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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of medications to treat a specific type of colon or rectal cancer that has spread. It tests the safety and effectiveness of combining chemotherapy drugs with monoclonal antibodies, which help the body fight cancer cells. The regimen, 3B-FOLFOX, includes drugs like Fluorouracil, Leucovorin Calcium, and Oxaliplatin. It targets individuals with colorectal cancer lacking a genetic trait known as microsatellite instability (MSS). This trial may suit those whose colorectal cancer has spread and who haven't received certain therapies. As a Phase 1, Phase 2 trial, it aims to understand how the treatment works in people and measures its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of botensilimab and balstilimab is generally safe, with no new immune-related safety issues reported. Some patients experienced side effects, but these were usually mild. Many participants in studies of these drugs did not have any unusual immune reactions.

Bevacizumab has been used before for treating advanced colorectal cancer, and its safety is well-known. Common side effects include high blood pressure and nosebleeds, which can be managed with medical care. Serious side effects are rare.

Fluorouracil, leucovorin calcium, and oxaliplatin are standard chemotherapy drugs used for many years to treat colorectal cancer. Common side effects include tiredness and nausea, which are well-understood and manageable. Oxaliplatin can cause nerve damage, leading to tingling in the hands and feet, especially with long-term use.

Overall, past studies have shown this combination of drugs to have a reasonable safety profile. However, as with any treatment, side effects can occur. Participants must be monitored closely to manage any potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the 3B-FOLFOX treatment for metastatic colorectal cancer because it combines several innovative approaches. Unlike the standard treatment options like FOLFOX alone, 3B-FOLFOX incorporates balstilimab and botensilimab, which are both checkpoint inhibitors. These drugs are designed to enhance the immune system's ability to fight cancer by blocking proteins that prevent immune cells from attacking cancer cells. Additionally, the trial is testing different doses of botensilimab to find the most effective and safest dosage, potentially improving patient outcomes. This multifaceted approach aims to offer a more targeted and powerful treatment for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer?

In this trial, participants will receive a combination of treatments for metastatic colorectal cancer. Research has shown that combining the drugs botensilimab and balstilimab, included in the treatment arms of this trial, may effectively treat a type of colorectal cancer without certain genetic changes, known as microsatellite stable (MSS) metastatic colorectal cancer. Specifically, this combination resulted in 42% of patients surviving for two years, with an average survival time of nearly 21 months. Another drug in the trial, bevacizumab, stops the growth of blood vessels that tumors need to survive, potentially improving treatment results. The chemotherapy mix, FOLFOX, directly attacks cancer cells to halt their growth. Together, these treatments in the various arms of this trial may better control the disease and improve patient outcomes. ^{1 2 6 7 8}

Who Is on the Research Team?

Marwan Fakih, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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

My kidneys are working well enough for treatment.

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

Life expectancy >= 3 months

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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 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]

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]

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]

Citations

1.

nature.com

nature.com/articles/s41591-024-03083-7

Botensilimab plus balstilimab in relapsed/refractory ...

Median follow-up was 6.3 months (range, 0.7–42.6 months), and the median duration of response (DOR) was not reached (NR; 95% CI, 4.2 months–NR).

2.

investor.agenusbio.com

investor.agenusbio.com/news/news-details/2025/Agenus-Presents-Data-at-ASCO-GI-Demonstrating-Impact-of-BOTBAL-in-Colorectal-Cancer-Across-Neoadjuvant-and-Advanced-Disease/default.aspx

Agenus Presents Data at ASCO GI Demonstrating Impact ...

Data from five presentations underscore the transformative potential of BOT/BAL across multiple lines of therapy in colorectal cancer.

3.

cancernetwork.com

cancernetwork.com/view/botensilimab-balstilimab-elicits-sustained-efficacy-in-mss-metastatic-crc

Botensilimab/Balstilimab Elicits Sustained Efficacy in MSS ...

Specifically, the combination attained a 42% 2-year survival rate as well as a median overall survival (OS) of 20.9 months among 123 patients ...

4.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.23

Preliminary results from a randomized, open-label, phase 2 ...

Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD−1; NCT ...

5.

oncodaily.com

oncodaily.com/oncolibrary/botensilimab-balstilimab-esmo-gi-2025

Botensilimab and Balstilimab Show Durable Survival in ...

Botensilimab plus balstilimab delivers 21-month overall survival in MSS colorectal cancer, per updated Phase 1b data at ESMO GI 2025.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06336902

NCT06336902 | Botensilimab Plus Balstilimab and Fasting ...

This phase Ib trial tests the safety, side effects, and effectiveness of botensilimab, and balstilimab in combination with a fasting mimicking diet and high ...

7.

investor.agenusbio.com

investor.agenusbio.com/news/news-details/2025/Agenus-BOTBAL-Achieves-42-Two-Year-Survival-in-Refractory-MSS-CRC-Advances-Toward-Registration-with-FDA-Alignment-on-Phase-3/default.aspx

Agenus' BOT/BAL Achieves 42% Two-Year Survival in ...

“Deep, durable responses and survival plateaus emerging at two years and beyond are rarely seen in microsatellite stable refractory colorectal ...

8.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38871975/

Botensilimab plus balstilimab in relapsed/refractory ... - PubMed

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. 2024 Sep ...