3B-FOLFOX for Metastatic Colorectal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 1

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of chemotherapy, a drug that blocks blood vessel growth, and two immune-boosting drugs in patients with advanced colorectal cancer. The goal is to find the best dose and see how well this combination works. The treatment aims to kill cancer cells, cut off their nutrient supply, and help the immune system fight the cancer.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot be on systemic corticosteroids or other immunosuppressive medications within 30 days of starting the trial, except for certain conditions like inhaled or topical steroids. Additionally, you must wait 4 weeks after your last chemotherapy before starting the trial.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on certain immunosuppressive medications or corticosteroids above a specific dose before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the idea that 3B-FOLFOX for Metastatic Colorectal Cancer is an effective treatment?

The available research shows that combining drugs like oxaliplatin and irinotecan with 5-fluorouracil (5-FU) and leucovorin (LV) improves outcomes for patients with metastatic colorectal cancer. Specifically, these combinations have been shown to increase the time patients live without the disease getting worse and overall survival time. For example, adding oxaliplatin to 5-FU/LV has become a standard treatment because it leads to longer survival times. Additionally, bevacizumab, another component of 3B-FOLFOX, has been shown to improve survival when combined with other treatments. These findings suggest that 3B-FOLFOX is an effective treatment option for this condition. ^{1 2 3 4 5}

What data supports the effectiveness of the drug 3B-FOLFOX for treating metastatic colorectal cancer?

Research shows that combining bevacizumab (Avastin) with chemotherapy drugs like 5-fluorouracil (5-FU) and leucovorin (LV) improves survival in patients with metastatic colorectal cancer. Additionally, oxaliplatin, a component of the 3B-FOLFOX regimen, has been shown to enhance survival when used with 5-FU/LV in similar treatments. ^{1 2 3 4 5}

What safety data is available for the 3B-FOLFOX treatment in metastatic colorectal cancer?

The safety data for treatments involving components of 3B-FOLFOX, such as bevacizumab, fluorouracil, leucovorin, and oxaliplatin, have been evaluated in various studies. Bevacizumab combined with fluorouracil and leucovorin has shown improved survival rates but also increased adverse events. The FOLFOX4 regimen with bevacizumab was assessed for safety and efficacy as a first-line treatment. Additionally, the FOLFOXIRI regimen, which includes oxaliplatin, fluorouracil, leucovorin, and irinotecan, plus bevacizumab, showed improved survival but also a higher incidence of adverse events. These studies indicate that while the treatment can be effective, it is associated with significant safety concerns. ^{1 6 7 8 9}

Is the 3B-FOLFOX treatment generally safe for humans?

Research shows that treatments involving bevacizumab, fluorouracil, leucovorin, and oxaliplatin, which are part of the 3B-FOLFOX regimen, have been studied for safety in patients with metastatic colorectal cancer. While these treatments can improve survival, they may also increase the risk of side effects, especially in older patients. ^{1 6 7 8 9}

Is the drug combination Balstilimab, Bevacizumab, Botensilimab, Fluorouracil, Leucovorin Calcium, and Oxaliplatin promising for treating metastatic colorectal cancer?

Yes, this drug combination is promising for treating metastatic colorectal cancer. The use of Fluorouracil and Leucovorin Calcium with Oxaliplatin has shown improved outcomes in patients. Bevacizumab, a targeted therapy, has been proven to prolong survival in patients with advanced colorectal cancer. These advancements suggest that the combination could be effective. ^{2 10 11 12 13}

What makes the 3B-FOLFOX drug unique for treating metastatic colorectal cancer?

The 3B-FOLFOX drug is unique because it combines traditional chemotherapy agents like 5-fluorouracil, leucovorin, and oxaliplatin with newer targeted therapies such as balstilimab and botensilimab, which are designed to enhance the immune system's ability to fight cancer. This combination aims to improve treatment effectiveness by targeting cancer cells more precisely and boosting the body's natural defenses. ^{2 10 11 12 13}

Research Team

Marwan Fakih, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

Adults with microsatellite stable (MSS) metastatic colorectal cancer who haven't had certain treatments, have a life expectancy of at least 3 months, and are in good physical condition (ECOG <=1). They must not be allergic to oxaliplatin, agree to use contraception if applicable, and have no history of severe organ dysfunction or fistulas. Prior chemotherapy should be completed at least 4 weeks before the trial.

Inclusion Criteria

I am 18 years old or older.

My kidneys are working well enough for treatment.

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

I have moderate to severe nerve damage.

I have never had lung inflammation or similar lung issues that needed strong steroids.

I rely on IV for nutrition or hydration.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase I Treatment

Patients receive FOLFOX, bevacizumab, balstilimab, and botensilimab intravenously (IV) on study. Patients undergo imaging and blood sample collection.

