Ursodiol + Chemotherapy + Bevacizumab for Colorectal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Systemic steroids

Disqualifiers: Significant medical, psychiatric condition, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks per course

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs to determine the best dose and understand side effects for treating stage IV colorectal cancer. It includes chemotherapy drugs and a special antibody called bevacizumab (Avastin), which can help stop cancer growth by cutting off the tumor's blood supply. Individuals with advanced colorectal cancer that has spread and who completed other treatments at least three weeks ago might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot use systemic steroids within 7 days of starting the trial.

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

Research shows that the treatments in this trial have been studied for safety in humans. Ursodiol, a type of bile acid, has been examined in earlier studies, but limited information exists on its safety when combined with chemotherapy. Some studies suggest it might help treat colorectal cancer, but its safety remains under exploration.

Bevacizumab, another treatment in this trial, has been used with chemotherapy for advanced colorectal cancer. Research indicates it can improve survival rates, and its safety is well-established. Most side effects can be managed.

Fluorouracil is a common chemotherapy drug for colorectal cancer. It is widely used and generally safe, though it can cause side effects like mouth sores and low blood cell counts, which doctors can manage.

Leucovorin enhances the effectiveness of fluorouracil. It has been used in cancer treatment for a long time and is considered safe.

Oxaliplatin is another chemotherapy drug in this trial. It can cause side effects like nerve damage, leading to tingling or numbness, and fatigue. These are common but can often be managed by adjusting the dose.

This trial is in an early phase, mainly focusing on safety and dosage. Researchers are still gathering detailed safety information, but these drugs have been used before, aiding doctors in managing potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for colorectal cancer because it incorporates ursodiol, which is not typically used in standard care. While current treatments often combine chemotherapy drugs like fluorouracil, leucovorin, and oxaliplatin with bevacizumab, ursodiol adds a unique twist. Ursodiol is known for its role in managing liver conditions, and its inclusion here could help improve how these drugs are processed in the body, potentially enhancing their effectiveness and reducing side effects. This novel approach could offer a new avenue for better outcomes in colorectal cancer treatment.

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

Research has shown that the combination of drugs in this trial fights colorectal cancer by attacking the tumor in different ways. Participants will receive a combination of Ursodiol, Bevacizumab, Fluorouracil, Leucovorin, and Oxaliplatin. Ursodiol, a type of bile acid, has been found to slow the growth of colon cancer cells and may lower the risk of developing colorectal cancer. Bevacizumab cuts off the blood supply to tumors, helping to slow their growth in advanced colorectal cancer. Fluorouracil, a chemotherapy drug, can initially shrink tumors, although some patients might experience a recurrence. Leucovorin enhances the effectiveness of fluorouracil, leading to better results in treating colorectal cancer. When combined with fluorouracil and leucovorin, oxaliplatin has doubled response rates and delayed cancer progression. Each of these drugs has shown promise individually, suggesting they work well together in treating colorectal cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Lily L. Lai

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced, biopsy-confirmed metastatic colorectal cancer. Participants must have normal levels of certain blood proteins and liver enzymes, a specific white blood cell count, and kidney function within set limits. They should be in good physical condition (Karnofsky Performance Status >= 80), not have had recent significant weight loss, and must agree to use contraception if applicable.

Inclusion Criteria

I have advanced colorectal cancer confirmed by a biopsy.

I finished my last treatment 3 weeks ago and have recovered from side-effects.

I can carry out normal activities with minimal symptoms.

Exclusion Criteria

I have not taken systemic steroids in the last 7 days.

I have lost more than 10% of my weight in the past 6 months.

I do not have any severe health or mental conditions that make treatment risky.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive oral ursodiol twice daily, leucovorin calcium IV, fluorouracil IV, oxaliplatin IV, and bevacizumab IV. Courses repeat every 4 weeks.

4 weeks per course

Visits on days 1 and 15 of each 4-week course

Pharmacokinetic Studies

Blood samples are collected periodically for pharmacokinetic studies and analysis of FXR activation.

