Sorafenib + Doxorubicin for Liver Cancer

Recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Sorafenib

Must not be taking: Rifampin, St John's Wort

Disqualifiers: Cardiac disease, Pregnancy, HIV, others

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: Unknown

Duration: Until unacceptable toxicity or disease progression

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out what effects, good and/or bad, the combination of the drug sorafenib in combination with the drug doxorubicin might have on the growth and spread of liver cancer (HCC).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must stop taking Rifampin or St John's Wort at least 4 weeks before starting the trial. If you are on anti-viremic treatment for hepatitis B or C, you can continue those medications, except for interferon.

What data supports the effectiveness of the drug Sorafenib + Doxorubicin for liver cancer?

Research shows that combining Sorafenib with Doxorubicin improves overall survival in patients with advanced liver cancer compared to using Sorafenib alone. Additionally, this combination is well tolerated and more effective than Doxorubicin alone in controlling the disease. ^{1 2 3 4 5}

What safety data exists for the use of Doxorubicin in humans?

Doxorubicin is known to cause heart-related side effects, such as damage to the heart muscle, and can also affect the liver and kidneys. There are medications like dexrazoxane that can help protect the heart when using Doxorubicin, but they may reduce the effectiveness of cancer treatment. Liposomal formulations of Doxorubicin may have fewer side effects compared to the conventional form. ^{4 6 7 8 9}

How is the drug combination of sorafenib and doxorubicin unique for liver cancer treatment?

The combination of sorafenib and doxorubicin is unique because it appears to be more effective in controlling liver cancer than doxorubicin alone, with a disease control rate of 69%. Sorafenib, taken orally, is a multikinase inhibitor that works well with doxorubicin, an intravenous chemotherapy drug, and this combination is generally well tolerated by patients. ^{2 10 11 12 13}

Research Team

Ghassan Abou-Alfa, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with advanced liver cancer (HCC) who have seen their disease progress despite being treated with Sorafenib. They should not have severe cirrhosis, heart issues, or other serious illnesses and must not be pregnant. Prior treatments are allowed under certain conditions, but they can't have had systemic doxorubicin before.

Inclusion Criteria

Informed consent must be obtained prior to study initiation

Absolute neutrophil count (ANC) ≥1,500/μL

Expected survival of at least 3 months

Exclusion Criteria

Pregnancy or lactation

Participation in concurrent investigational studies

Uncontrolled inter-current illness or psychiatric illness or social situations that would limit compliance with study requirements

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Doxorubicin 60 mg/m2 IV on Day 1 of each 3-week cycle and Sorafenib 400 mg PO BID until unacceptable toxicity or disease progression

Until unacceptable toxicity or disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Doxorubicin
• Sorafenib

Trial Overview The study tests the combination of two drugs: Sorafenib and Doxorubicin on liver cancer growth after previous treatment failure with just Sorafenib. It aims to understand the effects—both good and bad—of this drug duo on controlling cancer progression.

Participant Groups

Group I: Sorafenib plus Doxorubicin Experimental Treatment 2 Interventions

Doxorubicin 60 mg/m2 IV on Day 1 of each 3 weeks cycle until unacceptable toxicity Sorafenib 400 mg PO BID or last dose patient from previous sorafenib based therapy, until unacceptable toxicity or disease progression, after which sorafenib can be continued as a single agent.

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

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Findings from Research

In a phase 3 clinical trial involving 356 patients with advanced hepatocellular cancer, the addition of doxorubicin to sorafenib did not improve overall survival (OS) or progression-free survival (PFS) compared to sorafenib alone, with median OS being 9.3 months for the combination therapy and 9.4 months for sorafenib alone.

The combination therapy resulted in significantly higher rates of severe adverse events, such as grade 3 or 4 neutropenia and thrombocytopenia, indicating that while doxorubicin was added to enhance treatment, it also increased the risk of serious side effects without providing additional survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. Abou-Alfa, GK., Shi, Q., Knox, JJ., et al.[2023]

Kleinhovia sp. extract significantly protects against liver toxicity caused by doxorubicin (DOX) in rats, as evidenced by improved levels of liver enzymes (ALT and AST) and histopathological analysis of liver tissue.

At a dose of 250 mg/kg, Kleinhovia sp. extract also reduces cardiac toxicity indicated by lower CK-MB levels, while showing improvements in the structure of cardiac, liver, and renal tissues, suggesting its potential as a protective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential Roles of Kleinhovia hospita L. Leaf Extract in Reducing Doxorubicin Acute Hepatic, Cardiac and Renal Toxicities in Rats. Djabir, YY., Arsyad, MA., Sartini, S., et al.[2020]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

In a study involving male rats treated with doxorubicin (DOX) and paclitaxel (PTX), the addition of dexrazoxane (DZR) significantly reduced the cardiotoxic effects of DOX, demonstrating its cardioprotective properties.

The combination of DOX and PTX did not worsen the heart damage caused by DOX alone, and DZR maintained its protective effects without increasing noncardiac toxicity, suggesting a safer treatment regimen for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. Della Torre, P., Imondi, AR., Bernardi, C., et al.[2015]

Doxorubicin (DOX) is effective for treating childhood cancers but can cause heart damage, and while Dexrazoxane (DXR) is a known cardioprotectant, Amifostine (AMF) also shows protective properties but may negatively impact bone health.

In a study with female rats, treatments involving AMF, with or without DOX and DXR, led to significant decreases in bone mineral density and deterioration of bone microarchitecture, highlighting the need for careful consideration in cancer treatment combinations to avoid bone damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. Mwale, F., Ciobanu, I., Demers, CN., et al.[2013]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

References

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

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The antitumor activity of a lactosaminated albumin conjugate of doxorubicin in a chemically induced hepatocellular carcinoma rat model compared to sorafenib. [2018]

4. India pubmed.ncbi.nlm.nih.gov

Potential Roles of Kleinhovia hospita L. Leaf Extract in Reducing Doxorubicin Acute Hepatic, Cardiac and Renal Toxicities in Rats. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

pH-sensitive doxorubicin-loaded polymeric nanocomplex based on β-cyclodextrin for liver cancer-targeted therapy. [2023]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. [2015]

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

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. [2013]

9. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

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

Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study. [2022]

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

Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma. [2022]

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

Prolonged survival in patients with hand-foot skin reaction secondary to cooperative sorafenib treatment. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial. [2022]