(P 536) PHASE 1 STUDY OF DISULFIRAM WITH COPPER GLUCONATE AND LIPOSOMAL DOXORUBICIN IN PATIENTS WITH TREATMENT REFRACTORY SARCOMAS

Objective: Relapsed sarcomas carry very poor prognoses and often show resistance to chemotherapy. High expression of the enzyme aldehyde dehydrogenase (ALDH) in sarcomas correlates with aggressive disease and resistance to chemotherapy drugs used to treat these cancers.
Reducing ALDH levels reverses this resistance. Disulfiram (Antabuse) is an inhibitor of ALDH that has been used safely for over 60 years for the treatment of alcoholism. Several pre-clinical studies have demonstrated an anti-cancer effect of disulfiram (DSF), which is enhanced when given with copper (Cu), and its ability to make tumors more sensitive to chemotherapy. We are conducting a clinical trial of disulfiram/copper gluconate (DSF/Cu) in combination with liposomal-doxorubicin in adults with relapsed/refractory sarcomas, with the intention to expand the study to patients < 18yo once safety is demonstrated in adult patients. Primary objective is to determine the feasibility, safety and tolerability of DSF/Cu in combination with liposomal doxorubicin as measured by adverse events, using CTCAE 5.0 guidelines, in patients with relapsed/refractory sarcomas and establish the recommended phase 2 dose (RP2D) of DSF/Cu in combination with liposomal doxorubicin. Secondary objectives include determining tumor response to the DSF/Cu and liposomal doxorubicin combination using RECIST criteria on imaging, overall and event free survival, and pharmacokinetics of DSF/Cu in combination with liposomal doxorubicin based on samples collected at hour 0, 2, 4 and 24 of Day -6 of lead-in week and Day 1 of cycle 1. Correlative objectives include assessment of ALDH expression and intra-tumoral copper levels in pre- and post treatment tumor biopsies.

Methods: We are conducting a 3+3 dose escalation trial of disulfiram/ copper gluconate with liposomal doxorubicin in patients >18yo with relapsed or refractory sarcomas. Inclusion criteria includes histologically confirmed sarcoma in relapsed or refractory to prior therapy, measurable disease by RECIST criteria, age > 18yo, Karnofskyperformance status ≥50%, adequate organ function, normal serum copper levels and serum cerulopasmin >17mg/dL, able to swallow pills or consume the contents of the DSF and Cu capsules sprinkled on food, ability to understand and the willingness to sign a written informed consent document, abstanance from alcohol during study, agreement to pre- and post-treatment core needle tumor biopsies. Exclusion criteria includes uncontrolled infection, hypersensitivity to any of the agents, patient unwilling or unable to comply with study requirements, known conditions preventing the absorption or safe administration of copper, or Alcohol Use Disorders Identification Test (AUDIT) score of >8 for men and >4 for women. Core needle tumor biopsy will be performed prior to starting therapy and at the end of cycle 2 of treatment.
DSF will be administered orally every morning and Cu administered orally every evening beginning with a lead-in week (Day -6 to 0) and then as part of 28 day cycles. Liposomal doxorubicin will be administered on Day 1 of every 28 day cycle. The dose of Cu will be 5.2mg/m2/day and liposomal doxorubicin will be 30mg/m2 IV throughout the study, while the DSF dose will begin at 225mg/m2/day at dose level 0 and if safe, increased to 300mg/m2/day at dose level 1, or de-escalated to dose level -1 with 150mg/m2/day. Dose-limiting toxicities will be evaluated during cycle 1 while response will be assessed with RECIST criteria after every 2 cycles.

Results: The study opened to enrollment in January 2023 and as of June 2023, 4 patients were enrolled at dose level 0, one patient needing to be replaced per protocol for having to come off study due to progressive disease in the first week of cycle 1 and not having received at least 80% of study drug. Two patients completed 2 cycles of therapy successfully without any dose-limiting toxicities, but had progressive disease at response assessment. The replacement study candidate is soon to begin therapy. Histologies included 1 Ewing sarcoma, 1 osteosarcoma, 1 rhabdomyosarcoma and 1 synovial sarcoma. 3 of the patients had prior doxorubicin exposure. Adverse events at least possibly related to study medication were Grade 2 or lower and included rash, diarrhea, constipation, nausea, vomiting, fatigue, blurred vision, presyncope, and depression.

Conclusion: While the trial is still underway, the combination of disulfiram/copper gluconate with liposomal doxorubicin for the treatment of relapsed or refractory sarcomas appears feasible with no dose-limiting toxicities to date. Blood and tumor samples are being collected for pharmacokinetic and pharmacodynamic analyses. Accrual has thus far been relatively brisk.