6 weeks

Weekly visits (in-person)

Phase II Treatment

Patients are randomized to receive FOLFOX, bevacizumab, and balstilimab IV with botensilimab IV at either a lower or higher dose. Patients undergo imaging and blood sample collection.

Ongoing, up to 5 years

Regular visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including overall survival and progression-free survival assessments.

Up to 5 years

Periodic visits (in-person)

Treatment Details

Interventions

• Balstilimab
• Bevacizumab
• Botensilimab
• Fluorouracil
• Leucovorin Calcium
• Oxaliplatin

Trial Overview The trial is testing FOLFOX combined with Bevacizumab plus two monoclonal antibodies: Botensilimab and Balstilimab. It aims to find the safest doses and see how effective this combination is against MSS metastatic colorectal cancer by inhibiting tumor growth through various mechanisms including blocking blood vessel formation and activating immune responses.

Participant Groups

Group I: Phase II, Arm II (3B-FOLFOX) Experimental Treatment 11 Interventions

Patients receive FOLFOX, bevacizumab and balstilimab IV with botensilimab IV at a higher dose on study. Patients undergo an x-ray, CT scan, PET scan, and/or MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.

Group II: Phase II, Arm I (3B-FOLFOX) Experimental Treatment 11 Interventions

Patients receive FOLFOX, bevacizumab and balstilimab IV with botensilimab IV at a lower dose on study. Patients undergo an x-ray, CT scan, PET scan, and/or MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.

Group III: Phase I (3B-FOLFOX) Experimental Treatment 11 Interventions

Patients receive FOLFOX, bevacizumab, balstilimab, and botensilimab IV on study. Patients undergo an x-ray, CT scan, PET scan, and/or MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase IV trial involving 209 treatment-naïve patients with metastatic colorectal cancer, the combination of bevacizumab and FOLFIRI resulted in a median progression-free survival (PFS) of 11.1 months and a median overall survival (OS) of 22.2 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with most adverse events being mild (grade 1/2), while serious side effects like neutropenia and venous thromboembolic events occurred in over 10% of patients, indicating manageable safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Sobrero, A., Ackland, S., Clarke, S., et al.[2022]

Combination therapy using 5-fluorouracil (5-FU) with folinic acid (FA) alongside irinotecan or oxaliplatin is more effective than 5-FU/FA alone for first-line treatment of metastatic colorectal cancer, improving patient outcomes.

Oral fluoropyrimidines, such as capecitabine and UFT, show comparable effectiveness to intravenous 5-FU/FA in treating metastatic colorectal cancer, providing more treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of advanced colorectal cancer: where are we now and where do we go? Van Cutsem, E., Verslype, C., Demedts, I.[2013]

Capecitabine has been approved as a first-line treatment for metastatic colorectal carcinoma, showing similar effectiveness in disease progression and survival rates compared to traditional 5-FU/LV regimens, but its role as a single-agent substitute is still being evaluated.

Combining irinotecan or oxaliplatin with 5-FU/LV improves response rates and overall survival, with studies indicating that both regimens have equivalent efficacy, but irinotecan may offer better safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New systemic frontline treatment for metastatic colorectal carcinoma. Braun, AH., Achterrath, W., Wilke, H., et al.[2007]

Adding oxaliplatin and irinotecan to first-line therapies for metastatic colorectal cancer increases treatment options but complicates the choice of the best second-line therapy, highlighting the importance of considering patient-specific factors.

Irinotecan has been shown to improve survival in patients who previously failed 5-fluorouracil-based therapy, and combination regimens like IFL, FOLFOX, and FOLFIRI have demonstrated benefits in the second-line treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line treatment of patients with metastatic colorectal cancer. Rougier, P., Lepere, C.[2018]

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

A study of 106 metastatic colorectal cancer patients showed that FOLFIRI chemotherapy is similarly effective and safe for patients aged 75 years and older compared to those younger than 75, with no significant differences in response rates or survival outcomes.

While the elderly group had a lower rate of receiving FOLFIRI combined with bevacizumab and showed a tendency for higher rates of anemia and alopecia, the overall adverse event frequency was comparable between the two age groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of FOLFIRI or combined FOLFIRI and bevacizumab treatment as second-line chemotherapy for metastatic colorectal cancer patients aged 75 years and older]. Chika, N., Ishibashi, K., Okada, N., et al.[2015]

In a study of 69 Asian patients with metastatic colorectal cancer, the combination of FOLFOXIRI and bevacizumab resulted in a high progression-free survival (PFS) rate of 75.2% at 10 months, indicating its effectiveness as a first-line treatment.

