Chemotherapy + Bevacizumab + Tumor Treating Fields Therapy for Liver Cancer

Overseen By Siqing Fu

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antiepileptics, Steroids

Disqualifiers: Infection, Heart failure, Hypertension, 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: 2

Duration: 28 days per cycle

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of combination chemotherapy and bevacizumab, and to see how well they work with the NovoTTF-100L(P) system in treating participants with cancer that has come back or does not respond to treatment and has spread to the liver. Drugs used in chemotherapy, such as oxaliplatin, leucovorin, fluorouracil, pegylated liposomal doxorubicin hydrochloride, and temsirolimus, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. The NovoTTF-100L(P) system is a portable device that uses electrical fields to stop the growth of tumor cells. Giving combination chemotherapy and monoclonal antibody therapy while using the NovoTTF-100L(P) system may kill more tumor cells.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that any treatment specific for tumor control should not have been received within certain time frames before starting the trial, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment for liver cancer?

The combination of atezolizumab and bevacizumab has been shown to be more effective than sorafenib for treating advanced liver cancer, suggesting that bevacizumab, a component of the trial treatment, can be beneficial in this context. ^{1 2 3 4 5}

What is the safety profile of bevacizumab when used in combination with chemotherapy?

Bevacizumab, when used with chemotherapy, is generally well-tolerated but can cause some side effects. Common side effects include high blood pressure, protein in the urine, and minor bleeding, which are usually mild to moderate and manageable. Less common but serious side effects include gastrointestinal perforation, wound healing issues, and blood clots. ^{6 7 8 9 10}

What makes the treatment with Bevacizumab, Fluorouracil, Oxaliplatin, Pegylated Liposomal Doxorubicin Hydrochloride, and Temsirolimus for liver cancer unique?

This treatment is unique because it combines chemotherapy with Bevacizumab, which blocks the growth of new blood vessels that tumors need to grow, and Tumor Treating Fields Therapy, a novel approach that uses electric fields to disrupt cancer cell division. This combination aims to enhance the effectiveness of traditional chemotherapy by targeting the cancer in multiple ways. ^{11 12 13 14 15}

Research Team

Siqing FU, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced colorectal cancer that has spread to the liver and isn't responding to treatment. They must have a certain level of white blood cells, at least half their tumor in the liver, specific genetic features in their cancer, and measurable disease. Participants need normal organ function and can't be pregnant or breastfeeding. They should not have serious illnesses or conditions that could interfere with the study.

Inclusion Criteria

I agree to use effective birth control during and for 30 days after the study.

Platelets >= 100,000/uL

Total bilirubin =< 1.5 x ULN (upper limit of normal) (except patients with Gilbert's syndrome, who must have a total bilirubin =< 3.0 mg/dL)

Exclusion Criteria

I am still recovering from a major surgery or significant injury.

Women who are pregnant will be excluded from the study

I haven't had cancer treatment in the last 3 weeks, or within the specific times for certain drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination chemotherapy and bevacizumab with the NovoTTF-100L(P) system. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Visits on days 1, 8, 15, and 22

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

1 visit (in-person) at 30 days post-treatment

Treatment Details

Interventions

• Bevacizumab
• Fluorouracil
• Oxaliplatin
• Pegylated Liposomal Doxorubicin Hydrochloride
• Temsirolimus
• Tumor Treating Fields Therapy

Trial Overview The trial tests how well a combination of chemotherapy drugs (oxaliplatin, leucovorin, fluorouracil) plus pegylated liposomal doxorubicin hydrochloride and temsirolimus works alongside Bevacizumab (a monoclonal antibody) when used with NovoTTF-100L(P), a device designed to disrupt cancer cell growth using electrical fields.

