Ramucirumab + Trifluridine/Tipiracil or Paclitaxel for Gastric Cancer

Recruiting at 7 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Academic and Community Cancer Research United

Must not be taking: Antiplatelets, Antiretrovirals

Disqualifiers: Pregnancy, Severe disease, Recent surgery, 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: 31

Duration: Up to 36 cycles (approximately 3 years)

116 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on warfarin, you must switch to low molecular weight heparin before starting the trial. Also, if you are on full-dose anticoagulation, you need to be on a stable dose for at least 14 days before starting the trial.

What data supports the effectiveness of the drug combination of Ramucirumab and Trifluridine/Tipiracil for gastric cancer?

Trifluridine/Tipiracil has been shown to improve overall survival and disease control in patients with metastatic gastric cancer, as demonstrated in the TAGS trial. Additionally, Ramucirumab, alone or with Paclitaxel, has been effective as a second-line therapy for advanced gastric cancer, according to the REGARD and RAINBOW trials. ^{1 2 3 4 5}

Is the combination of Ramucirumab and Trifluridine/Tipiracil safe for treating gastric cancer?

The combination of Ramucirumab and Trifluridine/Tipiracil for advanced gastric cancer has shown an acceptable safety profile in clinical trials. Common side effects include blood-related issues like neutropenia (low white blood cell count) and gastrointestinal problems such as nausea and diarrhea, which are generally manageable with dosage adjustments and supportive care. ^{1 4 5 6 7}

What makes the drug combination of Ramucirumab, Trifluridine/Tipiracil, and Paclitaxel unique for treating gastric cancer?

This drug combination is unique because it combines Ramucirumab, which targets blood vessel growth in tumors, with Trifluridine/Tipiracil, a chemotherapy that disrupts cancer cell DNA, and Paclitaxel, another chemotherapy that prevents cancer cells from dividing. This multi-faceted approach aims to enhance effectiveness against advanced gastric cancer compared to using these drugs individually. ^{3 5 6 8 9}

What is the purpose of this trial?

This phase II trial studies the effect of the combination of ramucirumab and trifluridine/tipiracil or paclitaxel in treating patients with previously treated gastric or gastroesophageal junction cancer that has spread to other places in the body (advanced). Ramucirumab may damage tumor cells by targeting new blood vessel formation. Trifluridine/tipiracil is a chemotherapy pill and that may damage tumor cells by damaging their deoxyribonucleic acid (DNA). Paclitaxel may block cell growth by stopping cell division which may kill tumor cells. Giving ramucirumab and trifluridine/tipiracil will not be worse than ramucirumab and paclitaxel in treating gastric or gastroesophageal junction cancer.

Research Team

Mohamad B Sonbol

Principal Investigator

Academic and Community Cancer Research United

Eligibility Criteria

Adults with advanced gastric or gastroesophageal junction cancer that has worsened within 6 months after treatment can join. They must have had prior chemotherapy, be in good physical condition, and able to take oral meds. Pregnant women, nursing mothers, those with recent serious health issues like heart attacks or uncontrolled hypertension are excluded.

Inclusion Criteria

Hemoglobin >= 9.0 g/dL (obtained =< 7 days prior to registration)

Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3 x ULN ( =< 5.0 x UNL, if with liver metastasis) (obtained =< 7 days prior to registration)

My advanced cancer has worsened within 6 months after my last treatment.

Exclusion Criteria

I understand the study drug's effects on unborn babies are unknown.

I have been treated with TAS-102 or ramucirumab before.

I received taxane therapy less than 6 months ago.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either TAS-102 and ramucirumab or paclitaxel and ramucirumab. Treatment repeats every 28 days for up to 36 cycles.

Up to 36 cycles (approximately 3 years)

Visits on days 1, 8, and 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

Follow-up at 30-35 days post-treatment, then every 3 months

Treatment Details

Interventions

• Paclitaxel
• Ramucirumab
• Trifluridine and Tipiracil Hydrochloride

Trial Overview The trial is testing the effectiveness of ramucirumab combined with either trifluridine/tipiracil or paclitaxel in patients who've already been treated for advanced stomach cancers. Ramucirumab targets blood vessel growth in tumors while the other drugs aim to damage tumor DNA or block cell growth.

Participant Groups

Group I: Arm A (TAS-102, ramucirumab) Experimental Treatment 3 Interventions

Patients receive TAS-102 PO BID on days 1-5 and 8-12, and ramucirumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (paclitaxel, ramucirumab) Active Control 3 Interventions

Patients receive paclitaxel IV over 1-96 hours on days 1, 8, and 15, and ramucirumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Taxol for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Approved in European Union as Taxol for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Approved in Canada as Paclitaxel for:

• Ovarian cancer
• Breast cancer
• Non-small cell lung cancer
• Kaposi's sarcoma

Who Is Running the Clinical Trial?

Academic and Community Cancer Research United

Lead Sponsor

Trials

54

Recruited

4,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Trifluridine/tipiracil (Lonsurf®) has been shown to significantly improve overall survival in patients with metastatic gastric cancer who have previously undergone at least two treatment regimens, as demonstrated in the phase III TAGS trial.