However, this regimen was associated with significant adverse events, particularly high rates of neutropenia (72.5%) and hypertension (34.8%), highlighting the need for careful monitoring, especially in patients with specific UGT1A1 genetic polymorphisms that increase the risk of severe neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. Oki, E., Kato, T., Bando, H., et al.[2022]

In a study of 59 elderly patients (aged 70 and above) with metastatic colorectal cancer, the combination of capecitabine and bevacizumab resulted in a 34% overall response rate and 71% disease control, indicating its efficacy as a treatment option.

While the treatment was generally effective, 54% of patients experienced grade 3/4 adverse events, with some serious complications, highlighting the need for careful monitoring, especially in patients with lower kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. Feliu, J., Safont, MJ., Salud, A., et al.[2022]

In a study involving 84 patients with advanced colorectal cancer, the FOLFOX4 regimen showed a significantly higher overall response rate (ORR) of 40.5% compared to 9.5% for the FFG regimen, indicating greater efficacy for FOLFOX4.

While both treatment regimens were generally well tolerated, FOLFOX4 was associated with a higher incidence of peripheral neuropathy (42.9%) compared to FFG (2.4%), highlighting a safety concern with the FOLFOX4 regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer. Madajewicz, S., Waterhouse, DM., Ritch, PS., et al.[2021]

In a study of 107 patients with metastatic colorectal cancer, the combination of irinotecan plus bevacizumab showed similar efficacy to FOLFIRI plus bevacizumab, with median progression-free survival of 6.4 months versus 5.8 months, and overall survival of 16.6 months versus 16.5 months, respectively.

Omitting fluorouracil from the FOLFIRI regimen resulted in fewer adverse events, such as nausea and neutropenia, suggesting that irinotecan plus bevacizumab may be a safer second-line treatment option for patients who are refractory to fluoropyrimidines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. Matsubara, Y., Masuishi, T., Ogata, T., et al.[2023]

Adjuvant systemic therapy with 5-fluorouracil (5-FU) and folic acid is the established standard for treating stage III colorectal cancer, while new studies suggest that capecitabine may replace this standard treatment.

In metastatic colorectal cancer, combining 5-FU/folic acid with agents like CPT-11 or oxaliplatin (FOLFOX) has shown to significantly improve progression-free survival and overall survival, and targeted therapies like bevacizumab and cetuximab are emerging as effective options that enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adjuvant and palliative anticancer treatment of colon carcinoma in 2004]. Medinger, M., Steinbild, S., Mross, K.[2015]

In a phase III study involving 220 previously untreated patients with metastatic colorectal cancer, both treatment sequences (FOLFIRI followed by FOLFOX6 and vice versa) resulted in similar median survival rates of approximately 21.5 months and 20.6 months, indicating comparable efficacy.

The study revealed distinct toxicity profiles for each treatment sequence, with FOLFIRI causing more mucositis and nausea/vomiting, while FOLFOX6 was associated with higher rates of neutropenia and neurosensory toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. Tournigand, C., André, T., Achille, E., et al.[2023]

In a phase III study of 220 previously untreated patients with metastatic colorectal cancer, both treatment sequences (FOLFIRI followed by FOLFOX6 and vice versa) resulted in similar median survival rates of approximately 21.5 months and 20.6 months, indicating comparable efficacy.

The study revealed distinct toxicity profiles for the two treatment sequences, with FOLFIRI causing more mucositis and nausea/vomiting, while FOLFOX6 was associated with higher rates of neutropenia and neurosensory toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. Tournigand, C., André, T., Achille, E., et al.[2023]

References

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

Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

The treatment of advanced colorectal cancer: where are we now and where do we go? [2013]

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

New systemic frontline treatment for metastatic colorectal carcinoma. [2007]

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

Second-line treatment of patients with metastatic colorectal cancer. [2018]

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

Rapid evolution in colorectal cancer: therapy now and over the next five years. [2007]

6. Japan pubmed.ncbi.nlm.nih.gov

[The efficacy and safety of FOLFIRI or combined FOLFIRI and bevacizumab treatment as second-line chemotherapy for metastatic colorectal cancer patients aged 75 years and older]. [2015]

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

A Multicenter Clinical Phase II Study of FOLFOXIRI Plus Bevacizumab as First-line Therapy in Patients With Metastatic Colorectal Cancer: QUATTRO Study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer. [2022]

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

Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Impact of omitting fluorouracil from FOLFIRI plus bevacizumab as second-line chemotherapy for patients with metastatic colorectal cancer. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

[Adjuvant and palliative anticancer treatment of colon carcinoma in 2004]. [2015]

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

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. [2023]

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

FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. [2023]