FOLFOX + Botensilimab + Balstilimab for Rectal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Prior treatment, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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: 38

Duration: 16 weeks

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs to treat rectal cancer that hasn't spread. The goal is to determine if adding two immune-boosting medicines, botensilimab and balstilimab, to the usual chemotherapy mix (FOLFOX) can help avoid surgery and reduce complications. Individuals with early-stage, untreated rectal cancer might find this trial suitable. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or other immunosuppressive medications, you may need to stop them before starting the trial. It's best to discuss your specific medications with the study team.

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

Previous studies have shown that the combination of botensilimab and balstilimab has a manageable safety profile, with side effects that are generally not severe or unexpected. No new immune-related safety issues emerged. These treatments have been tested in various cancer types and have shown promising results in extending patient survival, indicating they are generally well-tolerated.

Since this clinical trial is in Phase 2, earlier stages have already conducted some safety testing. This phase often focuses more on the treatment's effectiveness, but safety remains closely monitored. Serious safety issues would likely have prevented the drugs from advancing to this phase. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of FOLFOX with botensilimab and balstilimab for treating rectal cancer because it introduces a new approach to immunotherapy. Botensilimab and balstilimab are both checkpoint inhibitors, which help the immune system recognize and attack cancer cells more effectively. This is different from standard chemotherapy treatments, which typically target rapidly dividing cells indiscriminately. By using these targeted immunotherapies, there's potential for more specific action against cancer cells, possibly reducing side effects and improving patient outcomes. Additionally, this combination could offer a new line of defense for patients who don't fully respond to existing treatments.

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

Research shows that combining FOLFOX with the drugs botensilimab and balstilimab, as tested in this trial, may be promising for treating rectal cancer. Other studies have demonstrated that similar combinations help patients with other types of colorectal cancer live longer and have smaller tumors. FOLFOX is a chemotherapy that attacks cancer cells, while botensilimab and balstilimab are immunotherapy drugs that assist the immune system in fighting the cancer. This method has the potential to completely eliminate detectable cancer and reduce the need for surgery. Early results are encouraging, but more research is needed to confirm these benefits specifically for rectal cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Marwan Fakih

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with localized rectal adenocarcinoma, which hasn't spread elsewhere. Participants should be candidates for neoadjuvant therapy before surgery and must not have received prior treatments that would conflict with the study drugs.

Inclusion Criteria

If unavailable, exceptions may be granted with study principal investigator (PI) approval

My kidney function, measured by creatinine levels or clearance, is within the required range.

Hemoglobin ≥ 9g/dL

Exclusion Criteria

Prior allergic reaction or hypersensitivity to any of the study drug components

I am not pregnant or breastfeeding.

Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive FOLFOX, botensilimab, and balstilimab intravenously in cycles every 14 days for up to 8 cycles

16 weeks

8 visits (in-person)

Extension

Participants with complete clinical response may continue to receive balstilimab alone for an additional 12 cycles

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Follow-up at 30 and 90 days, then every 3 months within 1 year, followed by every 6 months for up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Balstilimab
• Botensilimab
• FOLFOX

Trial Overview The trial tests a combination of chemotherapy (FOLFOX) and immunotherapy (botensilimab and balstilimab) given before surgery to see if it can improve complete response rates in rectal cancer, potentially reducing the need for surgery or radiation.

How Is the Trial Designed?

Group I: Treatment (FOLFOX, botensilimab, balstilimab) Experimental Treatment 13 Interventions

Patients receive leucovorin calcium IV over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV over 46 hours on day 1 of each cycle. Patients also receive botensilimab IV over 60 minutes on day 1 of cycles 1 and 4 and balstilimab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 14 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with complete clinical response may continue to receive balstilimab alone for an additional 12 cycles. Patients without complete clinical response may receive radiation therapy QD on weekdays and capecitabine PO BID concurrently on days of radiation therapy per standard of care. Additionally, patients undergo blood sample collection, biopsy with endoscopy exam, sigmoidoscopy, digital rectal exam, CT and MRI throughout the 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 III study, both bevacizumab (BV) combined with irinotecan, fluorouracil, and leucovorin (IFL) and oxaliplatin with fluorouracil and leucovorin (FOLFOX) showed significant improvements in progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer, regardless of whether they responded to the initial treatment.

