Immunotherapy + Chemotherapy for Liver Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticoagulants, High-dose steroids

Disqualifiers: Other malignancy, Organ allografts, Autoimmune disease, Active hepatitis, others

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

Compensation: Varies

Number of Visits: 58

Duration: Up to 2 years

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and how well nivolumab, fluorouracil, and interferon alpha 2b work for the treatment of fibrolamellar cancer (liver cell cancer) that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Interferon alpha 2b may help stimulate the immune system to fight cancer. Giving nivolumab, fluorouracil, and interferon alpha 2b may work better in treating unresectable fibrolamellar cancer compared to fluorouracil and interferon alpha 2b alone.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, patients on high-dose steroids or other potent immune suppression medications are excluded, and only aspirin is allowed for anticoagulation. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Fluorouracil, Nivolumab, and Recombinant Interferon Alpha 2b-like Protein for liver cancer?

Research shows that a combination of 5-fluorouracil (5-FU) and interferon (IFN) is effective against advanced liver cancer, specifically hepatocellular carcinoma, when delivered directly into the liver's blood supply. This suggests that similar combinations could be beneficial for liver cancer treatment. ^{1 2 3 4 5}

Is the combination of 5-FU and interferon safe for humans?

The combination of 5-FU (Fluorouracil) and interferon has been studied in various cancers and is generally considered safe, though it can cause side effects like diarrhea, fatigue, flu-like symptoms, and mucositis (inflammation of the mouth lining). While some studies reported substantial toxicity, others found the side effects to be within acceptable limits, with no life-threatening toxicities observed. ^{1 6 7 8 9}

What makes the Immunotherapy + Chemotherapy treatment for liver cancer unique?

This treatment combines immunotherapy (using the body's immune system to fight cancer) with chemotherapy, specifically using drugs like 5-Fluorouracil and Recombinant Interferon Alpha 2b, which have shown effectiveness in other cancers and are potentially tolerable for patients with liver cirrhosis, a common condition in liver cancer patients. ^{1 5 10 11 12}

Research Team

Sunyoung Lee

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients with a specific liver cancer called unresectable fibrolamellar carcinoma. Eligible participants must have measurable disease, be in good physical condition (ECOG PS <=1 or Karnofsky >=70), and have proper organ function. They should not be pregnant, breastfeeding, or planning to conceive, and must agree to use contraception. Those with serious health issues like heart disease, uncontrolled hypertension, severe liver dysfunction, or active infections are excluded.

Inclusion Criteria

Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in these sections. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception, which have a failure rate of < 1% per year when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below: HIGHLY EFFECTIVE METHODS OF CONTRACEPTION: Male condoms with spermicide, Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices such as Mirena by WOCBP subject or male subject's WOCBP partner, Nonhormonal intrauterine devices, such as ParaGard, Tubal ligation, Vasectomy, Complete Abstinence, LESS EFFECTIVE METHODS OF CONTRACEPTION: Diaphragm with spermicide, Cervical cap with spermicide, Vaginal sponge, Male condom without spermicide, Progestin-only pills by WOCBP subject or male subject's WOCBP partner, Female condom

Patients with histologically confirmed FLHCC (or with documentation of original biopsy for diagnosis is acceptable if tumor tissue is unavailable). The determination of resectability status will ultimately lie in the clinical judgment of the surgical oncologist and medical oncologist involved in the care of the patient. The definition of resectability is as follows: hepatectomy can achieve a negative margin while preserving more than 30% of the total estimated liver volume, sparing two contiguous hepatic segments, and maintaining vascular inflow, vascular outflow, and biliary drainage. Patients with extrahepatic disease are defined as having unresectable disease

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 times institutional ULN (within 14 days of the first dose of study drug)

Exclusion Criteria

Patients who have active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening

History of serious systemic disease, including myocardial infarction or unstable angina within the last 12 months, history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (blood pressure of > 140/90 mmHg) at the time of enrollment, New York Heart Association grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), or significant vascular disease or symptomatic peripheral vascular disease

Patients who require ongoing anticoagulation will be excluded. Only aspirin will be permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive fluorouracil and interferon alpha 2b for 2 cycles, then add nivolumab starting in cycle 3. Treatment cycles repeat every 28 days for up to 2 years.

Up to 2 years

Regular visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

6 years

Follow-up at 30 days post-treatment, then every 12 weeks

Treatment Details

Interventions

• Fluorouracil
• Nivolumab
• Recombinant Interferon Alpha 2b-like Protein

Trial Overview The study is testing the effectiveness of combining nivolumab (an immunotherapy drug), fluorouracil (a chemotherapy drug), and interferon alpha 2b (an immune system stimulator) for treating this type of liver cancer that can't be surgically removed. It's a phase I/II trial aiming to see how well these drugs work together compared to using just fluorouracil and interferon alpha 2b.

