Pump Chemotherapy for Colorectal Cancer

Recruiting at 39 trial locations

Overseen By Midhun Malla

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: ECOG-ACRIN Cancer Research Group

Must be taking: Standard chemotherapy

Disqualifiers: Liver tumor burden >70%, Prior liver radiation, Prior HAI, Cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 5 years

408 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial compares hepatic arterial infusion (HAI) (pump chemotherapy) in addition to standard of care chemotherapy versus standard of care chemotherapy alone in treating patients with colorectal cancer that has spread to the liver (liver metastases) and cannot be removed by surgery (unresectable). HAI uses a catheter to carry a tumor-killing chemotherapy drug called floxuridine directly into the liver. HAI is already approved by the Food and Drug Administration (FDA) for use in metastatic colorectal cancer to the liver, but it is only available at a small number of hospitals, and most of the time it is not used until standard chemotherapy stops working. Standard chemotherapy drugs 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. Adding HAI to standard chemotherapy may be effective in shrinking or stabilizing unresectable colorectal liver metastases.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it does require that you have stable or responding disease on first-line chemotherapy, which suggests you may need to continue with your existing chemotherapy regimen.

What data supports the effectiveness of the drug combination used in pump chemotherapy for colorectal cancer?

Research shows that combining oxaliplatin with 5-FU and leucovorin improves response rates and time to progression in colorectal cancer patients compared to using 5-FU and leucovorin alone. Additionally, targeted agents like bevacizumab enhance the outcomes of 5-FU-based regimens, further supporting the effectiveness of this drug combination. ^{1 2 3 4 5}

What safety data exists for pump chemotherapy treatments for colorectal cancer?

Pump chemotherapy treatments, like those involving oxaliplatin, leucovorin, and 5-fluorouracil (5-FU), can cause side effects such as neutropenia (low white blood cell count), peripheral neuropathy (nerve damage), nausea, diarrhea, and mucositis (inflammation of the digestive tract). Irinotecan and 5-FU can also cause diarrhea, which may be severe. It's important to monitor for these side effects during treatment. ^{6 7 8 9 10}

What makes the pump chemotherapy treatment for colorectal cancer unique?

Pump chemotherapy for colorectal cancer is unique because it combines multiple drugs like Floxuridine, Fluorouracil, Irinotecan, Leucovorin, and Oxaliplatin, which are administered through a pump, allowing for continuous infusion. This method can enhance the effectiveness of the treatment by maintaining a steady drug level in the body, potentially improving outcomes compared to traditional bolus (single large dose) administration. ^{3 11 12 13 14}

Research Team

Michael Lidsky

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

Adults with colorectal cancer that has spread to the liver and can't be surgically removed may join. They should have stable or no extra liver disease, possibly small lung nodules, and must have had 3-6 months of initial chemotherapy with certain drugs. Those who've had new liver metastases within a year after adjuvant therapy for stage II-III colorectal cancer are also eligible.

Inclusion Criteria

My primary cancer tumor has not been removed.

My cancer cannot be removed with surgery.

Patient must meet specific laboratory criteria

Exclusion Criteria

My liver metastases cannot be removed with a two-stage surgery.

Patient must not have certain medical conditions

All patients of childbearing potential must have a negative pregnancy test within 14 days prior to randomization

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either hepatic arterial infusion (HAI) with floxuridine and standard chemotherapy or standard chemotherapy alone. Treatment includes surgery for HAI pump placement and regular CT scans.

Up to 5 years

Regular visits for chemotherapy administration and imaging

Follow-up

Participants are monitored for overall survival, progression-free survival, and response rate through regular imaging every 3 months.

Up to 5 years

Imaging every 3 months

Treatment Details

Interventions

• Bevacizumab
• Cetuximab
• Floxuridine
• Fluorouracil
• Intrahepatic Infusion Procedure
• Irinotecan
• Leucovorin
• Oxaliplatin
• Panitumumab

Trial Overview The PUMP trial is testing if adding pump chemotherapy (HAI) directly into the liver using floxuridine improves outcomes compared to standard chemotherapy alone in patients with unresectable colorectal liver metastases. The study will compare tumor shrinkage and stability between both treatments.

Participant Groups

Group I: Arm A (HAI, floxuridine, standard chemotherapy) Experimental Treatment 11 Interventions

Patients undergo surgery to place the HAI pump, followed by SPECT/CT on study. Patients then receive floxuridine via the HAI pump on study. Patients also receive one of the following standard chemotherapy regimens per the treating physician: FOLFOX, FOLFIRI, or OX/IRI with or without cetuximab IV and/or panitumumab IV on study. Patients also undergo CT scans throughout the trial.

