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

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ClinicalTrials.gov Identifier: NCT05210374
Recruitment Status : Recruiting
First Posted : January 27, 2022
Last Update Posted : January 26, 2023
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Relapsed Sarcomas Drug: Disulfiram Drug: Copper Gluconate Drug: Liposomal Doxorubicin (Doxil) Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Patients With Treatment-Refractory Sarcomas
Actual Study Start Date : January 24, 2023
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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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:
  • Pegylated Liposomal Doxorubicin (PLD)
  • Doxorubicin HCl Liposome Injection
  • Dox-SL


Outcome Measures
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Primary Outcome Measures :
  1. Safety as measured by percent of participants experiencing grade 3+ with at least possible attribution to study drug using CTCAE 5.0 guidelines [ Time Frame: up to 30 days after last treatment ]
    Safety as measured by percent of participants experiencing grade 3+ with at least possible attribution to study drug using CTCAE 5.0 guidelines

  2. Recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin [ Time Frame: at end of cycle 1 (day 28) ]
    RP2D of DSF/Cu in combination with liposomal doxorubicin

  3. Number of participants able to take at least 80% of the drug doses during the first cycle of treatment [ Time Frame: up to 30 days after last 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

  4. Number of dose-limiting toxicities (DLT) [ Time Frame: up to 30 days after last treatment ]
    Tolerability, as total number of defined as number of DLTs

  5. Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0 [ Time Frame: up to 30 days after last treatment ]
    Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0


Secondary Outcome Measures :
  1. Percent of participants with tumor response evaluated using RECIST v1.1 [ Time Frame: At 2 months ]
    Tumor response will be evaluated per RECIST v1.1 criteria - percent of participants with complete response, partial response, stable disease and progressive disease reported

  2. Median Overall Survival (OS) [ Time Frame: up to 30 days after last treatment ]
    Median OS defined as the time from participant enrollment on study to time of death

  3. Median Event free survival [ Time Frame: up to 30 days after last treatment ]

    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.


  4. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [ Time Frame: At hour 0 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)

  5. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [ Time Frame: At hour 2 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)

  6. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [ Time Frame: At hour 4 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)

  7. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [ Time Frame: At hour 24 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)

  8. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [ Time Frame: Day 1 of cycle 1 (day 8) ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - Peak concentration (Cmax)

  9. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)] [ Time Frame: At hour 0 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)

  10. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)] [ Time Frame: At hour 2 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)

  11. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)] [ Time Frame: At hour 4 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)

  12. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)] [ Time Frame: At hour 24 of Day 1 of lead-in week ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)

  13. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)] [ Time Frame: Day 1 of cycle 1 (day 8) ]
    Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicinbased on samples collected - area under the concentration-vs-time curve (AUC)

  14. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites] [ Time Frame: At hour 0 of Day 1 of lead-in week ]
    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)

  15. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites] [ Time Frame: At hour 2 of Day 1 of lead-in week ]
    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)

  16. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites] [ Time Frame: At hour 4 of Day 1 of lead-in week ]
    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)

  17. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites] [ Time Frame: At hour 24 of Day 1 of lead-in week ]
    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)

  18. Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [clearance and average steady state concentrations for disulfiram and its active metabolites] [ Time Frame: Day 1 of cycle 1 (day 8) ]
    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)


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05210374


Contacts
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Contact: Matteo Trucco, MD +1 216-444-8950 truccom@ccf.org

Locations
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United States, Ohio
Cleveland Clinic, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44122
Contact: Matteo Trucco, MD    216-444-8950    truccom@ccf.org   
Principal Investigator: Matteo Trucco, MD         
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
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Principal Investigator: Matteo Trucco, MD Cleveland Clinic, Case Comprehensive Cancer Center
More Information
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Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT05210374    
Other Study ID Numbers: CASE1720
First Posted: January 27, 2022    Key Record Dates
Last Update Posted: January 26, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: all collected IPD
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Immediately following publication and for 3 years following publication
Access Criteria: Researchers who provide a sound rationale for access

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Case Comprehensive Cancer Center:
Sarcoma,
osteosarcoma
rhabdomyosarcoma
Ewing sarcoma
Additional relevant MeSH terms:
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Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Copper
Doxorubicin
Liposomal doxorubicin
Disulfiram
Antibiotics, Antineoplastic
Antineoplastic Agents
 Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Trace Elements
Micronutrients
Physiological Effects of Drugs
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors