Trial Outcomes & Findings for Disulfiram/Copper With Concurrent Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma (NCT NCT02715609)

Last Updated: 2025-04-10

Results Overview

* The maximum tolerated dose (MTD) of DSF is defined as the dose level at which 20% of the cohort experience dose-limiting toxicity (DLT) within 18 weeks from start of RT (or 12 weeks from the end of RT if there is a delay in RT). MTD is assessed from the first dose of DSF in combination with TMZ and RT; patients will not be assessed for DLT during the pre-surgery period when they are receiving the lead-in doses of DSF. * A DLT is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications/TMZ which occurs within 18 weeks following the first dose of DSF with RT+TMZ (corresponding to approximately 6 weeks during RT and 12 weeks after RT)

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

35 participants

Primary outcome timeframe

Estimated to be 2 years and 28 weeks

Results posted on

2025-04-10

Participant Flow

Participant milestones

Participant milestones
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2) * Disulfiram (DSF) dose level 2=250mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 3) * Disulfiram (DSF) dose level 3=375mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Overall Study STARTED	9	10	16
Overall Study COMPLETED	8	10	15
Overall Study NOT COMPLETED	1	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2) * Disulfiram (DSF) dose level 2=250mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 3) * Disulfiram (DSF) dose level 3=375mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Overall Study Patient only completed pre-operative treatment	1	0	0
Overall Study Withdrawal by Subject	0	0	1

Baseline Characteristics

Disulfiram/Copper With Concurrent Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2) n=9 Participants * Disulfiram (DSF) dose level 2=250mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 3) n=10 Participants * Disulfiram (DSF) dose level 3=375mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=16 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Total n=35 Participants Total of all reporting groups
Age, Continuous	56 years n=5 Participants	48 years n=7 Participants	51.5 years n=5 Participants	51 years n=4 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	8 Participants n=7 Participants	3 Participants n=5 Participants	14 Participants n=4 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	2 Participants n=7 Participants	13 Participants n=5 Participants	21 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=5 Participants	10 Participants n=7 Participants	16 Participants n=5 Participants	35 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants	33 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	9 participants n=5 Participants	10 participants n=7 Participants	16 participants n=5 Participants	35 participants n=4 Participants

PRIMARY outcome

Timeframe: Estimated to be 2 years and 28 weeks

Population: One participant was not evaluable in dose escalation - dose level 2 as the participant did not receive DSF + RT + TMZ. This outcome measure is not for dose expansion portion of the trial.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) n=18 Participants * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Maximum Tolerated Dose (MTD) of DSF (Dose-escalation Phase Only)	375 mg	—	—

PRIMARY outcome

Timeframe: 1 year

Population: This outcome measure is for participants enrolled in dose expansion only.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=15 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Kaplan-Meier Estimate of Overall Survival (Dose-expansion Phase Only)	—	—	80 percentage of participants-Kaplan Meier

PRIMARY outcome

Timeframe: 2 years

Population: This outcome measure is for participants enrolled in dose expansion only.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=15 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Kaplan-Meier Estimate of Overall Survival (Dose-expansion Phase Only)	—	—	67 percentage of participants-Kaplan Meier

PRIMARY outcome

Timeframe: 3 years

Population: This outcome measure is for participants enrolled in dose expansion only.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=15 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Kaplan-Meier Estimate of Overall Survival (Dose-expansion Phase Only)	—	—	52 percentage of participants-Kaplan Meier

PRIMARY outcome

Timeframe: Through completion of follow-up (up to 5 years)

Population: This outcome measure is for participants enrolled in dose expansion only.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=15 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Mean Overall Survival (Dose-expansion Phase Only)	—	—	37.4 months Interval 26.2 to 48.6

SECONDARY outcome

Timeframe: Through completion of DSF treatment (up to 38 weeks)

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) n=8 Participants * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=10 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=15 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 fatigue	1 Participants	1 Participants	3 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 3 fatigue	0 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 nausea	0 Participants	2 Participants	2 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 diarrhea	0 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 alanine aminotransferase increased	1 Participants	0 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 3 alanine aminotransferase increased	0 Participants	1 Participants	2 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 4 alanine aminotransferase increased	0 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 aspartate aminotransferase increased	0 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 3 aspartate aminotransferase increased	0 Participants	1 Participants	2 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 fall	0 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 ataxia	1 Participants	0 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 3 confusion	0 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 urinary incontinence	1 Participants	1 Participants	0 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 3 urinary incontinence	0 Participants	0 Participants	1 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 4 neutrophil count decreased	0 Participants	0 Participants	1 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 anorexia	0 Participants	0 Participants	1 Participants
Toxicity of DSF When Given Concurrently With Radiation Therapy and Temozolomide as Measured by the Grade and Frequency of Grade 2 or Greater Adverse Events Related to DSF Grade 2 dizziness	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: At the time of surgery (day 4)

Population: Only 3 patients had tumor resection after preoperative DSF/Cu administration.

Will be determined using mass spectrometer

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) n=2 Participants * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=1 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex) Plasma CuET concentration - patient #1	0.11 ng/mL	—	—
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex) Plasma CuET concentration - patient #2	—	0.44 ng/mL	—
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex) Plasma CuET concentration - patient #3	4.59 ng/mL	—	—
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex) Tumor CuET concentration - patient #1	0.00 ng/mL	—	—
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex) Tumor CuET concentration - patient #2	—	0.00 ng/mL	—
Intratumor and Plasma Concentration of DSF Metabolite (Ditiocarb-copper Complex) Tumor CuET concentration - patient #3	0.00 ng/mL	—	—

SECONDARY outcome

Timeframe: Through completion of follow-up (up to 5 years)

Will be determined from the first day of RT to the time of tumor progression or death, whichever occurs first. Tumor progression will be determined using the RANO criteria.

Outcome measures

Outcome measures
Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2 & 3) n=8 Participants * Disulfiram (DSF) dose level 2=250mg, dose level 3=375mg * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=10 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=15 Participants * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery.
Mean Progression-free Survival (PFS)	24.4 months Interval 12.9 to 35.8	32.3 months Interval 13.0 to 51.7	34.5 months Interval 22.0 to 46.9

OTHER_PRE_SPECIFIED outcome

Timeframe: Through completion of follow-up (up to 5 years)

-Pseudoprogression is defined as a transient increase of tumor after chemoradiotherapy that subsequently stabilizes without a change of therapy

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 6

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 6

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Through completion of follow-up (up to 5 years)

-≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids. The absolute increase in any dimension must be at least 5mm when calculating the products * Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy not caused by comorbid events * Any new measureable lesion * Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. seizures, medication adverse effects, complications of therapy, cerebrovascular events, infection, and so on) or changes in corticosteroid dose * Failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 6

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 6

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 6

Outcome measures

Outcome data not reported

Adverse Events

Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2)

Serious events: 3 serious events

Other events: 9 other events

Deaths: 5 deaths

Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 3)

Serious events: 5 serious events

Other events: 10 other events

Deaths: 5 deaths

Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion)

Serious events: 7 serious events

Other events: 16 other events

Deaths: 9 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Jiayi Huang

Washington University School of Medicine

Phone: 314-362-8516

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 2) n=9 participants at risk * Disulfiram (DSF) dose level 2=250mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Escalation - Dose Level 3) n=10 participants at risk * Disulfiram (DSF) dose level 3=375mg. * Preoperative DSF/Copper (CU) x 3 days (optional) * Surgery performed per routine clinical care. * After surgery, evaluation to confirm the final pathological diagnosis as GBM (if not the patient will not continue with the 2nd part of the study). * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * DSF daily and Cu three times daily during chemoradiotherapy as per preoperative dose. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles.	Disulfiram, Copper, Surgery, Radiation Therapy, Temozolomide (Dose Expansion) n=16 participants at risk * Surgery performed per routine clinical care. * Radiation therapy (RT) 4-6 weeks following surgery at 60 Gy in 30 daily fractions. * Temozolomide (TMZ) from Day 1 of RT to the last day of RT at a daily oral dose for a maximum of 49 days as per standard clinical care. * Disulfiram (DSF) daily (250 mg) and Copper (Cu) three times daily during chemoradiotherapy. * 4-6 weeks after completion of chemoradiotherapy, adjuvant TMZ may be administered for 6 cycles. TMZ on Days 1-5 of every 28-day cycle. Daily DSF of 500mg will be continued with adjuvant TMZ for up to 6 cycles. * If a patient develops recurrent tumor during follow-up and plans to undergo another resection, he/she may opt for an optional preoperative DSF study prior to salvage surgery..
General disorders Death NOS	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	25.0% 4/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
General disorders Fever	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Infections and infestations Lung infection	11.1% 1/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Investigations Alanine aminotransferase increased	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Investigations Aspartate aminotransferase increased	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	6.2% 1/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Musculoskeletal and connective tissue disorders Generalized muscle weakness	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	6.2% 1/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Ataxia	11.1% 1/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Confusion	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	6.2% 1/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Headache	11.1% 1/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Lethargy	11.1% 1/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Seizure	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	6.2% 1/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Somnolence	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Nervous system disorders Stroke	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	6.2% 1/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Psychiatric disorders Delirium	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	10.0% 1/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/9 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	0.00% 0/10 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).	6.2% 1/16 • Adverse events were collected from the start of treatment until the last dose of DSF (median length of follow-up 131 days, full range 2-288 days). All-cause mortality was collected from start of treatment through completion of follow-up (up to 5 years).