Chemoradiation + Pembrolizumab/Lenvatinib for Esophageal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Immune checkpoint inhibitors, Multi-tyrosine kinase inhibitors

Disqualifiers: Active autoimmune disease, Brain metastasis, 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

3 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery in treating patients with esophageal or esophageal/gastroesophageal junction cancer that has not spread to other places in the body (non-metastatic). Pembrolizumab is an immunotherapy drug that works by harnessing the immune system to attack cancer. Lenvatinib is an anti-cancer drug that works by stopping or slowing down the growth of cancer cells. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery may kill more tumor cells.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on certain treatments like immune checkpoint inhibitors, multi-tyrosine kinase inhibitors, or chronic systemic steroids. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug pembrolizumab for esophageal cancer?

Research shows that pembrolizumab, when combined with chemotherapy, is effective for treating advanced esophageal cancer. It has been approved for use in combination with other chemotherapy drugs for esophageal or gastroesophageal cancer, indicating its potential benefit in these conditions. ^{1 2 3 4 5}

Is the combination of chemoradiation and pembrolizumab safe for esophageal cancer?

Research indicates that pembrolizumab combined with chemoradiotherapy has been studied for esophageal cancer, and these studies generally focus on evaluating both the effectiveness and safety of the treatment. While specific safety outcomes are not detailed, the studies imply that the combination is considered feasible and safe enough to be tested in clinical settings. ^{1 2 5 6 7}

What makes the chemoradiation plus pembrolizumab/lenvatinib treatment for esophageal cancer unique?

This treatment is unique because it combines chemoradiation (a mix of chemotherapy and radiation therapy) with pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, and lenvatinib, which targets cancer cell growth. This combination aims to improve outcomes for patients with esophageal cancer, especially those with advanced or unresectable cases, by enhancing the effectiveness of traditional therapies. ^{1 2 3 4 8}

Research Team

Vincent Chung, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

Adults with non-metastatic esophageal or gastroesophageal junction cancer suitable for chemoradiation and surgery. Participants must have certain blood cell levels, organ function within specific limits, and agree to use birth control. Excluded are those with recent other treatments, immune conditions, severe allergies to similar drugs, active infections like HIV or hepatitis B/C, pregnant/breastfeeding women, and anyone unlikely to follow the study plan.

Inclusion Criteria

I have received a specific dose of radiation therapy.

Exceptions may be granted only with study principal investigator (PI) approval if archival tissue is unavailable

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

I have not had radiotherapy in the last 21 days.

I have an active case of tuberculosis.

I have not been treated with immune checkpoint inhibitors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiation

Patients receive carboplatin and paclitaxel intravenously once a week and undergo external beam radiation therapy over 6 weeks. Pembrolizumab is administered on day 1 of radiation therapy.

6 weeks

Window Period

Patients receive pembrolizumab intravenously on day 1 of week 3 and lenvatinib mesylate orally once daily from weeks 3 to 6.

4 weeks

Surgery/Surveillance

Patients without complete response undergo standard surgical resection. Patients with complete response undergo surveillance via periodic endoscopic biopsy.

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 3 years

Treatment Details

Interventions

• Carboplatin, Paclitaxel
• Endoscopic Biopsy
• External Beam Radiation Therapy
• Lenvatinib Mesylate
• Pembrolizumab
• Resection

Trial Overview The trial is testing if a combination of chemoradiation (carboplatin/paclitaxel) and immunotherapy drug pembrolizumab followed by pembrolizumab plus anti-cancer drug lenvatinib before surgery can effectively treat patients. The goal is to see if this regimen kills more tumor cells compared to current standard treatments.

Participant Groups

Group I: Treatment (chemoradiation, pembrolizumab, lenvatinib) Experimental Treatment 7 Interventions

CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity. SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 39 patients with locally advanced esophageal squamous cell carcinoma (ESCC), pembrolizumab combined with neoadjuvant chemotherapy resulted in a high objective response rate of 87.2% and a disease control rate of 100%.

The treatment led to significant surgical outcomes, with a major pathological response rate of 68.2% and a complete pathological response rate of 45.5% among those who underwent radical surgery, while maintaining a manageable safety profile with only 15.4% experiencing severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study. Lin, W., Huang, Y., Zhu, L., et al.[2023]

Preoperative treatment with pembrolizumab combined with chemoradiotherapy was found to be safe for 20 patients with resectable esophageal squamous cell carcinoma, with a high pathologic complete response (pCR) rate of 55.6%.

Despite some patients experiencing significant adverse events, including grade III lymphopenia in 65% of cases, the treatment did not delay surgery, indicating its feasibility for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Li, C., Zhao, S., Zheng, Y., et al.[2021]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

In a study of 55 patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC), pembrolizumab combined with chemotherapy or radiotherapy showed favorable long-term survival outcomes, with a 12-month overall survival rate of 78.8%.

The treatment was found to be safe and manageable, with long-term adverse effects reported in only a small number of patients, indicating that pembrolizumab is a promising option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. Wang, HC., Huang, X., Chen, J., et al.[2023]

Pembrolizumab, a monoclonal antibody that inhibits PD-1, shows significant survival benefits for patients with metastatic or recurrent esophageal cancer who have a PD-L1 CPS ≥10 when used as a second-line treatment.

Current research is exploring the effectiveness of combining pembrolizumab with other treatments, which may enhance outcomes for patients with esophageal squamous cell carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of esophageal cancer. Yamamoto, S., Kato, K.[2021]

The KEYNOTE-975 trial is a Phase III study designed to evaluate the effectiveness of pembrolizumab combined with chemoradiotherapy as a first-line treatment for patients with locally advanced, unresectable esophageal or gastroesophageal junction cancer.

This trial aims to improve survival outcomes, as current treatments have poor results, and will measure overall survival and event-free survival as its primary endpoints.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Shah, MA., Bennouna, J., Doi, T., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with paclitaxel and platinum as induction therapy for locally advanced esophageal squamous cell carcinoma: a retrospective, single-center, three-arm study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). [2021]

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]

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

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. [2023]

5. China pubmed.ncbi.nlm.nih.gov

The feasibility and safety of radical esophagectomy in patients receiving neoadjuvant chemoradiotherapy with pembrolizumab for esophageal squamous cell carcinoma. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pembrolizumab Combined With Neoadjuvant Chemotherapy Versus Neoadjuvant Chemoradiotherapy Followed by Surgery for Locally Advanced Oesophageal Squamous Cell Carcinoma: Protocol for a Multicentre, Prospective, Randomized-Controlled, Phase III Clinical Study (Keystone-002). [2023]

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

Pembrolizumab for the treatment of esophageal cancer. [2021]

8. England pubmed.ncbi.nlm.nih.gov

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. [2021]