Ramucirumab + Chemotherapy for Small Bowel Cancer

Recruiting at 451 trial locations

Overseen By Dana Sparks

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Southwest Oncology Group

Must not be taking: Antiplatelet therapy

Disqualifiers: Irinotecan, Taxane, Ramucirumab, 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: 8

Duration: 28 days per cycle

94 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies how well ramucirumab and paclitaxel or the FOLFIRI regimen (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) work in treating patients with small bowel cancers that have spread extensively to other anatomic sites (advanced) or are no longer responding to treatment (refractory). Ramucirumab is a monoclonal antibody that attaches to and inhibits a molecule called VEGFR-2. This may restrain new blood vessel formation therefore reducing nutrient supply to tumor which may interfere with tumor cell growth and expansion. Drugs used in chemotherapy, such as paclitaxel, leucovorin calcium, fluorouracil, and irinotecan hydrochloride work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving Ramucirumab plus paclitaxel or FOLFIRI, may be helpful in treating advanced or refractory small bowel cancers and may help patients live longer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on chronic antiplatelet therapy like dipyridamole or clopidogrel. You also need to have completed any prior chemotherapy, immunotherapy, or radiation therapy at least 14 days before joining the trial.

Is the combination of Ramucirumab and chemotherapy safe for humans?

The combination of chemotherapy drugs like fluorouracil, leucovorin, and irinotecan has been studied for safety in various cancers, showing that they can cause side effects such as diarrhea, myelosuppression (reduced bone marrow activity), and neurotoxicity (nerve damage). However, supportive measures and dose adjustments can help manage these side effects. Ramucirumab, when combined with chemotherapy, has been used in other cancers, but specific safety data for small bowel cancer is not detailed in the provided research. ^{1 2 3 4 5}

What makes the drug combination of Ramucirumab and chemotherapy unique for small bowel cancer?

This treatment is unique because it combines ramucirumab, a drug that targets blood vessel growth in tumors, with a chemotherapy regimen that includes drugs like fluorouracil and irinotecan, which are typically used for colorectal cancer. This combination may offer a novel approach for small bowel cancer, a condition with limited standard treatment options. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination Ramucirumab + Chemotherapy for Small Bowel Cancer?

Research shows that chemotherapy, including drugs like 5-fluorouracil (5-FU) and irinotecan, can help prolong survival in patients with small bowel adenocarcinoma. Additionally, studies on similar drug combinations for colorectal cancer have shown positive responses, suggesting potential benefits for small bowel cancer as well. ^{6 10 11 12 13}

Who Is on the Research Team?

Michael J Overman

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for patients with advanced or refractory small bowel adenocarcinoma, excluding ampullary types. Participants must have previously progressed on fluoropyrimidine and/or oxaliplatin treatments, be at least 30 days stable post-brain metastases treatment if applicable, and not have had recent major surgery. They should not be pregnant/nursing, must agree to use contraception if of reproductive potential, and cannot have certain conditions like uncontrolled hypertension or a history of significant thromboembolism.

Inclusion Criteria

I have another cancer type, but it won't affect this trial's treatment.

I can carry out all my usual activities without help.

My liver function tests are within the required range.

Exclusion Criteria

Patients must not be currently enrolled in or have discontinued within the last 28 days a clinical trial involving an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Patients participating in surveys or observational studies are eligible to participate in this study

My liver functions well, without severe disease or complications like serious fluid buildup.

I have not had a heart attack or stroke in the last 4 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ramucirumab and paclitaxel or FOLFIRI regimen. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Multiple visits per cycle for IV administration

Follow-up

Participants are monitored every 8 weeks until disease progression, then every 6 months for up to 3 years post registration.

Up to 3 years

Every 8 weeks, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Fluorouracil
• Irinotecan
• Irinotecan Hydrochloride
• Leucovorin
• Leucovorin Calcium
• Paclitaxel
• Ramucirumab

Trial Overview The study compares the effectiveness of Ramucirumab combined with Paclitaxel versus the FOLFIRI regimen (Fluorouracil, Leucovorin Calcium, Irinotecan Hydrochloride) in treating advanced small bowel cancers. Ramucirumab is an antibody that may inhibit tumor growth by blocking blood vessel formation while other drugs aim to kill or stop cancer cells from dividing.

