Sorafenib + Doxorubicin for Liver Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effects of combining two drugs, sorafenib (Nexavar) and doxorubicin, on liver cancer. Researchers aim to determine if this combination can slow the cancer's growth and spread. This trial may benefit individuals whose liver cancer has progressed despite previous treatment with sorafenib. Participants should not have mixed types of liver cancer but can join if they have undergone certain local treatments, like radiation, provided specific conditions are met. The study seeks to identify both potential benefits and side effects of this drug combination. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that the combination of sorafenib and doxorubicin is likely to be safe for humans?

Research has shown that the combination of sorafenib and doxorubicin has been tested for safety in liver cancer patients. In one study, 69% of patients taking both drugs experienced disease control, meaning the treatment helped prevent their cancer from worsening. However, doxorubicin increased sorafenib levels in the blood by 21% and 33%, which could affect safety.

Another study compared patients taking sorafenib and doxorubicin with those taking doxorubicin and a placebo (a harmless pill with no active drug). In this study, 25 out of 63 patients in the sorafenib-doxorubicin group died, compared to 38 in the placebo group. This suggests potential safety concerns but also indicates a possible survival benefit.

As this combination remains under investigation in clinical trials, researchers are closely monitoring for any side effects. Always consult a healthcare professional for more personalized information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of sorafenib and doxorubicin for treating liver cancer because it brings together two powerful approaches. Sorafenib is a targeted therapy that works by blocking certain proteins that help cancer cells grow, while doxorubicin is a chemotherapy drug that kills cancer cells by directly damaging their DNA. This combination has the potential to be more effective than current standard treatments, which often involve either targeted therapy or chemotherapy alone. By using these two drugs together, there's hope for improved outcomes, such as slowing down cancer progression and overcoming resistance that sometimes develops with single treatments.

What evidence suggests that the combination of sorafenib and doxorubicin might be an effective treatment for liver cancer?

Research has shown that combining sorafenib and doxorubicin can help manage liver cancer. In one study, 69% of patients had their disease under control with this combination. Another study found that patients lived for about 13.7 months on average when treated with both drugs, compared to 9.2 months with sorafenib alone. This suggests that adding doxorubicin may improve survival. Additionally, some patients experienced partial or complete tumor shrinkage with both drugs. This trial will evaluate the effectiveness of the sorafenib and doxorubicin combination in slowing liver cancer growth. ^{2 3 4 6 7}

Who Is on the Research Team?

Ghassan Abou-Alfa, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7812207/

Sorafenib plus doxorubicin in advanced hepatocellular ... The primary endpoint of median OS was 9.3 months (95% CI, 7.3–10.8 months) for sorafenib plus doxorubicin and 9.4 months (95% CI, 7.3–12.9 months) for sorafenib ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0959804908008344

Combination of sorafenib and doxorubicin in patients with ... Doxorubicin moderately increased AUC (21%) and Cmax (33%) when administered with sorafenib. The disease control rate for 16 evaluable patients was 69%.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa0708857

Sorafenib in Advanced Hepatocellular Carcinoma Sorafenib treatment resulted in a median overall survival of 9.2 months and a median time to progression of 5.5 months (as assessed by independent radiologic ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7812160/

Doxorubicin for the treatment of hepatocellular carcinoma For the sorafenib plus doxorubicin arm, 1 patient achieved a complete response (0.7%) and 14 achieved partial responses (9.3%). For the sorafenib alone arm, no ...

5. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/186918

Doxorubicin Plus Sorafenib vs Doxorubicin Alone in ... Sixty-three patients died: 25 in the doxorubicin-sorafenib group; 38 in the doxorubicin-placebo group. Median overall survival was 13.7 months ( ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32841541/

Phase II trial of sorafenib and doxorubicin in patients with ... Sorafenib plus doxorubicin following progression on sorafenib did not show any improved outcome. We do not recommend further development or use of this ...

7. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-018-5173-0

Safety and efficacy of cytotoxic chemotherapy ... - BMC Cancer The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) ...