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

Trial Summary

What is the purpose of this trial?

The purpose of the study is to test the effects, both good and bad, of the research study drug Neratinib in combination with Trastuzumab, Pembrolizumab and FOLFOX chemotherapy. This study will also look at the safety of Neratinib in combination with Trastuzumab, Pembrolizumab and FOLFOX in HER2 overexpressing Gastroesophageal cancers.

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.

What data supports the effectiveness of the drug combination Neratinib + Chemotherapy for Stomach Cancer?

Research shows that 5-Fluorouracil (5-FU) and leucovorin are standard treatments for gastric cancer, and Trastuzumab has shown a survival benefit for patients with Her-2 positive gastric cancer, which is a type of stomach cancer. This suggests that combining these drugs with others like Neratinib could be effective. ^{1 2 3 4 5}

Is the combination of 5-FU, leucovorin, and oxaliplatin generally safe for humans?

The combination of 5-FU (a chemotherapy drug), leucovorin (a vitamin that enhances the effect of 5-FU), and oxaliplatin (a platinum-based drug) has been studied for safety in humans, particularly in treating colorectal cancer. These studies suggest that while the combination can be effective, it may also cause side effects, which are common with chemotherapy treatments. ^{6 7 8 9 10}

What makes the drug combination of Neratinib, Chemotherapy, and other agents unique for stomach cancer?

This treatment is unique because it combines multiple drugs, including Neratinib and Trastuzumab, which target specific cancer cell receptors, with chemotherapy agents like 5-Fluorouracil and Oxaliplatin. This approach aims to enhance effectiveness by targeting cancer cells more precisely, especially in cases where the cancer overexpresses certain proteins like Her-2, which is not addressed by standard chemotherapy alone. ^{3 4 9 11 12}

Research Team

Dae Won Kim, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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]

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]

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]

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 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]

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]

References

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

S-1 for the treatment of gastrointestinal cancer. [2022]

2. United States 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. [2017]

3. India pubmed.ncbi.nlm.nih.gov

Modified 5-fluorouracil/leucovorin/irinotecan as a feasible and efficacious second-line chemotherapeutic regimen in advanced gastric cancers. [2022]

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

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

5. England 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. [2022]

6. Germany 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. [2021]

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

Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. [2021]

8. United States 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. [2017]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer. [2021]

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

Novel chemotherapeutic agents for gastrointestinal cancers. [2019]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

Chemotherapy for advanced gastric cancer: review and update of current practices. [2023]

12. England 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. [2020]