Neratinib + Chemotherapy for Stomach Cancer

Overseen By Lauren Andersen

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Immunotherapy, Corticosteroids

Disqualifiers: Active CNS metastases, Autoimmune disease, Cardiac 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: 5

Duration: 24 months

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of the drug Neratinib when combined with other treatments for stomach cancer. It specifically targets HER2 overexpressing gastroesophageal cancers, where cancer cells have an excess of the HER2 protein. Participants will receive a combination of drugs, including chemotherapy (such as 5-Fluorouracil and leucovorin) and immunotherapy, to evaluate their combined effectiveness and safety. Individuals with stomach, esophageal, or gastroesophageal junction cancer with high HER2 levels may be suitable for this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, if you are on certain treatments like chemotherapy or immunotherapy for metastatic disease, you may need to have recovered from any side effects before starting the trial. It's best to discuss your specific medications with the trial team.

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

Previous studies have shown that Neratinib is generally well-tolerated, especially by patients with HER2+ cancers. The FDA has already approved it for early-stage HER2+ breast cancer, indicating a certain level of established safety. Some patients have reported side effects like diarrhea, but treatment can often manage these.

Trastuzumab has a strong safety record. Studies show that patients generally tolerate it well, experience longer survival times, and have few serious side effects. Its effective use in treating HER2+ gastric cancer adds confidence to its safety.

Pembrolizumab also has a good safety profile. When combined with chemotherapy, it improves survival rates and has manageable side effects. Its approval for some HER2+ gastric cancers reflects its established safety.

The mFOLFOX regimen, which includes 5-Fluorouracil, leucovorin, and oxaliplatin, is commonly used in cancer treatment. Studies show it is effective and generally safe, with expected and manageable side effects.

Overall, while each drug has potential side effects, previous research suggests they are generally well-tolerated. This study aims to further understand their combined safety in treating stomach cancer. Joining the trial would provide more data on how these treatments work together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for stomach cancer, which often include chemotherapy and targeted therapies like trastuzumab, this new treatment combination adds neratinib and pembrolizumab, which bring exciting possibilities. Neratinib is a potent inhibitor that targets specific proteins involved in cancer cell growth, offering a fresh mechanism compared to existing options. Pembrolizumab, an immunotherapy, helps the immune system better recognize and attack cancer cells, potentially boosting the overall effectiveness of the treatment. Researchers are particularly excited about the synergy of these drugs working together, which could lead to improved outcomes for patients with this challenging condition.

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

Research shows that Neratinib, when combined with other treatments, may effectively treat HER2-positive gastroesophageal cancers. In this trial, participants will receive a combination treatment including Neratinib, Trastuzumab, Pembrolizumab, and mFOLFOX. Neratinib, already approved for HER2-positive breast cancer, has demonstrated effectiveness against tumors. When combined with Trastuzumab and immune system boosters like Pembrolizumab, it significantly enhances tumor response to treatment. This combination might extend patient survival. Although Neratinib can cause some stomach-related side effects, its ability to target cancer cells makes it a promising treatment option. ^{6 7 8 9 10}

Who Is on the Research Team?

Dae Won Kim, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with HER2-positive gastroesophageal cancer who haven't had chemotherapy for advanced stage IV disease or have been treatment-free for six months post-adjuvant therapy. They must be in good physical condition, not have severe heart issues, and women of childbearing age must use birth control.

Inclusion Criteria

My cancer in the esophagus, stomach, or GE junction is HER2 positive.

I haven't had chemotherapy for stage IV disease or it's been over 6 months since my last adjuvant therapy.

My heart functions normally, with an LVEF of 53% or higher.

Exclusion Criteria

I haven't needed systemic therapy for an autoimmune disease in the last 2 years.

Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

I had no severe reactions to the COVID-19 vaccine or they have improved.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Neratinib in combination with Trastuzumab, Pembrolizumab, and FOLFOX chemotherapy

24 months

Standard dose 5FU/oxaliplatin/trastuzumab every 2 weeks, Pembrolizumab every 6 weeks, Neratinib daily

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-Fluorouracil + leucovorin
• Neratinib
• Oxaliplatin
• Pembrolizumab
• Trastuzumab

Trial Overview The study tests the combination of Neratinib with Trastuzumab, Pembrolizumab, and FOLFOX chemotherapy to assess its effectiveness and safety in treating HER2 overexpressing gastroesophageal cancers.

How Is the Trial Designed?

Group I: Treatment with Neratinib with Trastuzumab, Pembrolizumb and mFOLFOX Experimental Treatment 5 Interventions

All patients will be treated with combination of neratinib with trastuzumab, pembrolizumab and mFOLFOX. All patients will receive standard dose 5FU/oxaliplatin/trastuzumab every 2 weeks. Pembrolizumab 400 mg intravenously will be administered once every 6 weeks. Neratinib will be dosed 240 mg orally daily

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

Approved in United States as 5-FU for:

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

Approved in European Union as 5-Fluorouracil for:

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

Approved in Canada as 5-FU for:

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

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Published Research Related to This Trial

In Korea, patients with advanced gastric cancer who undergo D2 resection benefit from postoperative adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin, indicating a potential effective treatment strategy in this population.

Trastuzumab is now part of the standard chemotherapy for gastric cancers that overexpress the HER2 protein, highlighting the importance of targeted therapies in improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for advanced gastric cancer: review and update of current practices. Park, SC., Chun, HJ.[2023]

The modified 5-fluorouracil/leucovorin/irinotecan (mFOLFIRI) regimen showed a response rate of 29.7% and a clinical benefit rate of 57.2% in 91 patients with advanced gastric cancer, indicating its efficacy as a second-line treatment.

