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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат 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
• Препарат Liposomal Doxorubicin (Doxil)
  To be given IV, 30mg/m2/dose To be administered day 1 of cycles Cycle length: 28 days, maximum 12 cycles

Первичные конечные точки

• Safety as measured by percent of participants experiencing grade 3+ with at least possible attribution to study drug using CTCAE 5.0 guidelines [Срок оценки: up to 30 days after last treatment]
• Recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin [Срок оценки: 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 [Срок оценки: up to 30 days after last treatment]
• Number of dose-limiting toxicities (DLT) [Срок оценки: up to 30 days after last treatment]
• Number of participants who experienced drug-attributed grade 3+ Adverse events per CTCAE5.0 [Срок оценки: up to 30 days after last treatment]

Вторичные конечные точки (12)

• Percent of participants with tumor response evaluated using RECIST v1.1 [Срок оценки: At 2 months]
• Median Overall Survival (OS) [Срок оценки: up to 30 days after last treatment]
• Median Event free survival [Срок оценки: up to 30 days after last treatment]
• Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [Срок оценки: At hour 0 of Day 1 of lead-in week]
• Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [Срок оценки: At hour 2 of Day 1 of lead-in week]
• Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [Срок оценки: At hour 4 of Day 1 of lead-in week]
• Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [Срок оценки: At hour 24 of Day 1 of lead-in week]
• Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [Peak concentration (Cmax)] [Срок оценки: Day 1 of cycle 1 (day 8)]
• Pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin [area under the concentration-vs-time curve (AUC)] [Срок оценки: 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)] [Срок оценки: 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)] [Срок оценки: 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)] [Срок оценки: At hour 24 of Day 1 of lead-in week]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Cleveland Clinic, Case Comprehensive Cancer Center — Cleveland

Идентификаторы

NCT: NCT05210374 · CASE1720

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