The treatment not only enhances survival and progression-free survival but also maintains health-related quality of life, with manageable side effects primarily related to blood cell counts and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer. Kang, C., Dhillon, S., Deeks, ED.[2020]

In a study involving 167 patients with advanced gastric cancer, ramucirumab was found to be well tolerated, with a low incidence of severe toxicity (9.6%) and only 3% of patients discontinuing treatment due to adverse effects.

The treatment showed a 20.2% overall response rate and a median overall survival of 8.0 months, indicating that ramucirumab is effective in a real-life setting, consistent with results from previous randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study. Di Bartolomeo, M., Niger, M., Tirino, G., et al.[2023]

In a study of 23 advanced gastric cancer patients, those treated with ramucirumab (RAM) plus paclitaxel (PTX) showed a higher overall response rate (30%) and longer progression-free survival (187 days) compared to those treated with RAM alone (10% response rate and 54 days progression-free survival).

Both treatment regimens were found to be safe for outpatient administration, with fewer severe hematological adverse events in the RAM group (1 case) compared to the PTX+RAM group (6 cases), indicating that while combination therapy may be more effective, it also carries a higher risk of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Experience of Ramucirumab for Treating Advanced Gastric Cancer]. Kimura, Y., Makari, Y., Mikami, J., et al.[2023]

Trifluridine/tipiracil (TAS-102) has been approved for treating metastatic gastric and gastroesophageal junction adenocarcinoma after showing significant improvement in overall survival (5.7 months) compared to placebo (3.6 months) in a Phase III trial with patients who had undergone at least two lines of chemotherapy.

The treatment demonstrated a disease control rate of over 50% after eight weeks and did not impair quality of life, while the most common serious side effect was neutropenia, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date. Wheelden, M., Yee, NS.[2020]

In a study of 101 advanced gastric cancer patients, the combination of trifluridine/tipiracil and ramucirumab showed a higher objective response rate (13.5%) and disease control rate (64.9%) compared to trifluridine/tipiracil alone (3.8% and 42.3%, respectively).

Patients receiving the combination treatment also experienced significantly longer median progression-free survival (3.0 months vs. 1.8 months) and overall survival (7.2 months vs. 3.8 months), indicating that this combination therapy may be more effective than monotherapy without unexpected adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trifluridine/tipiracil plus ramucirumab in comparison with trifluridine/tipiracil monotherapy for patients with advanced gastric cancer-single institutional experience. Okunaka, M., Kawazoe, A., Nakamura, H., et al.[2023]

In a phase 2 study involving 64 patients with advanced gastric cancer, the combination of trifluridine/tipiracil and ramucirumab demonstrated a high disease control rate of 85% in patients previously treated with one line of chemotherapy and 77% in those treated with two to four lines, indicating strong clinical activity.

The treatment was generally well-tolerated, with serious adverse events occurring in only three patients from the cohort treated with one prior chemotherapy, while no serious treatment-related adverse events were reported in the cohort with more extensive prior treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial. Kawazoe, A., Ando, T., Hosaka, H., et al.[2023]

Trifluridine/tipiracil is an effective oral chemotherapy for patients with advanced gastric cancer who have not responded to standard treatments, showing improved survival rates in heavily pretreated patients.

The therapy has been approved in multiple regions, including the U.S., Japan, and the EU, and is currently being studied in combination with other treatments, indicating its potential as a key option in gastric cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trifluridine/tipiracil for the treatment of metastatic gastric cancer. Kawazoe, A., Shitara, K.[2020]

Ramucirumab, a monoclonal antibody targeting VEGFR-2, has been shown to be safe and effective for patients with advanced gastric cancer, particularly when combined with paclitaxel.

However, there is a risk of serious adverse events, such as gastrointestinal perforation, as demonstrated in a case of a 67-year-old man who developed this complication after treatment, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of ramucirumab-related gastrointestinal perforation in gastric cancer with small bowel metastasis. Urakawa, S., Sakai, D., Miyazaki, Y., et al.[2020]

In a study of 26 patients with advanced gastric cancer, high levels of placental growth factor (PlGF) were associated with poor treatment outcomes for ramucirumab (RAM), indicating that PlGF expression could serve as a predictive biomarker for RAM efficacy.

Patients with low PlGF levels had a 50% overall response rate to RAM treatment, while those with high PlGF levels showed no response, suggesting that targeting PlGF may enhance the effectiveness of RAM therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer. Natsume, M., Shimura, T., Iwasaki, H., et al.[2023]

References

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

Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer. [2020]

2. France pubmed.ncbi.nlm.nih.gov

Ramucirumab as Second-Line Therapy in Metastatic Gastric Cancer: Real-World Data from the RAMoss Study. [2023]

3. Japan pubmed.ncbi.nlm.nih.gov

[Clinical Experience of Ramucirumab for Treating Advanced Gastric Cancer]. [2023]

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

Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date. [2020]

5. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and safety of trifluridine/tipiracil plus ramucirumab in comparison with trifluridine/tipiracil monotherapy for patients with advanced gastric cancer-single institutional experience. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial. [2023]

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

Trifluridine/tipiracil for the treatment of metastatic gastric cancer. [2020]

8. Germany pubmed.ncbi.nlm.nih.gov

A case of ramucirumab-related gastrointestinal perforation in gastric cancer with small bowel metastasis. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer. [2023]