Combination Chemotherapy for Stomach and Esophageal Cancer

Overseen By Cancer Connect

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Wisconsin, Madison

Must not be taking: Corticosteroids, Immunosuppressants, others

Disqualifiers: Active malignancy, Autoimmune disease, CNS metastases, 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: 1

Duration: up to 1 year

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, phase II, multi-site trial evaluating the efficacy and safety of the combination of 5-FU, oxaliplatin, nal-IRI, and immunotherapy (plus trastuzumab for HER2-positive tumors) as first-line therapy for participants with advanced Esophageal and Gastric Adenocarcinoma (EGA). The investigators hypothesize that this drug combination will be better tolerated than current first-line chemotherapy combinations for this disease.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot be on other investigational drugs or have certain conditions that require systemic treatment with corticosteroids or immunosuppressive medications within 14 days of starting the trial.

What data supports the effectiveness of the drug combination including Nal-IRI, Onivyde, Liposomal Irinotecan, Nal-IRI, Oxaliplatin, Eloxatin, Trastuzumab, Herceptin, Trazimera, Herzuma, Ontruzant for stomach and esophageal cancer?

Trastuzumab, one of the drugs in the combination, is recommended for patients with HER2-positive esophageal and gastric cancers, and has shown effectiveness when combined with chemotherapy. Additionally, combining trastuzumab with pembrolizumab and chemotherapy has demonstrated promising results in improving response rates in HER2-positive gastric cancer. ^{1 2 3 4 5}

Is the combination chemotherapy for stomach and esophageal cancer safe for humans?

Trastuzumab, one of the drugs in the combination, has been generally tolerable in patients with advanced gastric cancer, with common side effects like nausea and fatigue. However, it carries warnings for serious lung issues and risks to unborn babies. The safety of other drugs in the combination, like oxaliplatin and liposomal irinotecan, is not specifically detailed in the provided research. ^{4 5 6 7 8}

What makes the combination chemotherapy with Nal-IRI, Oxaliplatin, and Trastuzumab unique for stomach and esophageal cancer?

This treatment is unique because it combines Nal-IRI (a liposomal form of irinotecan), Oxaliplatin, and Trastuzumab, targeting HER2-positive cancers, which may offer a novel approach compared to traditional regimens like cisplatin and 5-fluorouracil. Trastuzumab specifically targets HER2, a protein that can promote the growth of cancer cells, making it a targeted therapy option for patients with HER2-positive tumors. ^{4 9 10 11 12}

Research Team

Nataliya V. Uboha

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

This trial is for adults with advanced Esophageal and Gastric Adenocarcinoma who haven't had systemic therapy for it. They should be relatively fit (ECOG 0-2), have certain blood counts, organ function within set limits, known HER2/PDL1 status, measurable disease by RECIST v1.1 standards, and not pregnant or breastfeeding. Participants must agree to use effective contraception.

Inclusion Criteria

Albumin >3.0 g/dL

Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

My hemoglobin level is at least 8 g/dL, or I've had a transfusion to reach this.

Exclusion Criteria

Pregnant or breastfeeding

I haven't had major surgery in the last 28 days or minor surgery in the last 14 days, except for a biopsy or port placement.

I haven't needed treatment for an autoimmune disease in the last 2 years, except for certain conditions like vitiligo or type I diabetes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 5-FU, oxaliplatin, nal-IRI, and immunotherapy (plus trastuzumab for HER2-positive tumors) as first-line therapy for advanced Esophageal and Gastric Adenocarcinoma

up to 1 year

Treatments on day 1 and 15 of each 28-day cycle for Cohorts 1, 2, and 3; day 1, 15, and 29 of each 42-day cycle for Cohort 4

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• Nal-IRI
• Oxaliplatin
• Trastuzumab

Trial Overview The study tests a combination of chemotherapy drugs (5-FU, oxaliplatin, nal-IRI) with immunotherapy agents (pembrolizumab or nivolumab; trastuzumab added if HER2-positive). It's an open-label phase II trial aiming to see if this mix is safer and more effective than current treatments for these cancers.

Participant Groups

Group I: Cohort 4: HER2 Positive Experimental Treatment 5 Interventions

Participants in Cohort 4 (HER2-positive) will be treated with nal-IRI (50 mg/m\^2 - intravenously over 90 min), trastuzumab (6 mg/kg C1D1, then 4 mg/kg on each subsequent treatment days), 5-FU (2400 mg/m\^2 over 46 hrs), oxaliplatin (60 mg/m\^2), and pembrolizumab (400 mg). Each cycle is 42 days. Participants will receive chemotherapy and trastuzumab treatments on day 1, 15, and 29 of each cycle. Pembrolizumab will be given on day 1 of each cycle.