How Is the Trial Designed?

Group I: Arm II (irinotecan, leucovorin, fluorouracil) Experimental Treatment 5 Interventions

Patients receive irinotecan IV over 90 minutes on days 1 and 15, leucovorin IV over 2 hours on days 1 and 15, and fluorouracil IV bolus on days 1 and 15. Patients also receive fluorouracil IV over 46-48 hours on days 1-3 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (ramucirumab, paclitaxel) Experimental Treatment 2 Interventions

Patients receive ramucirumab IV over 30-60 minutes on days 1 and 15, and paclitaxel IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 20 patients with advanced small bowel adenocarcinoma, chemotherapy combining 5-fluorouracil (5-FU) with platinum compounds showed a 21% overall response rate, with median progression-free survival of 8 months and overall survival of 14 months, indicating moderate efficacy and tolerability.

The combination of 5-FU and irinotecan demonstrated promising results, with 50% of patients achieving disease stabilization and one patient experiencing a complete biological response, suggesting that this combination warrants further investigation as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy in advanced small bowel adenocarcinoma. Locher, C., Malka, D., Boige, V., et al.[2022]

In a phase II study involving 24 patients with metastatic or recurrent small bowel adenocarcinoma, the mFOLFOX6 chemotherapy regimen demonstrated a 1-year progression-free survival (PFS) rate of 23.3%, indicating some efficacy as a first-line treatment.

The treatment was generally well tolerated, with no treatment-related deaths reported, although significant side effects included neutropenia (38%) and anemia/peripheral neuropathy (25%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. Horimatsu, T., Nakayama, N., Moriwaki, T., et al.[2022]

In a study of 74 patients with metastatic colorectal cancer (mCRC) receiving second-line treatment with FOLFIRI plus ramucirumab, the median progression-free survival (PFS) was 6.2 months and median overall survival (OS) was 17.0 months, indicating a significant therapeutic benefit.

Patients who had not previously received bevacizumab (bevacizumab-naïve) showed better treatment responses, with a response rate of 23% and a disease control rate of 85%, compared to only 3% and 69% in those who had received bevacizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line FOLFIRI plus ramucirumab with or without prior bevacizumab for patients with metastatic colorectal cancer. Suzuki, T., Shinozaki, E., Osumi, H., et al.[2023]

Irinotecan has shown significant activity against advanced colorectal cancer when combined with traditional chemotherapy agents like fluorouracil, leading to clinical responses including complete remissions in patients.

The combination therapies have acceptable toxicity profiles, with neutropenia and delayed diarrhea being the most common side effects, indicating that irinotecan could be a safe option for treatment, although further large-scale phase III studies are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Khayat, D., Gil-Delgado, M., Antoine, EC., et al.[2018]

In a phase II study involving 97 patients with metastatic colorectal cancer, the combination of methotrexate, leucovorin, and 5-fluorouracil resulted in a partial or complete response in 31% of patients, with a median response duration of 6.4 months.

The treatment showed a median overall survival of 13 months and a 1-year survival rate of 53.7%, with manageable side effects such as mucositis, nausea, and vomiting, indicating a modest clinical benefit of this chemotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer--a phase II study. Tomlinson, SK., Melin, SA., Higgs, V., et al.[2019]

A systematic review of 13 studies found that reducing the dose of leucovorin in chemotherapy regimens combining it with fluorouracil does not significantly impact the efficacy of treatment for colorectal cancer.

Lower doses of leucovorin also do not increase the frequency or severity of adverse effects, and in some cases, higher doses were associated with more side effects, indicating that dose adjustments may be a safe alternative during drug shortages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High vs. low-dose leucovorin in regimens with fluorouracil in colorectal cancer therapy. Juřica, J., Šuverová, P., Goněc, R., et al.[2023]

In a study involving 14 patients with stage III colon cancer undergoing FOLFOX6 chemotherapy, pretreatment with the MRI contrast agent mangafodipir significantly reduced severe adverse events (AEs) compared to a placebo, with no severe AEs reported in the mangafodipir group.

