Trial Outcomes & Findings for Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma (NCT NCT01610570)

Last Updated: 2018-03-02

Results Overview

The MTD will be the maximum dose at which fewer than one-third of patients experience Dose Limiting Toxicity (DLT) (i.e., non-hematologic toxicity and hematologic toxicity) during cycle 1 (or 28 days) of therapy.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

8 participants

Primary outcome timeframe

Cycle 1 of therapy (or 28 days)

Results posted on

2018-03-02

Participant Flow

The study was closed to enrollment before dose level I was completed and hence no patients were enrolled on other dose levels.

Participant milestones

Participant milestones
Measure	Phase 1 Dose Level 1 Dose Escalation Phase 13.0 mcg/kg/dose Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Mithramycin: Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously.
Ph I >/= 12 mo. Children & Adolescents STARTED	2	0
Ph I >/= 12 mo. Children & Adolescents COMPLETED	2	0
Ph I >/= 12 mo. Children & Adolescents NOT COMPLETED	0	0
Ph II >/= 18yrs of Age at Enrollment STARTED	0	6
Ph II >/= 18yrs of Age at Enrollment COMPLETED	0	6
Ph II >/= 18yrs of Age at Enrollment NOT COMPLETED	0	0
Ph II >/= 12 mo. & </=17yrs STARTED	0	0
Ph II >/= 12 mo. & </=17yrs COMPLETED	0	0
Ph II >/= 12 mo. & </=17yrs NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I Dose Level -1 Dose Escalation Phase 9.0 mcg/kg/dose Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously	Phase 1 Dose Level 1 n=2 Participants Dose Escalation Phase 13.0 mcg/kg/dose Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg/dose Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously	Phase 2 n=6 Participants Expansion phase 17.5 mcg/kg.dose Mithramycin: Phase I Portion: Mithramycin will be administered in escalating doses to children and adolescents intravenously over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Phase differs from the recommended adult dose for Phase II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously.	Total n=8 Participants Total of all reporting groups
Age, Categorical <=18 years	—	2 Participants n=7 Participants	—	0 Participants n=4 Participants	2 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	—	0 Participants n=7 Participants	—	6 Participants n=4 Participants	6 Participants n=21 Participants
Age, Categorical >=65 years	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Continuous	—	12.5 years STANDARD_DEVIATION 0 • n=7 Participants	—	23.8 years STANDARD_DEVIATION 5.3 • n=4 Participants	21.0 years STANDARD_DEVIATION 6.9 • n=21 Participants
Sex: Female, Male Female	—	0 Participants n=7 Participants	—	3 Participants n=4 Participants	3 Participants n=21 Participants
Sex: Female, Male Male	—	2 Participants n=7 Participants	—	3 Participants n=4 Participants	5 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	—	1 Participants n=7 Participants	—	0 Participants n=4 Participants	1 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	—	1 Participants n=7 Participants	—	6 Participants n=4 Participants	7 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	—	2 Participants n=7 Participants	—	6 Participants n=4 Participants	8 Participants n=21 Participants
Race (NIH/OMB) More than one race	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	—	0 Participants n=7 Participants	—	0 Participants n=4 Participants	0 Participants n=21 Participants
Region of Enrollment United States	—	2 Participants n=7 Participants	—	6 Participants n=4 Participants	8 Participants n=21 Participants

PRIMARY outcome

Timeframe: Cycle 1 of therapy (or 28 days)

Population: MTD was not determined because based on pharmacokinetic data, a clinically relevant dose could not be obtained with the dose strategy. A minimum of 3 patients must be enrolled on a dose level to complete that dose level. Because only 2 patients were enrolled on phase I portion of the trial, dose level 1 was not completed and an MTD was not reached.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 95 days

Here is the number of participants with serious and non-serious adverse events. For a detailed list of serious and non-serious adverse events see the adverse event module.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 n=2 Participants Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase n=6 Participants Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Number of Participants With Serious and Non-serious Adverse Events	—	2 Participants	—	6 Participants

SECONDARY outcome

Timeframe: 1-2 months

Population: This is a phase II objective, thus phase I groups are not shown here.