Throughout treatment phase

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Fluorouracil
• Leucovorin Calcium
• Oxaliplatin
• Ursodiol

Trial Overview The study tests the effectiveness of combining ursodiol with FOLFOX chemotherapy (fluorouracil, leucovorin calcium, oxaliplatin) and bevacizumab antibody treatment in stage IV colorectal cancer patients. It aims to find the best dose of ursodiol that's safe when used with this regimen.

How Is the Trial Designed?

Group I: Treatment (ursodiol, combination chemotherapy, bevacizumab) Experimental Treatment 14 Interventions

Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium IV over 2 hours on days 1 and 15, fluorouracil IV over 46 hours on days 1-2 and 15-16, and oxaliplatin IV over 2 hours and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

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 retrospective analysis of patients with metastatic colorectal cancer, bevacizumab significantly improved progression-free survival (PFS) and overall survival (OS) in patients aged 65 and older, showing similar benefits to younger patients.

While older patients experienced an increase in thromboembolic events when treated with bevacizumab, no other significant age-related increases in severe adverse events were noted, indicating a manageable safety profile for this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. Cassidy, J., Saltz, LB., Giantonio, BJ., et al.[2022]

In a study of 1,401 patients with metastatic colorectal cancer, adding bevacizumab to first-line oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) from 8.0 months to 9.4 months compared to placebo.

While overall survival was longer in the bevacizumab group (21.3 months vs. 19.9 months), this difference was not statistically significant, indicating that while bevacizumab helps delay disease progression, it may not necessarily extend overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. Saltz, LB., Clarke, S., Díaz-Rubio, E., et al.[2023]

Bevacizumab, a monoclonal antibody that targets VEGF, significantly improves response rates, time to tumor progression, and overall survival in patients with advanced colorectal cancer when added to fluorouracil-based chemotherapy regimens, based on two clinical trials.

While bevacizumab shows efficacy in treating advanced colorectal cancer, it is associated with serious safety concerns, including thromboembolic events, hypertension, hemorrhage, and gastrointestinal perforation, highlighting the need for careful monitoring and further studies comparing its effectiveness with other chemotherapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. Hadj Tahar, A.[2013]

In a study of six patients with unresectable colorectal cancer treated with bevacizumab, the combination chemotherapy was well-tolerated, with most adverse drug reactions being grade 2 or less.

Only one patient experienced grade 3 neutropenia, and there were no specific adverse effects directly related to bevacizumab, suggesting it can be safely used in combination with chemotherapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A clinical experience in treatment with bevacizumab for unresectable colorectal cancer]. Fujimoto, T., Yoshimatsu, K., Yokomizo, H., et al.[2016]

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]

Bevacizumab, when combined with chemotherapy (like irinotecan/5-FU/leucovorin), significantly improves survival rates in patients with metastatic colorectal cancer, leading to its approval for first-line treatment.

While generally well-tolerated, bevacizumab can cause manageable side effects such as hypertension (3-16%) and other serious but less common toxicities, highlighting the need for guidelines on managing these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and management of bevacizumab-related toxicities in colorectal cancer. Saif, MW., Mehra, R.[2022]

In a study of 570 patients with stage III colorectal cancer, three different administration types of 5-fluorouracil (5-FU) in FOLFOX treatment showed similar disease-free survival (DFS) and overall survival (OS) rates, indicating comparable efficacy.

While all treatment regimens were manageable in terms of toxicity, the modified FOLFOX-6 group experienced more grade 1-2 adverse events like thrombocytopenia and neuropathy, suggesting that while efficacy is similar, side effects may vary among the different regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison of FOLFOX regimens with different doses of 5-FU for the adjuvant treatment of colorectal cancer: a multicenter study. Akdeniz, N., Kaplan, MA., Uncu, D., et al.[2021]

In a combined analysis of three studies involving 490 patients, the addition of bevacizumab to FU/LV treatment resulted in a median overall survival of 17.9 months, compared to 14.6 months for the control group, indicating a significant survival benefit.