Patients receiving mangafodipir also had a significantly higher white blood cell count after treatment, suggesting that it may help protect against neutropenia, a common side effect of chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First clinical experience with the magnetic resonance imaging contrast agent and superoxide dismutase mimetic mangafodipir as an adjunct in cancer chemotherapy-a translational study. Karlsson, JO., Adolfsson, K., Thelin, B., et al.[2021]

In a case study of a 43-year-old man with rectal adenocarcinoma undergoing preoperative radiochemotherapy, severe colitis was observed, likely related to the chemotherapy drug 5-fluorouracil (5-FU), despite the inflammation being confined to non-irradiated areas.

The authors hypothesized that low-dose radiation may have an anti-inflammatory effect that mitigated 5-FU-induced colitis early in treatment, suggesting the need for careful differentiation between radiation and chemotherapy side effects to optimize individual therapy plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does radiation prevent 5-fluorouracil-induced colitis in the early phase of radiochemotherapy? A case report and literature review. Rischke, HC., Momm, F., Henke, M., et al.[2013]

In a study of 187 patients with metastatic colorectal cancer, the combination of S-1 and irinotecan (with or without bevacizumab) showed similar overall response rates and survival outcomes compared to the standard FOLFOX regimen, indicating comparable efficacy.

S-1 and irinotecan were well tolerated, with gastrointestinal side effects being the most common, while FOLFOX was associated with neutropenia and sensory neuropathy, suggesting a different safety profile for the two treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies. Iwasa, S., Nagashima, K., Yamaguchi, T., et al.[2018]

Chemotherapy agents like fluorouracil and oxaliplatin can cause significant side effects in colorectal cancer treatment, but strategies like therapeutic drug monitoring and chronomodulation have shown promise in reducing these adverse effects in clinical trials.

Supportive measures, including specific medications and schedule adjustments, are essential for managing side effects such as myelosuppression and nausea, emphasizing the need for individualized patient care and teamwork among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer. Jansman, FG., Sleijfer, DT., de Graaf, JC., et al.[2018]

In a study comparing FOLFIRI plus ramucirumab (F-RAM) to TAS-102 for treating metastatic colorectal cancer, both treatments showed no significant difference in overall survival, with median survival times of 6.1 months for both groups.

However, F-RAM was associated with more frequent adverse events and significantly higher costs ($81,724.8 for F-RAM vs. $18,931.4 for TAS-102), indicating that TAS-102 is a more favorable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk Benefit of FOLFIRI Plus Ramucirumab as Third-line and Later-line Treatment of Metastatic Colorectal Cancer. Kimura, M., Usami, E., Teramachi, H., et al.[2023]

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]

Ramucirumab, a monoclonal antibody targeting VEGFR2, has been approved for use with FOLFIRI in patients with metastatic colorectal cancer (mCRC) who have progressed after initial treatments, showing significant improvements in progression-free and overall survival.

The RAISE phase III trial demonstrated that adding ramucirumab to irinotecan-based chemotherapy resulted in manageable toxicity, indicating it is a safe and effective option for mCRC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of ramucirumab for the treatment of metastatic colorectal cancer. Diaz-Serrano, A., Riesco-Martinez, MC., Garcia-Carbonero, R.[2023]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Combination chemotherapy in advanced small bowel adenocarcinoma. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Second-line FOLFIRI plus ramucirumab with or without prior bevacizumab for patients with metastatic colorectal cancer. [2023]

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

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer--a phase II study. [2019]

6. Czech Republic pubmed.ncbi.nlm.nih.gov

High vs. low-dose leucovorin in regimens with fluorouracil in colorectal cancer therapy. [2023]

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

First clinical experience with the magnetic resonance imaging contrast agent and superoxide dismutase mimetic mangafodipir as an adjunct in cancer chemotherapy-a translational study. [2021]

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

Does radiation prevent 5-fluorouracil-induced colitis in the early phase of radiochemotherapy? A case report and literature review. [2013]

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

S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies. [2018]

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

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer. [2018]

11. Greece pubmed.ncbi.nlm.nih.gov

Risk Benefit of FOLFIRI Plus Ramucirumab as Third-line and Later-line Treatment of Metastatic Colorectal Cancer. [2023]

12. Germany pubmed.ncbi.nlm.nih.gov

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

13. England pubmed.ncbi.nlm.nih.gov

The safety and efficacy of ramucirumab for the treatment of metastatic colorectal cancer. [2023]