Participant Groups

Group I: Arm B(bevacizumab,liposomal doxorubicin, DAT, NovoTTF-100L[P]) Experimental Treatment 4 Interventions

Participants receive bevacizumab IV over 90 minutes on days 1 and 15, pegylated liposomal doxorubicin hydrochloride IV over 30 minutes-3 hours on days 1 and 15, and temsirolimus IV over 60-90 minutes on days 1, 8, 15, and 22. Participants also use NovoTTF-100L(P) system over 18 hours daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (FOLFOX6, bevacizumab, NovoTTF-100L[P]) Experimental Treatment 5 Interventions

Participants receive oxaliplatin, leucovorin, and fluorouracil via pump over 46 hours on beginning on day 1, bevacizumab IV over 30-90 minutes on days 1 and 15, and use NovoTTF-100L(P) system over 18 hours daily. Courses repeat every 28 days 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of ramucirumab and FOLFOX4 was not well tolerated in patients with advanced hepatocellular carcinoma (HCC), with all eight participants experiencing serious treatment-emergent adverse events, including severe hepatic hemorrhage and elevated bilirubin levels.

Despite the safety concerns, preliminary efficacy data suggest that this treatment combination may offer some clinical benefit, indicating that future studies should consider dose modifications and careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study. Lin, CC., Yang, TS., Yen, CJ., et al.[2023]

In a study of 1447 patients treated with tyrosine-kinase inhibitors for hepatocellular carcinoma, only 29% were eligible for the combination therapy of atezolizumab-bevacizumab based on the IMbrave-150 trial criteria, indicating limited real-world applicability.

Eligible patients showed a median overall survival of 14.9 months, which was longer than non-eligible patients, suggesting that those who meet the criteria have better baseline health and cancer characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors. Stefanini, B., Bucci, L., Santi, V., et al.[2022]

Intraarterial (IA) infusion chemotherapy, particularly using agents like FUDR and Adriamycin, shows promise for treating hepatocellular cancer due to the liver's unique blood supply, which allows for more targeted delivery of drugs.

While there is currently no standard treatment for hepatocellular cancer, emerging strategies combining chemotherapy with radiation and exploring new therapies like isotopic immunoglobulin and hormonal treatments offer hope for improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary hepatocellular cancer--present results and future prospects. Friedman, MA.[2019]

The combination therapy of atezolizumab and bevacizumab significantly improves overall tumor response and progression-free survival in patients with unresectable hepatocellular carcinoma (HCC) compared to monotherapies with sorafenib or atezolizumab, based on a systematic review of completed trials.

Common adverse events associated with the combination therapy include hypertension and proteinuria, but the rates of these adverse events are similar to those seen with the monotherapies, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review. Ahmed, F., Onwumeh-Okwundu, J., Yukselen, Z., et al.[2021]

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with well-known risk factors, which allows for potential primary prevention and early detection strategies.

HCC exhibits a high degree of drug resistance due to its vascular nature and multidrug resistance (MDR) phenotype, highlighting the need for future biological therapies that specifically target these characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic advances in hepatocellular carcinoma]. Poupon, R., Fartoux, L., Rosmorduc, O.[2008]

Bevacizumab (Avastin) effectively targets VEGF to inhibit tumor angiogenesis, showing a safety profile that includes mostly mild to moderate side effects such as hypertension and proteinuria, which are manageable in clinical settings.

The side effects associated with bevacizumab, including rare but serious events like gastrointestinal perforation and arterial thrombosis, do not typically exacerbate the toxicity of standard chemotherapy, making it a suitable adjunct treatment for metastatic colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. Gordon, MS., Cunningham, D.[2015]

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 2212 patients with advanced non-small cell lung cancer, those over 65 years old showed similar safety and efficacy outcomes when treated with bevacizumab (Avastin) combined with standard chemotherapy, compared to younger patients.