Group II: Arm B (standard chemotherapy) Active Control 8 Interventions

Patients receive one of the following standard chemotherapy regimens per the treating physician: FOLFOXIRI, FOLFOX, FOLFIRI, or OX/IRI with or without cetuximab IV, panitumumab IV, and/or bevacizumab IV on study. Patients also undergo CT scans throughout the trial.

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

Approved in United States as Floxuridine for:

• Metastatic colorectal cancer
• Gastrointestinal adenocarcinoma metastatic to the liver

Approved in European Union as Floxuridine for:

• Gastrointestinal adenocarcinoma metastatic to the liver

Who Is Running the Clinical Trial?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 79 patients with advanced colorectal cancer, an alternating treatment schedule of 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan achieved a 54% objective response rate, indicating significant efficacy in managing the disease.

The treatment was associated with manageable toxicity, with no grade 3/4 neurotoxicity and no toxic deaths reported, suggesting a safer profile compared to traditional sequential therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. Aparicio, J., Fernandez-Martos, C., Vincent, JM., et al.[2022]

The evolution of chemotherapy for colorectal cancer has shifted from the single-agent use of 5-fluorouracil (5-FU) to more effective combination regimens that include irinotecan, oxaliplatin, and targeted agents like bevacizumab, significantly improving patient survival rates.

Combination therapies utilizing 5-FU as a base have been shown to enhance treatment outcomes, highlighting the importance of integrating newer drugs into established regimens for better management of colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to first-line treatment of advanced colorectal cancer. Goldberg, RM.[2019]

The combination of traditional chemotherapy agents like fluorouracil (5FU) with newer drugs such as irinotecan and oxaliplatin has significantly improved treatment effectiveness for colorectal cancer, leading to better patient outcomes.

Emerging targeted therapies are showing promise in reducing toxicity compared to traditional chemotherapy, and their integration into treatment protocols may extend survival rates for metastatic colorectal cancer patients from 2 to potentially 3 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The modern treatment of colorectal cancer. Present and future]. András, C., Farczádi, E., Szántó, J.[2018]

Oxaliplatin, a new platinum analog, shows high effectiveness in treating metastatic colorectal cancer, particularly when used in combination with 5-FU and leucovorin, which has led to its approval in Europe for first- and second-line treatments.

This ongoing compassionate-use study aims to provide oxaliplatin to patients in the United States who have no adequate second- or third-line therapy options available, highlighting the urgent need for safety data and FDA approval for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin with 5-FU or as a single agent in advanced/metastatic colorectal cancer. Mitchell, EP.[2018]

Fluorouracil (5-FU) has been the standard treatment for advanced colorectal cancer for over 40 years, but only a small number of patients show a significant clinical response, highlighting the need for improved therapies.

New oral fluoropyrimidines and combination therapies with oxaliplatin or irinotecan have shown comparable efficacy to traditional 5-FU treatments while reducing side effects like febrile neutropenia and mucositis, suggesting a promising direction for enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colorectal cancer: chemotherapy treatment overview. Royce, ME., Medgyesy, D., Zukowski, TH., et al.[2018]

In a phase II study involving 46 patients with advanced colorectal cancer resistant to previous treatments, the FOLFOX2 regimen (oxaliplatin, leucovorin, and 5-FU) achieved a high overall response rate of 46%, including one complete response and 20 partial responses.

The treatment was associated with manageable toxicities, primarily neutropenia (39%) and peripheral neuropathy (9%), indicating that while the regimen is effective, careful monitoring for these side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. de Gramont, A., Vignoud, J., Tournigand, C., et al.[2019]

In a study involving 19 patients with metastatic colorectal cancer, the combination of irinotecan (CPT-11) and doxifluridine (5'-DFUR) showed manageable safety, with severe diarrhea occurring in only one patient, indicating a favorable safety profile for this regimen.

The recommended dosing for further studies was established at CPT-11 150 mg/m2 and 5'-DFUR 800 mg, based on the observed tolerability and efficacy in both murine models and human trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential treatment with irinotecan and doxifluridine: optimal dosing schedule in murine models and in a phase I study for metastatic colorectal cancer. Mishima, H., Kato, T., Yanagisawa, M., et al.[2018]

Oral fluorinated pyrimidines, such as capecitabine and S-1, offer a more convenient and potentially less toxic alternative to traditional intravenous 5-fluorouracil (5-FU) chemotherapy, providing prolonged drug exposure at lower peak concentrations.

