Disulfiram + Copper Gluconate + Liposomal Doxorubicin for Sarcoma

Overseen By Matteo Trucco, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Case Comprehensive Cancer Center

Must not be taking: Antineoplastic compounds

Disqualifiers: Infections, Allergies, Psychiatric illness, others

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 48 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment combining a drug for alcoholism, a copper supplement, and a special chemotherapy for patients whose sarcomas came back or didn't respond to initial treatment. The goal is to make the chemotherapy work better by stopping the cancer from resisting it. Researchers are checking if this combination is safe and effective.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are currently enrolled in another clinical trial involving cancer treatment, you cannot participate in this study.

What data supports the effectiveness of the drug Disulfiram + Copper Gluconate + Liposomal Doxorubicin for Sarcoma?

Research shows that the combination of disulfiram and copper can form a complex with anticancer properties, which has been effective in reducing tumor size and increasing survival in animal models. Additionally, liposomal formulations have been shown to improve the delivery and stability of these compounds, enhancing their anticancer effects. ^{1 2 3 4 5}

What safety data exists for the combination of Disulfiram, Copper Gluconate, and Liposomal Doxorubicin in humans?

Liposomal Doxorubicin, a form of the chemotherapy drug doxorubicin, is generally safer than its conventional form, with fewer cases of hair loss, nausea, and heart problems. However, it can cause hand-foot syndrome (skin reactions on the palms and soles) and, in rare cases, kidney issues. There is no specific safety data available for the combination with Disulfiram and Copper Gluconate. ^{6 7 8 9 10}

What makes the drug combination of Disulfiram, Copper Gluconate, and Liposomal Doxorubicin unique for treating sarcoma?

This drug combination is unique because it uses Disulfiram, an alcohol-aversion drug, in combination with copper to form a complex called Cu(DDC)2, which has shown promising anticancer activity. The use of liposomal delivery helps improve the stability and bioavailability of this complex, potentially enhancing its effectiveness against tumors compared to traditional formulations. ^{1 2 3 11 12}

Research Team

Matteo Trucco, MD

Principal Investigator

Cleveland Clinic, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with sarcomas that didn't get better after initial treatment. They must have a certain level of health, be able to swallow pills or take them with food, not drink alcohol, and use effective birth control if needed. People allergic to the drugs used or with serious illnesses that could affect safety or data integrity can't join.

Inclusion Criteria

My sarcoma has come back or didn't respond to treatment.

My side effects from previous treatments are mild or gone, except for hair loss, nerve issues, or blood-related conditions.

Must abstain from alcohol during study

Exclusion Criteria

Has a concomitant serious medical or psychiatric illness that, in the opinion of the investigator, could compromise the participant's safety or the study data integrity

Is unwilling or unable to comply with study procedures

I have an ongoing serious infection that needs treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

A 7-day lead-in week of Disulfiram (DSF) and Copper Gluconate (Cu) administration

1 week

Daily dosing

Treatment

Participants receive DSF/Cu in combination with liposomal doxorubicin in 28-day cycles, up to a maximum of 12 cycles

Up to 48 weeks

Every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Copper Gluconate
• Disulfiram
• Liposomal Doxorubicin

Trial Overview The study tests combining disulfiram (DSF) and copper gluconate (Cu) with liposomal doxorubicin in treating stubborn sarcomas. It aims to see if this mix is safe for those whose cancer has come back or resisted first-line treatments.

Participant Groups

Group I: DSF/Cu Experimental Treatment 3 Interventions

A 3+3 dose escalation design will be used to determine the recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin. There will be a 7 day "lead-in" week of Disulfiram (DSF)/Copper Gluconate (Cu). The disulfiram and the copper gluconate will be dosed once a day. Disulfiram in the morning and copper gluconate in the evening. Same total daily dose every 4 week (28 days) administration of liposomal doxorubicin (Doxil) 30mg/m2/dose IV Cycle length: 28 days Maximum 12 cycles

Copper Gluconate is already approved in United States, Canada for the following indications:

Approved in United States as Copper gluconate for:

• Nutritional supplementation
• Treatment of copper deficiency

Approved in Canada as Copper gluconate for:

• Nutritional supplementation

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Findings from Research

An injectable formulation of the anticancer agent copper diethyldithiocarbamate (Cu(DDC)2) was developed using liposomes, which significantly improved its delivery and effectiveness in treating tumors, resulting in a 25% increase in median survival in a rat glioma model and a 45% reduction in tumor burden in a murine model.

The study also found that modifying the liposomal composition enhanced the circulation time of Cu(DDC)2, leading to a 4.2-fold increase in plasma concentration, which could improve its therapeutic potential in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent. Wehbe, M., Anantha, M., Shi, M., et al.[2019]

The study developed a new method called SMILE to create nanoparticles of Cu(DDC)2, a complex of disulfiram and copper, which showed excellent drug-loading efficiency and stability, making it a promising delivery system for cancer treatment.

Cu(DDC)2 nanoparticles demonstrated strong anticancer effects against drug-resistant prostate cancer cells, inducing cell death through a unique mechanism called paraptosis, with an IC50 of around 100 nM, highlighting their potential as an effective therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers. Chen, W., Yang, W., Chen, P., et al.[2019]

The study developed sphingomyelin-based PEGylated liposomes to enhance the water solubility and delivery of Cu (DDC)2, a promising cancer treatment derived from the alcohol-aversion drug disulfiram, achieving over 90% encapsulation efficiency.