Group II: Cohort 3: HER2 Negative Experimental Treatment 4 Interventions

Participants in Cohort 3 (HER2-negative) will be treated with nal-IRI (50 mg/m\^2 - intravenously over 90 min), 5-FU (2400 mg/m\^2 over 46 hrs), oxaliplatin (60 mg/m\^2), and nivolumab. (240 mg). Each cycle is 28 days. Participants will receive treatments on day 1 and 15 of each cycle

Group III: Cohort 2: HER2 Positive Experimental Treatment 4 Interventions

Participants in Cohort 2 (HER2-positive) will be treated with nal-IRI (50 mg/m\^2 - intravenously over 90 min), trastuzumab (6 mg/kg C1D1, then 4 mg/kg on each subsequent treatment days), 5-FU (2400 mg/m\^2 over 46 hrs), and oxaliplatin (60 mg/m\^2). Each cycle is 28 days. Participants will receive treatments on day 1 and 15 of each cycle.

Group IV: Cohort 1: HER2 Negative Experimental Treatment 3 Interventions

Participants in Cohort 1 (HER2-negative) will be treated with nal-IRI (50 mg/m\^2 - intravenously over 90 min), 5-FU (2400 mg/m\^2 over 46 hrs), and oxaliplatin (60 mg/m\^2). Each cycle is 28 days. Participants will receive treatments on day 1 and 15 of each cycle.

Nal-IRI is already approved in United States for the following indications:

Approved in United States as Onivyde for:

• Metastatic pancreatic adenocarcinoma as first-line treatment in combination with oxaliplatin, fluorouracil, and leucovorin
• Metastatic pancreatic cancer in patients who have received gemcitabine-based treatment

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Findings from Research

In the KEYNOTE-811 trial involving 698 patients with HER2-positive gastro-oesophageal cancer, pembrolizumab combined with standard chemotherapy significantly improved median progression-free survival to 10.0 months compared to 8.1 months for the placebo group, indicating its efficacy as a first-line treatment.

While pembrolizumab showed a trend towards improved overall survival (20.0 months vs. 16.8 months for placebo), it did not reach statistical significance, and the treatment was associated with a higher incidence of grade 3 or worse adverse events (58% vs. 51%), highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Janjigian, YY., Kawazoe, A., Bai, Y., et al.[2023]

Trastuzumab, an anti-HER2 agent, is approved for first-line treatment in HER2 positive gastro-esophageal adenocarcinoma, showing effectiveness when combined with chemotherapy, but not with neoadjuvant chemoradiotherapy for advanced cases.

Immune checkpoint inhibitors like nivolumab and pembrolizumab have been approved for specific uses in esophageal cancer, and combining these with other therapies may enhance treatment outcomes, with ongoing clinical trials exploring these combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction. Valkema, MJ., Mostert, B., Lagarde, SM., et al.[2023]

The Phase III KEYNOTE-811 study is designed to evaluate the efficacy and safety of pembrolizumab combined with trastuzumab and chemotherapy in patients with advanced HER2-positive gastric cancer, a group with limited treatment options and poor prognosis.

Pembrolizumab has shown promising antitumor activity in previous studies, suggesting that its combination with trastuzumab and chemotherapy could improve outcomes for patients with this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Chung, HC., Bang, YJ., S Fuchs, C., et al.[2021]

Biologic therapies, particularly those targeting HER2 and VEGF, are showing promise in treating esophageal and gastric cancers, with trastuzumab and ramucirumab currently recommended by the NCCN for specific patient groups.

Recent studies indicate that other agents like pertuzumab, apatinib, and pembrolizumab may improve overall and progression-free survival, suggesting a growing role for targeted biologic therapies in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. Samson, P., Lockhart, AC.[2020]

In a study of 45 patients with esophageal squamous cell carcinoma, the combination of lobaplatin and paclitaxel as first-line chemotherapy resulted in a 42.2% overall response rate, with 40% achieving partial remission and 2.2% achieving complete remission.