Objective response in children and adolescents with Ewings sarcoma - friend leukemia integration 1 transcription factor to mithramycin is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=6 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Objective Response Rate (Complete Response (CR) + Partial Response (PR)) Complete response (CR)	0 participants	—	—	—
Objective Response Rate (Complete Response (CR) + Partial Response (PR)) Partial response (PR)	0 participants	—	—	—

SECONDARY outcome

Timeframe: At date of progression, an average of 56 days

Population: TTP was not evaluated for patients on the phase I portion of the study (patients 4 and 6). TTP was evaluated on the phase II portion of the study only for patients 1, 2, 3, 5, 7, and 8.

TTP is defined as the number of days from enrollment until disease progression, death because of treatment complications, resection of measureable tumor, or last patient follow-up, whichever comes first, assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 n=6 Participants Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Time to Progression (TTP) Patient #1	—	—	56 Days	—
Time to Progression (TTP) Patient #2	—	—	56 Days	—
Time to Progression (TTP) Patient #3	—	—	126 Days	—
Time to Progression (TTP) Patient #5	—	—	54 Days	—
Time to Progression (TTP) Patient #7	—	—	56 Days	—
Time to Progression (TTP) Patient #8	—	—	56 Days	—

SECONDARY outcome

Timeframe: Pre-treatment and day 4 (+/- 1 day)

Population: This outcome measure was not done because none of the adult patients on this study had disease that was deemed accessible.

Biopsies were to be obtained in adult patients who have disease that could be safely biopsied.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: ≥4 weeks from baseline

Population: Changes in tumor burden was not evaluated for patients on the phase I portion of the study (patients 4 and 6). Changes in tumor burden was evaluated on the phase II portion of the study only for patients 1, 2, 3, 5, 7, and 8.

Measurable disease were to be quantified using volumetric magnetic resonance imaging analysis per the RECIST, measuring soft tissue disease. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes. Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 n=6 Participants Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) Complete Response	—	—	0 Participants	—
Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) Partial Response	—	—	0 Participants	—
Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) Progressive Disease	—	—	6 Participants	—
Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) Stable Disease	—	—	0 Participants	—

SECONDARY outcome

Timeframe: ≥4 weeks from baseline

Per the WHO criteria, progressive disease is a 25% increase in tumor lesions, or the appearance of any new measureable or non-measureable tumor lesions. Partial response is ≥50% decrease in tumor lesions. Complete response is disappearance of all tumor lesions. Stable disease is 50% decrease in tumor lesions compared to baseline, nor 25% increase compared with nadir.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 n=6 Participants Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria Complete Response	—	—	0 Participants	—
Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria Partial Response	—	—	0 Participants	—
Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria Progressive Disease	—	—	6 Participants	—
Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria Stable Disease	—	—	0 Participants	—

SECONDARY outcome

Timeframe: Prior to dose 1, 3hrs after dose 1 infusion, prior to end of 6hr infusion, 0.25, 0.5, 1,2,3,4,5, & 7hr post infusion, & between 9 & 12hr completion of 1st dose infusion. Trough & end of infusion samples obtained w/day 2,4,&7 doses & 24hr after day 7 dose

Population: After dose-limiting hepatotoxicity was observed in the 1st 2 adult patients (pts), the protocol was subsequently amended to allow PK analysis prior to and at the completion of the first dose during cycle 1 on both the ph 1 \& 2 portions of the trial in consenting pts. PK sampling was not mandatory, thus not all pts (i.e. 4/8 pts) had PK analysis.