Participant Groups

Group I: Treatment (fluorouracil, interferon alpha 2b, nivolumab) Experimental Treatment 3 Interventions

Patients receive fluorouracil IV continuously on days 1-7 and 15-21 and recombinant interferon alpha 2b-like protein SC on days 1, 3, 5, 15, 17, and 19. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 3, patients receive nivolumab IV over 30 minutes on day 1, fluorouracil IV continuously on days 1-7 and 15-21, and recombinant interferon alpha 2b-like protein interferon alpha 2b SC on days 1, 3, 5, 15, 17, and 19. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic 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

In a Phase II trial involving 21 patients with esophageal carcinoma, the combination of 5-fluorouracil (5FU) and recombinant alfa-2a-interferon (IFN) showed a 25% response rate, with some patients achieving complete pathological remission.

The treatment was generally well-tolerated, with acceptable toxicity levels, although an unexpected increase in neurological side effects was noted, highlighting the need for further investigation into this regimen for esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of carcinoma of the esophagus with 5-fluorouracil and recombinant alfa-2a-interferon. Wadler, S., Fell, S., Haynes, H., et al.[2019]

In a study of 106 patients with advanced colorectal cancer, adding interferon alfa-2b (IFN 2b) to the treatment regimen of fluorouracil (5-FU) and leucovorin (FA) did not improve response rates and actually resulted in decreased median survival (7.2 months vs. 10.1 months for 5-FU and FA alone).

The combination of IFN 2b with 5-FU and FA significantly increased toxicity, leading to worse side effects such as anemia, neutropenia, and flu-like symptoms, highlighting the importance of balancing efficacy with safety in cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group. Kosmidis, PA., Tsavaris, N., Skarlos, D., et al.[2018]

Adding low doses of interferon-2b (IFN) to the chemotherapy regimen of 5-fluorouracil (5-FU) and levofolinic acid (1-FA) did not improve response rates or survival in 204 patients with advanced colorectal carcinoma, and it increased the risk of side effects like diarrhea and fever.

Patients with limited liver involvement had a significantly better response rate and overall survival compared to those with extensive liver disease, highlighting the importance of tumor burden and liver status as prognostic factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Colucci, G., Maiello, E., Gebbia, V., et al.[2018]

In a study of 260 chemotherapy-naive patients with advanced colorectal cancer, the addition of interferon alpha-2a (IFN alpha) to fluorouracil (FUra) and leucovorin (LV) did not improve treatment efficacy, as there were no significant differences in objective response rates or survival outcomes between the two treatment groups.

While IFN alpha did not increase the toxicity of FUra, it negatively impacted patients' quality of life, leading to more reports of worsening symptoms, which suggests that IFN alpha should not be used to enhance FUra/LV treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council. Seymour, MT., Slevin, ML., Kerr, DJ., et al.[2018]

In a study of 31 patients with advanced hepatocellular carcinoma, both recombinant IFN-alpha-2b and natural IFN-alpha showed similar effectiveness in combination with 5-fluorouracil, with no significant differences in early response rates, time to progression, or survival rates.

The cost-effectiveness of recombinant IFN-alpha-2b was found to be better than that of natural IFN-alpha, suggesting it may be the preferred option for clinical use despite similar safety and efficacy profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar effects of recombinant interferon-alpha-2b and natural interferon-alpha when combined with intra-arterial 5-fluorouracil for the treatment of advanced hepatocellular carcinoma. Uka, K., Aikata, H., Takaki, S., et al.[2018]

The combination of 5-fluorouracil (5-FU) and interferon (IFN)-alpha showed initial promise in treating advanced colorectal cancer, but subsequent studies revealed a low response rate of only 28% with significant toxicity, including 2% toxic deaths.

Recent phase III trials involving 1727 patients have largely demonstrated that the 5-FU + IFN-alpha combination is either no more effective than standard therapies or results in worse outcomes, indicating that this treatment strategy is costly, toxic, and ineffective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining 5-fluorouracil with interferon-alpha in the treatment of advanced colorectal cancer: optimism followed by disappointment. Kjaer, M.[2019]

In a phase II trial involving 34 patients with advanced colorectal cancer who were resistant to previous 5-FU treatments, the combination of interferon-alpha2b and 5-FU resulted in a 6% objective response rate, indicating limited efficacy as a second-line therapy.

