Pembrolizumab + Chemotherapy for Endometrial Cancer

Recruiting at 431 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Systemic steroids

Disqualifiers: Autoimmune disease, Pneumonitis, Liver disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 5

813 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or other immunosuppressive treatments, you must stop them at least 7 days before registration, unless they are inhaled, topical, or physiologic doses of corticosteroids.

What data supports the effectiveness of the drug Pembrolizumab combined with chemotherapy for endometrial cancer?

Pembrolizumab (Keytruda) is approved for treating advanced endometrial cancer that has specific genetic features and has progressed after other treatments. However, the benefit of adding pembrolizumab to standard chemotherapy for endometrial cancer is still unclear. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and chemotherapy safe for treating endometrial cancer?

Pembrolizumab, when used with chemotherapy drugs like carboplatin and paclitaxel, has been studied for safety in treating advanced endometrial cancer. While generally considered less toxic than traditional chemotherapy, pembrolizumab can cause side effects like pneumonitis (lung inflammation) in 1%-5% of patients and, rarely, type 1 diabetes in 0.2% of cases. ^{3 4 6 7 8}

How is the drug combination of pembrolizumab, carboplatin, and paclitaxel unique for treating endometrial cancer?

This drug combination is unique because it adds pembrolizumab, an immune therapy that helps the body's immune system fight cancer, to the standard chemotherapy drugs carboplatin and paclitaxel, although the benefit of this addition is still being studied. ^{1 2 3 4 9}

What is the purpose of this trial?

This phase III trial studies how well the combination of pembrolizumab, paclitaxel and carboplatin works compared with paclitaxel and carboplatin alone in treating patients with endometrial cancer that is stage III or IV, or has come back after a period of improvement (recurrent). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Paclitaxel and carboplatin are chemotherapy drugs used as part of the usual treatment approach for this type of cancer. This study aims to assess if adding immunotherapy to these drugs is better or worse than the usual approach for treatment of this cancer.

Research Team

Ramez N Eskander

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for adults with stage III-IV or recurrent endometrial cancer. Eligible participants may have had prior hormonal therapy, but not chemotherapy for this cancer within the last year, and no previous treatment with certain immunotherapy drugs. They must not be pregnant, agree to use contraception if of childbearing potential, and cannot have severe allergies to the study drugs or significant health conditions that could affect safety.

Inclusion Criteria

My endometrial cancer is at stage III, IVA, IVB, or is recurrent.

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

For patients of child bearing potential: negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required

Exclusion Criteria

My hepatitis B virus load is undetectable with treatment.

I have not taken steroids or immunosuppressants in the last 7 days.

I do not have any severe illnesses that could interfere with the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Combination Phase

Patients receive pembrolizumab or placebo, paclitaxel, and carboplatin every 3 weeks for 6 cycles. Treatment may continue up to 10 cycles if necessary.

18-30 weeks

1 visit every 3 weeks

Maintenance Phase

Patients receive pembrolizumab or placebo every 6 weeks for up to 14 cycles.

84 weeks

1 visit every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

Every 3 months for 2 years, then every 6 months for 3 years

Treatment Details

Interventions

• Carboplatin
• Paclitaxel
• Pembrolizumab

Trial Overview The trial tests adding pembrolizumab (an immunotherapy drug) to the usual chemotherapy regimen of paclitaxel and carboplatin in treating advanced or recurrent endometrial cancer. It aims to see if this combination improves outcomes compared to chemotherapy alone.

Participant Groups

Group I: Arm II (pembrolizumab, paclitaxel, carboplatin) Experimental Treatment 6 Interventions

COMBINATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle, paclitaxel IV over 3 hours on day 1 of each cycle, and carboplatin IV over 30 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease may continue treatment for up to a total of 10 cycles (if deemed necessary by the treating physician) in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study.

Group II: Arm I (placebo, paclitaxel, carboplatin) Active Control 6 Interventions

COMBINATION PHASE: Patients receive placebo IV over 30 minutes on day 1 of each cycle, paclitaxel IV over 3 hours on day 1 of each cycle, and carboplatin IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease may continue treatment for up to a total of 10 cycles (if deemed necessary by the treating physician) in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE: Patients receive placebo IV over 30 minutes on day 1 of each cycle. Treatment repeats every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study. On February 6, 2023, all patient treatment assignments were unblinded. Patients randomized to Arm 1 will not receive additional placebo infusions.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Canadian Cancer Trials Group

Collaborator

Trials

135

Recruited

70,300+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Findings from Research

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 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 (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 study involving 46 patients with advanced endometrial cancer, the combination of pembrolizumab with carboplatin and paclitaxel resulted in a high objective response rate (ORR) of 74.4%, significantly exceeding the historical control rate of 50%.

The treatment was generally well-tolerated, with common mild side effects like anemia and fatigue, while immune profiling indicated that responders had enriched CD8+ and CD4+ T cell populations, suggesting a potential mechanism of action related to immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. Barber, EL., Chen, S., Pineda, MJ., 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]

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]

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, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

References

1. 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]

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

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. [2023]

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

New Approved Use for Keytruda. [2022]

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

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. [2023]

5. 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]

6. 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]

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

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

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. [2022]