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

11 Participants Needed

Trial Summary

What is the purpose of this trial?

RATIONALE: Drugs used in chemotherapy, such as ursodiol, oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Giving ursodiol together with leucovorin calcium, fluorouracil, oxaliplatin, and bevacizumab may be an effective treatment for colorectal cancer. PURPOSE: This phase I trial is studying the side effects and best dose of ursodiol when given together with combination chemotherapy and bevacizumab in treating patients with stage IV colorectal cancer.

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.

What data supports the effectiveness of the drug combination of Ursodiol, Chemotherapy, and Bevacizumab for treating colorectal cancer?

Research shows that Bevacizumab, when combined with chemotherapy drugs like 5-fluorouracil and leucovorin, significantly improves survival rates and delays disease progression in patients with metastatic colorectal cancer. Additionally, combining Bevacizumab with oxaliplatin-based regimens has shown promising results in clinical trials. ^{1 2 3 4 5}

Is the combination of Bevacizumab, chemotherapy, and Ursodiol generally safe for humans?

Bevacizumab, when combined with chemotherapy for colorectal cancer, has been associated with some serious side effects like blood clots, high blood pressure, bleeding, and gastrointestinal perforation (a hole in the stomach or intestines). However, studies have shown that it is generally well-tolerated, with most side effects being manageable. ^{1 6 7 8 9}

What makes the drug combination of Ursodiol, Chemotherapy, and Bevacizumab unique for colorectal cancer?

This treatment is unique because it combines Ursodiol, a bile acid, with a chemotherapy regimen and Bevacizumab, which targets blood vessel growth in tumors, potentially enhancing the effectiveness of chemotherapy in colorectal cancer. Bevacizumab has shown improved survival rates when added to chemotherapy, and the inclusion of Ursodiol may offer additional benefits not seen in standard treatments. ^{7 10 11 12 13}

Research Team

Lily L. Lai

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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 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]

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 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 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]

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 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, 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 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]

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. Germany pubmed.ncbi.nlm.nih.gov

A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The future development of bevacizumab in colorectal cancer. [2015]

4. England pubmed.ncbi.nlm.nih.gov

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

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

Targeted therapy of colorectal cancer: clinical experience with bevacizumab. [2019]

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

[A clinical experience in treatment with bevacizumab for unresectable colorectal cancer]. [2016]

7. Canada pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. [2013]

8. Germany 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. [2021]

9. United States 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. [2023]

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

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. [2022]

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

Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. [2022]

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

Incidence and management of bevacizumab-related toxicities in colorectal cancer. [2022]

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

Efficacy of FOLFOXIRI versus XELOXIRI plus bevacizumab in the treatment of metastatic colorectal cancer. [2022]