recurrent endometrial cancer. However, the benefit of adding pembrolizumab to chemotherapy is still unclear. ^{1 2 3 4 5}

Is the combination of immunotherapy, radiation, and chemotherapy safe for treating endometrial cancer?

Pembrolizumab (Keytruda), an immunotherapy drug, can cause pneumonitis (lung inflammation) in 1%-5% of patients, which is a serious side effect. Paclitaxel and carboplatin are standard chemotherapy drugs for endometrial cancer, and their safety profile is well-established, though they can have side effects like nausea and low blood counts. The safety of combining these treatments with radiation is still being studied, but each component has known safety data. ^{1 2 6 7 8}

How is the drug combination of Carboplatin, Paclitaxel, and Pembrolizumab unique for treating endometrial cancer?

This treatment is unique because it combines standard chemotherapy drugs, Carboplatin and Paclitaxel, with Pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells. While the benefit of adding Pembrolizumab to chemotherapy for endometrial cancer is still unclear, it represents a novel approach by integrating immunotherapy with traditional chemotherapy. ^{1 2 5 9 10}

Research Team

Christina Washington, MD

Principal Investigator

Stephenson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 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]

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]

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 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 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]

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]

References

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

New Approved Use for Keytruda. [2022]

2. England 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. [2023]

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

Dose dense carboplatin paclitaxel improves progression free survival in patients with endometrial cancer. [2022]

4. England 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. [2023]

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

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma. [2015]

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

Concurrent carboplatin/paclitaxel and intravaginal radiation in surgical stage I-II serous endometrial cancer. [2021]

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

A trial of outpatient paclitaxel and carboplatin for advanced, recurrent, and histologic high-risk endometrial carcinoma: preliminary report. [2016]