The treatment was associated with manageable toxicities, primarily mild to moderate nausea/vomiting and leucopenia, while 71% of patients experienced relief or improvement in dysphagia, indicating both efficacy and tolerability of the regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and toxicities of combined lobaplatin with paclitaxel as a first-line chemotherapy for advanced esophageal squamous cell carcinoma. Chen, MQ., Chen, C., Lu, HJ., et al.[2020]

The addition of trastuzumab and pertuzumab to the FLOT chemotherapy regimen significantly improved the pathologic complete response (pCR) rate in patients with HER2-positive resectable esophagogastric adenocarcinoma, with pCR rates of 35% compared to 12% in the FLOT-only group.

While the combination treatment showed better pCR and lymph node negativity rates, it also resulted in higher rates of severe adverse events, particularly diarrhea and leukopenia, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FLOT Versus FLOT/Trastuzumab/Pertuzumab Perioperative Therapy of Human Epidermal Growth Factor Receptor 2-Positive Resectable Esophagogastric Adenocarcinoma: A Randomized Phase II Trial of the AIO EGA Study Group. Hofheinz, RD., Merx, K., Haag, GM., et al.[2022]

In North America, about 70% of gastric cancer cases are diagnosed at an advanced or metastatic stage, leading to a lower 5-year overall survival rate of around 20%, compared to 40%-60% in Japan.

Trastuzumab, an anti-HER-2 monoclonal antibody, has been shown to improve survival by nearly three months in HER-2 positive advanced gastric cancer patients, making it a viable treatment option when combined with cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical appraisal of trastuzumab in treatment of advanced stomach cancer. Meza-Junco, J., Au, HJ., Sawyer, MB.[2021]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

Key chemotherapy drugs for gastroesophageal cancer include fluoropyrimidine, platinum, taxanes, and irinotecan, with concurrent chemoradiotherapy being a primary treatment approach, especially for esophageal cancer.

Targeted therapies like trastuzumab for HER2-positive gastric cancer and ramucirumab combined with paclitaxel have been shown to improve patient survival, while anti-PD-1 antibodies are now available for later-line treatment, highlighting the importance of molecular profiling in optimizing therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress of chemotherapy and biomarkers for gastroesophageal cancer. Maeda, O., Ando, Y.[2020]

Esophageal cancer is rapidly increasing in the U.S. and is aggressive, with poor survival rates from traditional treatments like surgery or chemoradiation alone.

New trials at Memorial Sloan-Kettering Cancer Center are exploring the use of weekly paclitaxel/cisplatin and irinotecan/cisplatin, which may reduce gastrointestinal toxicity while maintaining efficacy, compared to traditional cisplatin/5-FU regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modality therapy in esophageal cancer: the Memorial experience. Anderson, SE., Minsky, BD., Bains, M., et al.[2018]

In a phase II clinical trial, patients with gastric or esophagogastric cancer who received combination chemotherapy with rilotumumab experienced longer progression-free survival compared to those who received chemotherapy alone.

The greatest survival benefit was observed in patients with MET-positive disease, leading to the initiation of a phase III trial to further investigate this combination treatment in that specific population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rilotumumab extends PFS in gastric cancer. [2018]

Esophageal cancer, particularly adenocarcinoma, is increasingly common, with over half of patients presenting with metastatic disease, making palliative chemotherapy a crucial treatment option.

Recent studies show that weekly irinotecan and cisplatin is a highly effective and less toxic regimen for treating both adenocarcinoma and squamous cell carcinoma, while paclitaxel also shows promise with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in esophageal cancer. Enzinger, PC., Ilson, DH., Kelsen, DP.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction. [2023]

3. England pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. [2021]

4. China pubmed.ncbi.nlm.nih.gov

Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. [2020]

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

The efficacy and toxicities of combined lobaplatin with paclitaxel as a first-line chemotherapy for advanced esophageal squamous cell carcinoma. [2020]

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

FLOT Versus FLOT/Trastuzumab/Pertuzumab Perioperative Therapy of Human Epidermal Growth Factor Receptor 2-Positive Resectable Esophagogastric Adenocarcinoma: A Randomized Phase II Trial of the AIO EGA Study Group. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Critical appraisal of trastuzumab in treatment of advanced stomach cancer. [2021]

8. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. [2023]

9. China pubmed.ncbi.nlm.nih.gov

Recent progress of chemotherapy and biomarkers for gastroesophageal cancer. [2020]

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

Combined modality therapy in esophageal cancer: the Memorial experience. [2018]

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

Rilotumumab extends PFS in gastric cancer. [2018]

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

Chemotherapy in esophageal cancer. [2022]