Patients receiving FU/LV with bevacizumab also experienced improved progression-free survival (8.8 months vs. 5.6 months) and a higher response rate (34.1% vs. 24.5%), demonstrating the efficacy of bevacizumab in treating metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. Kabbinavar, FF., Hambleton, J., Mass, RD., et al.[2022]

Bevacizumab (Avastin) significantly improves overall and progression-free survival in patients with metastatic colorectal cancer when combined with standard chemotherapy regimens like IFL or 5-FU/LV, based on clinical data from various trials.

The drug shows potential for use in both first-line and second-line treatments, as well as in the adjuvant setting, by inhibiting vascular endothelial growth factor to prevent tumor angiogenesis, with ongoing Phase III trials exploring its efficacy in combination with oxaliplatin-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The future development of bevacizumab in colorectal cancer. Díaz-Rubio, E., Schmoll, HJ.[2015]

Bevacizumab, a targeted therapy that inhibits vascular endothelial growth factor, significantly improves treatment outcomes in metastatic colorectal cancer when added to standard chemotherapy, showing a higher objective response rate (40% vs. 17%) and longer median survival (21.5 months vs. 13.8 months).

While bevacizumab is associated with manageable safety concerns such as hypertension and thrombosis, its efficacy in extending time to disease progression (9.0 months vs. 5.2 months) highlights its potential as a valuable addition to colorectal cancer treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy of colorectal cancer: clinical experience with bevacizumab. Fernando, NH., Hurwitz, HI.[2019]

In a study of 138 patients with untreated metastatic colorectal cancer, the FOLFOXIRI-Bev treatment resulted in a longer progression-free survival of 13.5 months compared to 10.4 months for XELOXIRI-Bev, indicating better efficacy for FOLFOXIRI-Bev.

While FOLFOXIRI-Bev showed a higher objective response rate (71% vs. 52.2%), it also led to significantly more severe side effects, such as neurotoxicity and neutropenia, highlighting a trade-off between effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of FOLFOXIRI versus XELOXIRI plus bevacizumab in the treatment of metastatic colorectal cancer. Cheng, Y., Song, W.[2022]

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10832121/

Effectiveness of bevacizumab in the treatment of metastatic ... The addition of BEV can enhance the anti-tumor ability and disease control, while cetuximab and panitumumab may have stronger ability.

2. avastin.com avastin.com/hcp/mcrc/efficacy-data.html

Avastin® (bevacizumab) Clinical Trials | MCRC Treatment “Our results show that bevacizumab continued beyond disease progression, while switching chemotherapy, is beneficial for patients with metastatic colorectal ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10288425/

Real-world outcomes among patients with metastatic ... Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final results from the Avastin® Registry – investigation ...

4. nature.com nature.com/articles/s41598-025-13701-0

Real world effectiveness of chemotherapy plus ... Real world effectiveness of chemotherapy plus bevacizumab ... colorectal cancer: Phase 2 results from the CheckMate 9X8 randomized clinical trial.

5. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1552914/full

Advances in bevacizumab in colorectal cancer This study provides the first bibliometric analysis of research on bevacizumab and CRC, revealing the current status and future directions of this field.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3780632/

Efficacy and Safety of Bevacizumab in Metastatic ... The use of bevacizumab with chemotherapy resulted in statistically significant increases in overall and progression-free survival for patients with mCRC.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1533002823000944

Real-World Safety and Effectiveness of a Bevacizumab ... The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the ...

8. jnccn.org jnccn.org/view/journals/jnccn/22/10/article-p677.xml?print

Comparative Safety and Effectiveness of Bevacizumab ... Comparative Safety and Effectiveness of Bevacizumab Biosimilars to Originator for the Treatment of Metastatic Colorectal Cancer.

9. bmcgastroenterol.biomedcentral.com bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-024-03134-w

Effectiveness of bevacizumab in the treatment of metastatic ... Hazard ratio for objective remission rate and disease control rate were OR = 1.00 (95% CI: 0.80–1.24) and OR = 1.55 (95% CI: 1.13–2.12) ...