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

Official title

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

Overview

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.

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.

Interventions

• 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

Primary outcome measures

• 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]
• Recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin [Time frame: 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 [Time frame: up to 30 days after last treatment]
• Number of dose-limiting toxicities (DLT) [Time frame: up to 30 days after last treatment]
• Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0 [Time frame: up to 30 days after last treatment]

Secondary outcome measures (12)

• Percent of participants with tumor response evaluated using RECIST v1.1 [Time frame: At 2 months]
• Median Overall Survival (OS) [Time frame: up to 30 days after last treatment]
• Median Event free survival [Time frame: up to 30 days after last treatment]
• 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 doxorubicin [Peak concentration (Cmax)] [Time frame: At hour 2 of Day 1 of lead-in week]
• 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 doxorubicin [Peak concentration (Cmax)] [Time frame: At hour 24 of Day 1 of lead-in week]
• 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 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 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 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 doxorubicin [area under the concentration-vs-time curve (AUC)] [Time frame: At hour 24 of Day 1 of lead-in week]

Eligibility 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Cleveland Clinic, Case Comprehensive Cancer Center — Cleveland

Identifiers

NCT: NCT05210374 · CASE1720

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