The study found that even nonresponders to initial therapy benefited from these superior treatments, indicating that tumor response is not necessary for patients to experience survival benefits from these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. Grothey, A., Hedrick, EE., Mass, RD., et al.[2022]

In a retrospective analysis of 25 patients with KRAS wild-type metastatic colorectal cancer who progressed after cetuximab treatment, panitumumab showed promising activity, with a median progression-free survival of 5 months and overall survival of 8 months.

Despite the previous treatment failure, 25% of patients experienced stable disease for at least 9 months, and the treatment was generally well-tolerated, with minimal severe side effects, indicating that panitumumab may be a viable option for patients seeking continued treatment without chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients: a single institution experience. Marino, A., Caliolo, C., Sponziello, F., et al.[2018]

The combination of FOLFOXIRI and bevacizumab demonstrated a promising progression-free survival (PFS) rate of 74% at 10 months in patients with unresectable metastatic colorectal cancer, based on a phase 2 study involving 57 patients.

The treatment was found to be safe, with no unexpected adverse events reported, although common serious side effects included neutropenia and hypertension, indicating that while effective, careful monitoring for these side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Masi, G., Loupakis, F., Salvatore, L., et al.[2022]

In a study involving 1,186 patients with wild-type KRAS metastatic colorectal cancer, the combination of panitumumab and FOLFIRI significantly improved progression-free survival (PFS) compared to FOLFIRI alone, with a median PFS of 6.7 months versus 4.9 months.

While there was a trend towards improved overall survival (OS) with panitumumab-FOLFIRI (14.5 months vs. 12.5 months), it was not statistically significant; however, response rates increased dramatically from 10% to 36% with the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Peeters, M., Price, TJ., Cervantes, A., et al.[2022]

In a study of 43 patients with BRAF V600-mutant metastatic colorectal cancer, the combination of dabrafenib and trametinib showed activity, with 12% of patients achieving a partial response and one patient achieving a complete response lasting over 36 months.

All patients evaluated during treatment showed a significant reduction in phosphorylated ERK levels, indicating effective inhibition of the mitogen-activated protein kinase signaling pathway, although the response was less pronounced than in BRAF-mutant melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. Corcoran, RB., Atreya, CE., Falchook, GS., et al.[2022]

Citations

1. 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 ... "These findings set the stage for pivotal studies intended to create a new standard of care for colon and rectal cancer patients by reducing ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06780787

NCT06780787 | FOLFOX, Botensilimab, and Balstilimab for ... In fact, over half of rectal cancer patients go on to have surgery and often suffer post-surgery complications involving urine and bowel problems. Thus, there ...

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

Botensilimab plus balstilimab in relapsed/refractory ... However, response rates vary across tumor types, with particularly disappointing outcomes in patients with metastatic colorectal cancer (mCRC) ...

4. onclive.com onclive.com/view/dr-fakih-on-the-future-of-botensilimab-and-balstilimab-based-therapies-in-mss-mcrc

Dr Fakih on the Future of Botensilimab and Balstilimab ... Marwan Fakih, MD, discusses the advancement of botensilimab/balstilimab–based combination therapies in microsatellite-stable colorectal cancer.

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

Botensilimab/Balstilimab Elicits Sustained Efficacy in MSS ... ... combination in MSS metastatic colorectal cancer. Advertisement. The combination attained a 42% two-year survival rate as well as a median. The ...

6. 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 ... Agenus' BOT/BAL Achieves 42% Two-Year Survival in Refractory MSS CRC, Advances Toward Registration with FDA Alignment on Phase 3 · ESMO‑GI ...

7. 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 ...

8. targetedonc.com targetedonc.com/view/botensilimab-and-balstilimab-prove-notable-os-in-patients-with-advanced-solid-tumors

Botensilimab and Balstilimab Prove Notable OS in Patients ... Botensilimab and balstilimab showed promising survival outcomes in advanced solid tumors, with a median OS of 17.2 months and 39% 24-month ...

9. 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.