The treatment was generally well-tolerated, with acceptable toxicity levels, primarily causing mild side effects like fatigue, fever, mucositis, and diarrhea, suggesting that further studies are warranted to explore the potential of interferon-alpha2b in enhancing 5-FU effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomodulation with sequential intravenous IFN-alpha2b and 5-fluorouracil as second-line treatment in patients with advanced colorectal cancer. Pérez, JE., Lacava, JA., Domínguez, ME., et al.[2019]

In a phase I trial involving 29 patients with advanced cancer, the combination of fluorouracil (5-FU), leucovorin (LCV), and recombinant interferon-alpha-2b (rIFN-alpha-2b) showed partial remissions in 10% of patients, particularly those with previously untreated colon and pancreatic cancers.

The treatment was found to be tolerable with manageable side effects such as diarrhea and fatigue, and importantly, no fatal toxicities were reported, suggesting that this regimen is safe for further testing in gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of fluorouracil, leucovorin, and recombinant interferon alpha-2b in patients with advanced malignancy. Taylor, CW., Modiano, MR., Woodson, ME., et al.[2018]

The combination of 5-fluorouracil (5-FU) and recombinant interferon alfa-2a (rIFN) has shown improved response rates in patients with metastatic colorectal carcinoma compared to historical data on 5-FU alone, suggesting enhanced efficacy.

However, this combination therapy is associated with significant toxicities, including fever, chills, and granulocytopenia, indicating a need for future studies to optimize treatment schedules that minimize side effects while maintaining effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Fluorouracil and recombinant interferon alfa-2a: review of activity and toxicity in advanced colorectal carcinomas. Pazdur, R., Jackson, D., Shepherd, B., et al.[2018]

In a phase II trial involving 43 patients with hepatocellular carcinoma (HCC) and fibrolamellar HCC (FLHCC), the combination of continuous intravenous fluorouracil (FU) and subcutaneous recombinant interferon alfa-2b (rIFNalpha2b) demonstrated effectiveness, particularly in FLHCC patients, with a 25% overall response rate.

The treatment was well-tolerated by cirrhotic patients, with a median survival of 19.5 months for all patients, indicating that this regimen could be a viable option for treating HCC, even in those with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. Patt, YZ., Hassan, MM., Lozano, RD., et al.[2022]

In a study of 29 HCC patients with extrahepatic metastases, the combination of S-1 and interferon alpha (IFN-alpha) showed a 17% objective response rate, indicating some effectiveness in treating this challenging condition.

The treatment was found to be relatively safe, with only mild to moderate adverse reactions reported, and no severe toxicity or deaths related to the therapy, making it a potentially suitable option for patients, particularly those with lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy of oral fluoropyrimidine anticancer drug S-1 and interferon alpha for HCC patients with extrahepatic metastases. Uka, K., Aikata, H., Mori, N., et al.[2022]

In a Phase II clinical trial involving 29 patients with hepatocellular carcinoma (HCC), the combination of intravenous fluorouracil (5-FU) and subcutaneous recombinant interferon-alpha-2b (rIFN-alpha-2b) resulted in a partial response in 18% of patients, with responses lasting a median of 11.5 months.

The treatment was particularly effective in patients with low serum alpha-fetoprotein (AFP) levels (50 ng/ml or less) and those whose tumors involved 50% or less of the liver, while it was ineffective in patients with high AFP levels or extensive liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low serum alpha-fetoprotein level in patients with hepatocellular carcinoma as a predictor of response to 5-FU and interferon-alpha-2b. Patt, YZ., Yoffe, B., Charnsangavej, C., et al.[2019]

References

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

Treatment of carcinoma of the esophagus with 5-fluorouracil and recombinant alfa-2a-interferon. [2019]

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

Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group. [2018]

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

5-fluorouracil and levofolinic acid with or without recombinant interferon-2b in patients with advanced colorectal carcinoma: a randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. [2018]

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

Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council. [2018]

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

Similar effects of recombinant interferon-alpha-2b and natural interferon-alpha when combined with intra-arterial 5-fluorouracil for the treatment of advanced hepatocellular carcinoma. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Combining 5-fluorouracil with interferon-alpha in the treatment of advanced colorectal cancer: optimism followed by disappointment. [2019]

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

Biomodulation with sequential intravenous IFN-alpha2b and 5-fluorouracil as second-line treatment in patients with advanced colorectal cancer. [2019]

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

A phase I trial of fluorouracil, leucovorin, and recombinant interferon alpha-2b in patients with advanced malignancy. [2018]

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

5-Fluorouracil and recombinant interferon alfa-2a: review of activity and toxicity in advanced colorectal carcinomas. [2018]

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

Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Combination therapy of oral fluoropyrimidine anticancer drug S-1 and interferon alpha for HCC patients with extrahepatic metastases. [2022]

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

Low serum alpha-fetoprotein level in patients with hepatocellular carcinoma as a predictor of response to 5-FU and interferon-alpha-2b. [2019]