Elderly patients had comparable overall survival (14.6 months) and time to disease progression (8.2 months) as younger patients, with no significant increase in adverse events, indicating that bevacizumab is a safe and effective treatment option for older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390). Laskin, J., Crinò, L., Felip, E., et al.[2015]

In the BEVLiN trial involving 146 patients with metastatic renal cell carcinoma, combining low-dose interferon (3 MIU) with bevacizumab (10 mg/kg) resulted in a significant reduction in severe adverse events (10.3% grade ≥3) compared to higher doses used in previous studies.

The treatment maintained efficacy with a median progression-free survival of 15.3 months and an overall survival of 30.7 months, demonstrating that lower doses can be effective while minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN. Melichar, B., Bracarda, S., Matveev, V., et al.[2021]

Bevacizumab (Avastin) combined with FOLFOX4 significantly improves overall survival and objective response rates in patients with metastatic colon or rectal cancer compared to FOLFOX4 alone, based on a study of 829 patients.

While bevacizumab shows efficacy, it carries risks of serious side effects such as gastrointestinal perforation and hemorrhage, but no new safety concerns were identified in the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Cohen, MH., Gootenberg, J., Keegan, P., et al.[2021]

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]

Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has shown significant antitumor activity, particularly in renal cell carcinoma, where it extended the time to tumor progression compared to placebo.

In advanced colorectal cancer, adding bevacizumab to chemotherapy resulted in significantly longer overall survival and progression-free survival, indicating its effectiveness when combined with standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanding the clinical development of bevacizumab. Chen, HX.[2019]

Colorectal cancer treatment has significantly advanced in the last decade with the introduction of new drugs like irinotecan and oxaliplatin, alongside optimized use of fluorouracil through prolonged infusion schedules.

The monoclonal antibody bevacizumab, which inhibits angiogenesis, shows promising results when combined with chemotherapy, although it is currently only available in the USA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drugs for colorectal cancer]. Pestalozzi, BC., Jäger, D., Knuth, A.[2015]

In a phase II study involving patients with initially unresectable liver metastases from colorectal cancer, the combination of bevacizumab with FOLFOXIRI resulted in a higher overall resection rate (61%) compared to bevacizumab with modified FOLFOX-6 (49%), indicating greater efficacy in facilitating surgical options.

Patients receiving bevacizumab-FOLFOXIRI also experienced a higher overall tumor response rate (81%) and longer median progression-free survival (18.6 months) compared to those on bevacizumab-mFOLFOX-6 (62% response rate and 11.5 months PFS), although this regimen was associated with increased but manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Gruenberger, T., Bridgewater, J., Chau, I., et al.[2022]

In a phase III study involving 501 patients with unresectable hepatocellular carcinoma (HCC), those with baseline BCLC stage B disease showed a trend towards improved overall survival (OS) and progression-free survival (PFS) when treated with atezolizumab plus bevacizumab compared to sorafenib, with hazard ratios of 0.63 and 0.64, respectively.

The objective response rates (ORR) were significantly higher for the atezolizumab plus bevacizumab group (43% and 50% using different assessment criteria) compared to the sorafenib group (26% and 30%), indicating that this combination therapy may provide more effective tumor response in patients with BCLC stage B HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study. Kudo, M., Finn, RS., Galle, PR., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study. [2023]

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

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors. [2022]

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

Primary hepatocellular cancer--present results and future prospects. [2019]

4. China pubmed.ncbi.nlm.nih.gov

Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

[Therapeutic advances in hepatocellular carcinoma]. [2008]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Managing patients treated with bevacizumab combination therapy. [2015]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390). [2015]

9. England pubmed.ncbi.nlm.nih.gov

A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN. [2021]

10. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. [2021]

11. Canada pubmed.ncbi.nlm.nih.gov

Bevacizumab for advanced colorectal cancer. [2013]

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

Expanding the clinical development of bevacizumab. [2019]

13. Switzerland pubmed.ncbi.nlm.nih.gov

[New drugs for colorectal cancer]. [2015]

14. England pubmed.ncbi.nlm.nih.gov

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. [2022]

15. Switzerland pubmed.ncbi.nlm.nih.gov

IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study. [2023]