Disulfiram With Copper Gluconate and Liposomal Doxorubicin in Patients With Treatment-Refractory Sarcomas
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Number of participants able to take at least 80% of the drug doses during the first cycle of treatment
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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
干预措施: Copper Gluconate (Drug)
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
干预措施: Disulfiram (Drug)
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
干预措施: Liposomal Doxorubicin (Doxil) (Drug)
结局指标
主要结局
Number of participants able to take at least 80% of the drug doses during the first cycle of treatment
时间窗: 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
Number of dose-limiting toxicities (DLT)
时间窗: up to 30 days after last treatment
Tolerability, as total number of defined as number of DLTs
Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0
时间窗: up to 30 days after last treatment
Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0
Safety as measured by percent of participants experiencing grade 3+ with at least possible attribution to study drug using CTCAE 5.0 guidelines
时间窗: 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
Recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin
时间窗: at end of cycle 1 (day 28)
RP2D of DSF/Cu in combination with liposomal doxorubicin
次要结局
- Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [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)](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](Day 1 of cycle 1 (day 8))
- Percent of participants with tumor response evaluated using RECIST v1.1(At 2 months)
- Median Overall Survival (OS)(up to 30 days after last treatment)
- Median Event free survival(up to 30 days after last treatment)
- Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [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)](At hour 2 of Day 1 of lead-in week)
- Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [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)](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)](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)](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)](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)](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](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](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](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](At hour 24 of Day 1 of lead-in week)