Despite its effectiveness, the mFOLFIRI regimen was associated with significant adverse events, including neutropenia in 18.7% of patients, highlighting the need for careful monitoring and potential dose modifications during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified 5-fluorouracil/leucovorin/irinotecan as a feasible and efficacious second-line chemotherapeutic regimen in advanced gastric cancers. Ramaswamy, A., Ostwal, V., Gupta, K., et al.[2022]

In a study of 200 patients with untreated advanced gastric carcinoma, the PELF treatment regimen showed a significantly higher complete response rate (13%) compared to the FAMTX regimen (2%), indicating greater efficacy in treating this type of cancer.

The objective response rates were also better for PELF (39%) versus FAMTX (22%), suggesting that PELF is a more effective treatment option, although the survival rate differences were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Cocconi, G., Carlini, P., Gamboni, A., et al.[2022]

In a study involving 981 patients with metastatic colorectal cancer, the combination of eniluracil (EU) and fluorouracil (5-FU) showed a median overall survival of 13.3 months, which was not statistically equivalent to the 14.5 months observed with the standard treatment of 5-FU and leucovorin (LV).

Both treatment regimens were well tolerated, with similar rates of severe diarrhea (19% for EU/5-FU vs. 16% for 5-FU/LV) and significantly lower rates of severe granulocytopenia in the EU/5-FU group (5% vs. 47% for 5-FU/LV), indicating a potentially safer profile for EU/5-FU despite its inferior progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. Schilsky, RL., Levin, J., West, WH., et al.[2017]

In a study of 32 patients with advanced gastric cancer, modified FOLFIRI chemotherapy was found to be tolerable, with a disease control rate of 43.8%, but it showed a low response rate with only 9.4% achieving partial response.

The median overall survival after starting FOLFIRI was 5.84 months, indicating that while the treatment is manageable, its effectiveness as a second-line option after FOLFOX is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer. Jeon, EK., Hong, SH., Kim, TH., et al.[2021]

In a study of 570 patients with stage III colorectal cancer, three different administration types of 5-fluorouracil (5-FU) in FOLFOX treatment showed similar disease-free survival (DFS) and overall survival (OS) rates, indicating comparable efficacy.

While all treatment regimens were manageable in terms of toxicity, the modified FOLFOX-6 group experienced more grade 1-2 adverse events like thrombocytopenia and neuropathy, suggesting that while efficacy is similar, side effects may vary among the different regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. Akdeniz, N., Kaplan, MA., Uncu, D., et al.[2021]

No chemotherapy regimen has shown a survival benefit greater than 5-fluorouracil alone for advanced gastric cancer, but recent trials have introduced new agents and strategies that may improve outcomes.

Trastuzumab has demonstrated a survival benefit for patients with Her-2 positive gastric cancer, indicating a shift towards personalized treatment approaches using molecular targeted therapies in advanced gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives for personalization in chemotherapy of advanced gastric cancer. Boku, N.[2015]

In a study of 66 patients with chemotherapy-refractory metastatic colorectal cancer, the combination of cetuximab with bevacizumab and mFOLFOX6 showed manageable safety, but significant toxicity led to a high discontinuation rate, with 56% of patients stopping treatment before disease progression.

Despite not causing excessive life-threatening toxicity, the addition of cetuximab resulted in a notable number of patients experiencing severe side effects, prompting the conclusion that this combination therapy should not be used together for treating metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. Ocean, AJ., Polite, B., Christos, P., et al.[2021]

Irinotecan has been approved for patients with colorectal cancer who do not respond to 5-fluorouracil and has shown effectiveness both alone and in combination with other agents like 5-fluorouracil and leucovorin.

Oxaliplatin, when combined with 5-fluorouracil and leucovorin, results in a higher response rate compared to 5-fluorouracil alone, and it has shown clinical activity even in patients whose disease progressed on previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel chemotherapeutic agents for gastrointestinal cancers. Royce, ME., Pazdur, R.[2019]

In a study involving 397 patients who underwent radical resection for gastric cancer, the combination treatments of 5-fluorouracil+adriamycin or epirubicin and methotrexate did not show significant improvements in overall survival (OS) or disease-free survival (DFS) compared to the control group.

The 5-year overall survival rates were nearly identical between the treatment arm (43%) and the control arm (44%), indicating that these combination therapies cannot be recommended as effective adjuvant treatments for gastric cancer post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG. Nitti, D., Wils, J., Dos Santos, JG., et al.[2020]

The PELF regimen (cisplatin, epirubicin, and leucovorin) demonstrated a significantly higher overall response rate (43%) compared to the FAM regimen (15%) in treating advanced gastric carcinoma, indicating its greater efficacy in inducing tumor responses.

Although the PELF combination was more effective, it also had higher toxicity compared to FAM, making it less suitable for routine clinical use despite its potential for further investigation in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research. Cocconi, G., Bella, M., Zironi, S., et al.[2017]

S-1, an oral chemotherapy drug combining tegafur with modulators, has shown advantages over standard 5-FU-based treatments for gastric cancer in large Phase III studies, making it a recommended option in treatment guidelines.

S-1, either alone or in combination with cisplatin, is non-inferior to traditional 5-FU regimens while offering greater convenience and reduced toxicity, highlighting its potential for higher efficacy in treating gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. Satoh, T., Sakata, Y.[2022]

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