Combination Therapy for Esophageal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Case Comprehensive Cancer Center

Disqualifiers: Other cancers, Active infection, Heart disease, 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: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a combination of chemotherapy drugs followed by surgery, and possibly additional chemotherapy and radiation, for individuals with certain types of esophageal cancer. The trial uses drugs like oxaliplatin, leucovorin calcium, and fluorouracil to target and kill cancer cells. Participants are grouped based on the amount of tumor remaining after surgery to determine subsequent treatment steps. Individuals diagnosed with adenocarcinoma of the esophagus, gastroesophageal junction, or gastric cardia who have not received prior treatment for these cancers may be suitable candidates. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had prior chemotherapy, radiation, or surgery for this cancer, and you cannot be on any other investigational therapy.

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

Research shows that patients usually tolerate the combination of carboplatin and paclitaxel well. Studies have found that administering these drugs weekly results in low toxicity, meaning most people do not experience severe side effects. This makes the treatment more manageable for those undergoing therapy.

Similarly, the mFOLFOX6 regimen, which includes oxaliplatin, leucovorin calcium, and fluorouracil, has been studied for safety. Research suggests that this combination effectively treats esophageal and related cancers, with generally manageable side effects.

Since other studies have used both treatment combinations and found them well-tolerated, strong evidence indicates they are generally safe for people in clinical trials. However, as with any treatment, individual experiences may vary, so discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination therapy for esophageal cancer because it offers a tailored approach based on the patient's response to initial treatment. Unlike the standard of care, which usually follows a fixed regimen, this trial adapts therapy according to the tumor's response. Patients who still have significant tumor presence after surgery receive a combination of carboplatin and paclitaxel, which might be more aggressive in targeting remaining cancer cells. Those with a better initial response receive the mFOLFOX6 regimen, potentially minimizing unnecessary exposure to more intense treatment. This personalized approach aims to improve outcomes by tailoring therapy to the tumor's behavior.

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

Research has shown that using carboplatin and paclitaxel together may help treat esophageal cancer. Studies found that 54% of patients responded well to this treatment, with more than half experiencing positive results. This treatment is generally safe for patients. In this trial, patients with a negative pathologic response will receive postoperative chemo-radiotherapy with carboplatin and paclitaxel.

For the mFOLFOX6 treatment, which includes oxaliplatin, leucovorin, and fluorouracil, about 40% of patients saw their tumors shrink, meaning 4 out of 10 patients had a positive response. This regimen has been effective, especially for those who did not respond to other treatments. In this trial, patients with a positive pathologic response will receive postoperative chemo-radiotherapy with the mFOLFOX6 regimen. Both treatments have shown promising results in terms of effectiveness and safety for esophageal cancer. ^{1 3 6 7 8}

Who Is on the Research Team?

Michael McNamara, MD

Principal Investigator

Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with specific cancers of the esophagus, gastroesophageal junction, or gastric cardia. They must be in good physical condition (ECOG 0-1), have adequate blood counts and organ function, and no severe neuropathy. Pregnant women, those with distant metastasis or another active cancer (with some exceptions), prior treatments for this cancer, certain infections like hepatitis B/C or HIV, serious heart conditions, or other medical issues that could affect participation are excluded.

Inclusion Criteria

Alkaline phosphatase ≤ 3X the institutional ULN

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3X the institutional ULN

My cancer is a type of adenocarcinoma located in my esophagus, GEJ, or stomach.

Exclusion Criteria

My cancer diagnosis is specifically adenocarcinoma.

Patients who are pregnant or lactating will not be eligible; pregnant patients are ineligible

Patients with known infection with human immunodeficiency virus (HIV) will not be eligible

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Patients receive oxaliplatin, leucovorin calcium, and fluorouracil over 44 hours on days 1-3, repeated every 14 days for up to 4 courses

8 weeks

Surgery

Approximately 4-5 weeks after completion of induction chemotherapy, patients undergo a surgical procedure

4-5 weeks

Adjuvant Therapy

Within 6-12 weeks after surgery, patients undergo radiation therapy for 28 days. Additional chemotherapy is given based on pathological response

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, every 4-5 months for 3 years, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Fluorouracil
• Leucovorin Calcium
• Oxaliplatin
• Paclitaxel
• Radiation Therapy
• Therapeutic Conventional Surgery

Trial Overview The study tests a combination of chemotherapy drugs (oxaliplatin, leucovorin calcium, fluorouracil) followed by surgery and then more chemo alongside radiation therapy based on how well the patient responds to initial treatment. The goal is to see if this approach is effective at stopping tumor growth by killing cells or preventing them from dividing.

How Is the Trial Designed?

Group I: Negative Pathologic Response Experimental Treatment 7 Interventions

Patients with \>50% viable tumor cells remaining in the surgical specimen, will receive postoperative chemo-radiotherapy with weekly carboplatin and paclitaxel.

Group II: Positive Pathologic Response Active Control 5 Interventions

Patients with ≤50% viable tumor cells remaining in the surgical specimen will receive postoperative chemo-radiotherapy with the mFOLFOX6 regimen

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

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Published Research Related to This Trial

In a study of 35 patients with advanced esophageal cancer, the combination of oxaliplatin, leucovorin, and fluorouracil demonstrated a 40% overall response rate, indicating significant anti-tumor activity.

