Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Treatment-Refractory Sarcomas

Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Patients With Treatment-Refractory Sarcomas

The purpose of this study is to test the safety of combining the disulfiram (DSF) and copper gluconate (Cu) to liposomal doxorubicin to treat patients with sarcomas that recurred or did not respond to initial treatment.

Study Overview

• Status: Recruiting
• Conditions: Relapsed Sarcomas
• Intervention / Treatment: Drug: Disulfiram; Drug: Copper Gluconate; Drug: Liposomal Doxorubicin (Doxil)

Detailed Description

DSF blocks an enzyme called aldehyde dehydrogenase (ALDH). ALDH breaks down substances in the body that can be toxic. ALDH also appears to be important for making many cancers resistant to chemotherapy drugs like liposomal doxorubicin. The study team believes giving DSF with liposomal doxorubicin will help make the cancers sensitive to the liposomal doxorubicin, making it work better. Cu is an FDA approved dietary food supplement and has been shown in laboratory research to improve how DSF works, which is the rational for giving DSF with Cu. It is currently unknown if and at what dose DSF is safe to be given in this combination. Though DSF has been used for over 60 years for the treatment of alcoholism, this is the first time DSF/Cu is being tested in combination with liposomal doxorubicin in humans.

The primary objectives of this study are to:

Measure the feasibility, safety and tolerability of DSF/Cu in combination with liposomal doxorubicin

Secondary objectives of this study are to:

Measure tumor response, survival, and pharmacokinetics of the combination.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Matteo Trucco, MD; Phone Number: +1 216-444-8950; Email: truccom@ccf.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44122
      • Recruiting
      • Cleveland Clinic, Case Comprehensive Cancer Center
      • Principal Investigator: Matteo Trucco, MD
      • Contact: Matteo Trucco, MD; Phone Number: 216-444-8950; Email: truccom@ccf.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Must have histologically confirmed relapsed or refractory sarcoma.
• Must have measurable disease by RECIST criteria at study enrollment
• Performance status of Karnofsky/Lansky ≥50%

• Must have normal organ and marrow function as defined below:

  • Absolute neutrophil count ≥1,000/mcL
  • Platelet count ≥ 100,000/mcL
  • Total bilirubin within normal institutional limits
  • AST (SGOT) ≤ 2.5 X institutional upper limit of normal
  • ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
  • Serum Creatinine ≤1.5X institutional limit of normal
• Must be able to swallow pills or consume the contents of the DSF and Capsules sprinkled on food.
• Participants, or parent/guardians for participants <18 years old (yo), must have the ability to understand and the willingness to sign a written informed consent document.
• Must abstain from alcohol during study.
• Prior treatment toxicities must have stabilized or resolved to ≤ Grade 1 according to NCI CTCAE Version 5.0 except alopecia, neuropathy and hematologic criteria (must meet normal organ and marrow function criteria above).
• Participants ≥18yo must agree to pre-and post-treatment core needle tumor biopsies. For participants <18yo biopsies are optional. Biopsies will not be performed if deemed unsafe by interventional radiologists that will be performing the procedure and is not part of the study team to avoid bias.
• Must abstain from sexual intercourse or used appropriate, highly-effective birth control measures.

Exclusion Criteria:

• Has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
• Has a history of allergy or hypersensitivity to any of the study drugs, their pharmaceutical class or any of their excipients. The participant exhibits any of the events outlined in the Contraindications or Special Warnings and Precautions sections of Liposomal Doxorubicin Prescribing Information package inserts or on the Investigator's Brochure for DSF/Cu.
• 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 currently enrolled in any other clinical protocol or investigational trial involving administration of antineoplastic compounds for the treatment of their sarcoma.
• Is unwilling or unable to comply with study procedures.
• Know condition preventing safe administration of copper such as a copper allergy or Wilson's Disease.
• Investigator feels participation in this study would be harmful or of no benefit to the potential participant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: DSF/Cu; 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