Liposomal encapsulation of Cu (DDC)2 significantly improved its bioavailability, increasing the mean elimination half-life by 1.3 times and enhancing its anticancer effects, resulting in a tumor-inhibiting rate of 77.88% in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sphingomyelin-based PEGylation Cu (DDC)2 liposomes prepared via the dual function of Cu2+ for cancer therapy: Facilitating DDC loading and exerting synergistic antitumor effects. Liu, H., Kong, Y., Liu, Z., et al.[2022]

Disulfiram (DSF) combined with Cu2+-doped nanoparticles (D&I@HZIFCu-FA) enhances cancer therapy by providing a continuous supply of Cu2+, which is crucial for converting DSF into its active antitumor form, bis(N, N-diethyldithiocarbamate) copper(II) complex (CuET).

The D&I@HZIFCu-FA system not only facilitates the transformation of DSF but also triggers a Fenton-like reaction to produce reactive oxygen species (·OH) for chemo-dynamic therapy, while indocyanine green (ICG) enables photothermal therapy, showcasing a multi-faceted approach to effectively target tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buffet-style Cu(II) for enhance disulfiram-based cancer therapy. Zhao, L., Wang, X., Lou, H., et al.[2022]

The DSF-Ms-Cu-Glu-Gel system, which combines disulfiram and copper gluconate in a bi-layered microsphere and hydrogel format, demonstrated effective long-term drug release and anti-tumor effects in a mouse model of peritoneal carcinoma, with 83.79% of disulfiram released by day 10 without burst release.

This system not only maintained effective drug concentrations in the abdominal cavity but also facilitated the formation of a potent anti-tumor compound (Cu(DDC)2), enhancing the overall anti-tumor activity, suggesting its potential for future clinical use in treating peritoneal carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A disulfiram/copper gluconate co-loaded bi-layered long-term drug delivery system for intraperitoneal treatment of peritoneal carcinomatosis. Wang, P., Luo, Q., Zhang, L., et al.[2023]

Pegylated liposomal doxorubicin (PLD) is generally safer than traditional doxorubicin, with fewer severe side effects like alopecia, nausea, and cardiotoxicity, making it a favorable option for treating sarcoma.

However, this case highlights a rare but serious side effect of PLD: irreversible renal failure due to thrombotic microangiopathy, which occurred in a 50-year-old man after long-term treatment, emphasizing the need for monitoring kidney function during PLD therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated liposomal doxorubicin-induced renal toxicity in retroperitoneal liposarcoma: a case report and literature review. Savani, M., Woerner, K., Bu, L., et al.[2021]

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 trial involving 94 patients with advanced soft-tissue sarcoma, CAELYX (pegylated liposomal doxorubicin) demonstrated a significantly lower incidence of severe myelosuppression and alopecia compared to standard doxorubicin, indicating a better safety profile.

Both CAELYX and doxorubicin showed similar antitumor activity, with response rates of 10% and 9% respectively, suggesting that CAELYX is a viable alternative for treatment with reduced toxicity, warranting further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Judson, I., Radford, JA., Harris, M., et al.[2022]

In a phase II study involving 47 patients with various types of sarcoma, pegylated-liposomal doxorubicin (Doxil) demonstrated activity, with 3 patients achieving complete or partial responses and 15 experiencing clinical benefits despite being previously treated or unresponsive to chemotherapy.

The treatment was generally well tolerated, with mild toxicities primarily related to mucositis and hand-foot syndrome, and no significant cardiac toxicity observed, indicating a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. Skubitz, KM.[2022]

The study developed an aptamer-drug conjugate (ApDC) that targets the HER3 receptor, showing improved delivery and efficacy of doxorubicin (DOX) in tumor-bearing mice compared to traditional liposomal and free DOX.

This targeted approach not only enhanced tumor suppression but also reduced toxic side effects, such as weight loss and organ damage, indicating better tolerability for patients undergoing chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity. Dou, XQ., Wang, H., Zhang, J., et al.[2022]

The novel copper oleate liposome (Cu(OI)2-L) demonstrated over 85% loading efficiency and a stable release profile, retaining more than 70% of the drug after 8 hours, indicating its potential for effective drug delivery.

In animal studies, Cu(OI)2-L showed a prolonged circulation time and enhanced antitumor efficacy when used in combination with disulfiram, suggesting a promising synergistic effect for tumor treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo. Zhou, L., Yang, L., Yang, C., et al.[2019]

The study developed an injectable liposomal formulation of Cu(DDC)2, which showed effective cytotoxicity against neuroblastoma cells, particularly in 3D models that better mimic actual tumors compared to traditional 2D models.

Cu(DDC)2 liposomes demonstrated favorable properties for intravenous delivery, including compliance with nanoparticle size requirements, high drug-to-lipid ratios, and stability, suggesting they could be a promising option for anticancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical In Vitro Studies with 3D Spheroids to Evaluate Cu(DDC)2 Containing Liposomes for the Treatment of Neuroblastoma. Hartwig, F., Köll-Weber, M., Süss, R.[2021]

References

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

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent. [2019]

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

Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers. [2019]

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

Sphingomyelin-based PEGylation Cu (DDC)2 liposomes prepared via the dual function of Cu2+ for cancer therapy: Facilitating DDC loading and exerting synergistic antitumor effects. [2022]

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

Buffet-style Cu(II) for enhance disulfiram-based cancer therapy. [2022]

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

A disulfiram/copper gluconate co-loaded bi-layered long-term drug delivery system for intraperitoneal treatment of peritoneal carcinomatosis. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Pegylated liposomal doxorubicin-induced renal toxicity in retroperitoneal liposarcoma: a case report and literature review. [2021]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. [2022]

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

Phase II trial of pegylated-liposomal doxorubicin (Doxil) in sarcoma. [2022]

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

Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity. [2022]

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

Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo. [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical In Vitro Studies with 3D Spheroids to Evaluate Cu(DDC)2 Containing Liposomes for the Treatment of Neuroblastoma. [2021]