While the treatment was effective, it also had notable side effects, including a 29% incidence of severe neutropenia and 26% experiencing significant peripheral neuropathy, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. Mauer, AM., Kraut, EH., Krauss, SA., et al.[2020]

In a phase II study involving 50 patients with advanced oesophageal cancer, the addition of cetuximab to the standard treatment of 5-FU/cisplatin/docetaxel (TPF) and chemoradiotherapy resulted in a clinical complete response (cCR) rate of 12% and an overall response rate of 54%.

The median overall survival for patients who underwent complete surgical resection was significantly longer at 42.1 months compared to 24.9 months for those who did not have surgery, indicating that achieving a complete resection is crucial for improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients. Alsina, M., Rivera, F., Ramos, FJ., et al.[2019]

The study established a 5-Fluorouracil (5-FU) and cisplatin-resistant xenograft model in SCID mice to investigate the mechanisms behind acquired resistance in esophageal cancer treatment.

Gene expression analysis revealed that resistance to FP chemotherapy is linked to the activation of specific genes related to 5-FU and cisplatin, as well as the PI3K/AKT signaling pathway, suggesting potential targets for overcoming resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray. Yoshida, T., Miyoshi, T., Seike, J., et al.[2015]

In a study of 30 patients with resectable esophageal squamous cell carcinoma, a chemotherapy regimen combining 5-fluorouracil, cisplatin, and interferon-alpha showed promising results, with a median overall survival of 26.3 months.

The treatment led to a complete pathological response in 4 out of 23 patients who underwent esophagectomy, indicating significant effectiveness, although there was one toxic death due to esophageal perforation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. Bazarbashi, S., Abdelsalam, M., Amin, T., et al.[2013]

In a study involving 42 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium folinate (S-FA) administered via a continuous 24-hour infusion was found to be a safe and effective second-line treatment, achieving a 9% objective response rate and halting tumor progression in 74% of patients.

The treatment resulted in a median survival of 14.7 months and a median time to tumor progression of 5.7 months, with manageable side effects including grade III/IV diarrhea in 19% of patients, indicating that the new formulation allows for convenient simultaneous administration of both drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial. Kuhfahl, J., Steinbrecher, C., Wagner, T., et al.[2013]

The combination of oxaliplatin, 5-fluorouracil, and leucovorin with concurrent radiotherapy was found to be safe and effective for treating locally advanced esophageal carcinoma, with 42 patients showing promising results in a structured treatment regimen.

Patients who received preoperative concurrent chemoradiotherapy had a median survival of 28 months, with significant down-staging observed in 16 out of 24 patients, indicating the potential for improved outcomes with this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma. O'Connor, BM., Chadha, MK., Pande, A., et al.[2018]

In a study of 51 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium-folinic acid (S-FA) resulted in a 37.2% objective response rate, with 3.9% achieving complete remission and 33.3% showing partial remission.

The treatment demonstrated a median survival of 16.5 months and a median time to tumor progression of 8.5 months, with manageable toxicity levels, making S-FA a convenient and effective option for outpatient therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a weekly 24-hour infusion with 5-fluorouracil and simultaneous sodium-folinic acid in the first-line treatment of metastatic colorectal cancer. Hartung, G., Hofheinz, RD., Wein, A., et al.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6627268/

Efficacy and Toxicity of Weekly Carboplatin and Paclitaxel as ... This weekly regimen appeared to be very tolerable and effective with an overall response rate of 54%. Therefore, this regimen was utilized for ...

2. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)61852-1/fulltext

A phase II study of carboplatin and paclitaxel in ... The median survival time was 9 months (90%CI 7–13.8) and the 1-year survival rate was 43% (90% CI 0.29–0.57). The major grade 3–4 toxicity observed was ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.e16526

Study of efficacy and tolerability of paclitaxel ... Results: 23 out 64 patients underwent surgery while others were either lost to follow up or they refused for surgery. Of these 23, 87.5% could ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S093665551930439X

Outcome of Weekly Carboplatin–Paclitaxel-based ... Weekly carboplatin–paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin–fluoropyrimidine-based ...

5. journals.lww.com journals.lww.com/crst/fulltext/2022/05020/efficacy_and_safety_of_induction_weekly_paclitaxel.10.aspx

Efficacy and safety of induction weekly paclitaxel and... Paclitaxel has shown clinical activity in advanced esophageal malignancy with low toxicity.[13] The administration of paclitaxel and carboplatin once-a-week is ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01249443

Paclitaxel and Carboplatin in Treating Patients With ... The primary objective going forward will determine the safety and tolerability of the paclitaxel and carboplatin combination in this patient population.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9801619/

Safety and efficacy of paclitaxel plus carboplatin versus ... We evaluated and compared the efficacy and safety of chemotherapy with paclitaxel plus cisplatin (TP) or carboplatin (TC) in patients with locally advanced ...

8. healio.com healio.com/news/hematology-oncology/20220511/safety-of-paclitaxelbased-regimens-varies-among-patients-with-esophageal-cancer

Safety of paclitaxel-based regimens varies among patients ... “The weekly fluorouracil or carboplatin plans were accompanied by relatively mild toxic effects while the monthly cisplatin regimen led to ...