Drug: Disulfiram; To be taken orally (PO) daily in the AM, rounded for pill size (max 480mg/day). To be administered day 1-7 of lead-in week and day 1-28 cycles Cycle length: 28 days, maximum 12 cycles Level -1 (150mg/m^2/day) Level 0 (225mg/m^2/day) Level 1 (300mg/m^2/day), max 480mg/day; Drug: Copper Gluconate; To be taken orally (PO), 5.2mg/m2/day daily in the PM, rounded for pill size (max 9mg/day) To be administered day 1-7 Lead-in week and day 1-28 cycles Cycle length: 28 days, maximum 12 cycles; Drug: Liposomal Doxorubicin (Doxil); To be given IV, 30mg/m2/dose To be administered day 1 of cycles Cycle length: 28 days, maximum 12 cycles; Other Names: Dox-SL; Pegylated Liposomal Doxorubicin (PLD); Doxorubicin HCl Liposome Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as measured by percent of participants experiencing grade 3+ with at least possible attribution to study drug using CTCAE 5.0 guidelines	Safety as measured by percent of participants experiencing grade 3+ with at least possible attribution to study drug using CTCAE 5.0 guidelines	up to 30 days after last treatment
Recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin	RP2D of DSF/Cu in combination with liposomal doxorubicin	at end of cycle 1 (day 28)
Number of participants able to take at least 80% of the drug doses during the first cycle of treatment	Feasibility: Number of participants able to take at least 80% of the drug doses during the first cycle of treatment, assessed by the medication diary patients will be asked to keep	up to 30 days after last treatment
Number of dose-limiting toxicities (DLT)	Tolerability, as total number of defined as number of DLTs	up to 30 days after last treatment
Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0	Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0	up to 30 days after last treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of participants with tumor response evaluated using RECIST v1.1	Tumor response will be evaluated per RECIST v1.1 criteria - percent of participants with complete response, partial response, stable disease and progressive disease reported	At 2 months
Median Overall Survival (OS)	Median OS defined as the time from participant enrollment on study to time of death	up to 30 days after last treatment
Median Event free survival	Median Event free survival defined as the time from participant enrollment on study to time of disease progression (PD) per RECIST v1.1,. PD defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.	up to 30 days after last treatment
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)	At hour 0 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)	At hour 2 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)	At hour 4 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)	At hour 24 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)	Day 1 of cycle 1 (day 8)
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)	At hour 0 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)	At hour 2 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)	At hour 4 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)	At hour 24 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)	Day 1 of cycle 1 (day 8)
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - clearance and average steady state concentrations for disulfiram and its active metabolites, S-methyl N,N-dietylthiolcarbamate (DETC-ME) and bis-diethyldithiocarbamate-copper complex (CuET)	At hour 0 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - clearance and average steady state concentrations for disulfiram and its active metabolites, S-methyl N,N-dietylthiolcarbamate (DETC-ME) and bis-diethyldithiocarbamate-copper complex (CuET)	At hour 2 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - clearance and average steady state concentrations for disulfiram and its active metabolites, S-methyl N,N-dietylthiolcarbamate (DETC-ME) and bis-diethyldithiocarbamate-copper complex (CuET)	At hour 4 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - clearance and average steady state concentrations for disulfiram and its active metabolites, S-methyl N,N-dietylthiolcarbamate (DETC-ME) and bis-diethyldithiocarbamate-copper complex (CuET)	At hour 24 of Day 1 of lead-in week
Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites]	Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - clearance and average steady state concentrations for disulfiram and its active metabolites, S-methyl N,N-dietylthiolcarbamate (DETC-ME) and bis-diethyldithiocarbamate-copper complex (CuET)	Day 1 of cycle 1 (day 8)

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Investigators: Principal Investigator: Matteo Trucco, MD, Cleveland Clinic, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 14, 2022
• First Submitted That Met QC Criteria: January 14, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: osteosarcoma; Ewing sarcoma; rhabdomyosarcoma; Sarcoma,
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Myosarcoma; Sarcoma, Ewing; Sarcoma; Rhabdomyosarcoma; Osteosarcoma; Sulfur Compounds; Organic Chemicals; Carbohydrates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Sulfides; Carbamates; Ditiocarb; Thiocarbamates; Disulfides; Disulfiram; liposomal doxorubicin; Gluconates
• Other Study ID Numbers: CASE1720

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: all collected IPD
• IPD Sharing Time Frame: Immediately following publication and for 3 years following publication
• IPD Sharing Access Criteria: Researchers who provide a sound rationale for access
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No