The review highlights that different oral fluoropyrimidines exhibit varying toxicity profiles compared to 5-FU, and ongoing phase III trials are essential to determine their effectiveness in treating colorectal cancer compared to standard 5-FU regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral fluoropyrimidines: a closer look at their toxicities. Macdonald, JS.[2019]

5-fluorouracil (5-FU) combined with leukovorin is commonly used for treating metastatic colorectal cancer, but it can cause severe gastrointestinal side effects, including stomatitis and diarrhea, which can be life-threatening in up to 30% of patients.

This case report highlights therapy-induced enteritis as a serious complication of 5-FU treatment, emphasizing the need for early recognition and intervention to prevent significant morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteritis as a complication of adjuvant combination chemotherapy using 5-fluorouracil and leukovorin: clinical and helical computed tomographic features. Zamani, R., Heldmann, M.[2022]

The FOLFOX regimen, which combines Leucovorin and fluorouracil with oxaliplatin, is a standard first-line treatment for metastatic colorectal cancer, but it has significant side effects including neutropenia and sensory neuropathy.

Immediate hypersensitivity reactions, such as anaphylaxis, can occur in up to 0.6% of patients receiving FOLFOX, highlighting the importance of monitoring for adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[FOLFOX]. Mishima, H., Ikenaga, M., Tsujinaka, T., et al.[2013]

Five years after surgery and chemotherapy, about 10% more patients with Dukes C colon cancer are disease-free compared to those who did not receive treatment, highlighting the efficacy of adjuvant chemotherapy.

5-fluorouracil combined with folinic acid (5FU/FA) significantly improves survival rates for patients with disseminated colorectal cancer, doubling survival compared to best supportive care and enhancing quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Colorectal cancer: a controllable disease]. Bleiberg, H., Gerard, B.[2013]

In a study of 89 patients with advanced colorectal cancer, the combination of infusional 5-fluorouracil (5-FU) and oxaliplatin showed the best overall survival, with a median survival time of 17 months, compared to 15 months for bolus 5-FU and 11 months for 5-FU with CPT-11.

The results suggest that infusional 5-FU can be effectively used as a foundation for sequential chemotherapy regimens, particularly when combined with oxaliplatin, while CPT-11 alone did not provide sufficient efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mayo regimen plus three different second-line chemotherapy regimens in sequential therapy in patients with advanced colorectal cancer (ACRC). Popov, IP., Jelic, SB., Matijasevic, MM., et al.[2018]

5-Fluorouracil (5-FU) has been the standard treatment for colorectal cancer for 40 years, but its overall survival benefit remains limited to about 12 months, even with enhancements like leucovorin.

Capecitabine has been shown to be as effective as 5-FU and is now a first-line treatment, especially when combined with other agents like CPT-11 or oxaliplatin, which improve response rates and overall survival in patients with advanced colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of colorectal cancer metastasis: the role of chemotherapy. Xiong, HQ., Ajani, JA.[2019]

A patient with metastatic rectal cancer experienced port thrombosis after receiving a mixed infusion of calcium folinate and 5-fluorouracil (5-FU) over 24 hours, highlighting potential complications of this treatment method.

Analysis of the catheter revealed calcium carbonate buildup, indicating that the combination of these two drugs may not be safe for routine clinical use without further validated clinical data on their compatibility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Catheter occlusion by calcium carbonate during simultaneous infusion of 5-FU and calcium folinate. Bruch, HR., Esser, M.[2017]

References

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

FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. [2022]

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

Current approaches to first-line treatment of advanced colorectal cancer. [2019]

3. Hungary pubmed.ncbi.nlm.nih.gov

[The modern treatment of colorectal cancer. Present and future]. [2018]

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

Oxaliplatin with 5-FU or as a single agent in advanced/metastatic colorectal cancer. [2018]

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

Colorectal cancer: chemotherapy treatment overview. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Sequential treatment with irinotecan and doxifluridine: optimal dosing schedule in murine models and in a phase I study for metastatic colorectal cancer. [2018]

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

Oral fluoropyrimidines: a closer look at their toxicities. [2019]

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

Enteritis as a complication of adjuvant combination chemotherapy using 5-fluorouracil and leukovorin: clinical and helical computed tomographic features. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

[FOLFOX]. [2013]

11. Belgium pubmed.ncbi.nlm.nih.gov

[Colorectal cancer: a controllable disease]. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Mayo regimen plus three different second-line chemotherapy regimens in sequential therapy in patients with advanced colorectal cancer (ACRC). [2018]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of colorectal cancer metastasis: the role of chemotherapy. [2019]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Catheter occlusion by calcium carbonate during simultaneous infusion of 5-FU and calcium folinate. [2017]