The maximum observed analyte concentration in serum was reported. Mithramycin plasma concentrations were measured using high-performance liquid chromatography tandem mass spectroscopic method, and analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=4 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods	17.8 ng/mL Standard Deviation 4.6	—	—	—

SECONDARY outcome

Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=4 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Half-Life (HL) of Mithramycin	6.8 hours Standard Deviation 2.3	—	—	—

SECONDARY outcome

AUC is a measure of the serum concentration of mithramycin over time. It is used to characterize drug absorption. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=4 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Area Under the Curve Extrapolated to Infinity (AUCinf)	1544 h*ng/mL Standard Deviation 754	—	—	—

SECONDARY outcome

AUCtau is AUC for the dosing interval. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=4 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Area Under the Curve for the Dosing Interval (AUCtau)	394 h*ng/mL Standard Deviation 94	—	—	—

SECONDARY outcome

The CL is a quantitative measure of the rate at which a drug substance is removed from the body. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=4 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Clearance at Steady State (CLss)	1.9 L/h Standard Deviation 0.8	—	—	—

SECONDARY outcome

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=4 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Volume of Distribution at Steady State (Vss)	293 L Standard Deviation 88	—	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Cycle 1 of therapy (or 28 days)

Population: Hepatotoxicity

Hematologic DLT was defined as any grade 4 neutropenia (\<500/µL) or thrombocytopenia (\<25,000/µL) refractory to platelet transfusion, any grade 2 bleeding not promptly (within 6 h of appropriate intervention) corrected with blood product support. Non-hematologic DLT's were any mithramycin-related grade ≥3 toxicity with the exception of grade 3 nausea, vomiting, or diarrhea that was controlled by symptomatic treatment within 72h, asymptomatic grade 3 elevation of serum transaminases that return to ≤grade 1 within 14 days of completing mithramycin administration, and asymptomatic electrolyte abnormalities that are correctable to grade2 or less within 48h.

Outcome measures

Outcome measures
Measure	Phase I Dose Level -1 n=2 Participants Dose Escalation Ph 9.0 mcg/kg dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 n=6 Participants Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Number of Participants With Dose Limiting Toxicity (DLT)	2 Participants	0 Participants	0 Participants	—

Adverse Events

Phase I Dose Level -1

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase I Dose Level 1

Serious events: 2 serious events

Other events: 2 other events

Deaths: 0 deaths

Phase I Dose Level 2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Phase II - Expansion Phase

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I Dose Level -1 Dose Escalation Phase 9.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 n=2 participants at risk Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase n=6 participants at risk Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
General disorders Fever	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Alanine aminotransferase increased	— 0/0 • 95 days	100.0% 2/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Aspartate aminotransferase increased	— 0/0 • 95 days	100.0% 2/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Vascular disorders Hypotension	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days

Other adverse events

Other adverse events
Measure	Phase I Dose Level -1 Dose Escalation Phase 9.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 1 n=2 participants at risk Dose Escalation Phase 13.0 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase I Dose Level 2 Dose Escalation Phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.	Phase II - Expansion Phase n=6 participants at risk Expansion phase 17.5 mcg/kg.dose Ph I: Mithramycin will be administered in escalating doses to children and adolescents intravenously IV) over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression. If maximum tolerated dose (MTD) in this Ph differs from the recommended adult dose for Ph II, the protocol will be amended. Using a Simon two stage design, mithramycin will be administered IV at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults with Ewing sarcoma with Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1) fusion transcript Both Phases will enroll patients simultaneously. Ph II: mithramycin will be administered intravenously at 17.5 microgram/kg over 6 hours once daily for 7 days to be repeated every 28 days until unacceptable toxicity or disease progression to children and adults.
Gastrointestinal disorders Abdominal pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Psychiatric disorders Agitation	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Alanine aminotransferase increased	— 0/0 • 95 days	50.0% 1/2 • Number of events 4 • 95 days	— 0/0 • 95 days	100.0% 6/6 • Number of events 32 • 95 days
Investigations Alkaline phosphatase increased	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 2 • 95 days
Blood and lymphatic system disorders Anemia	— 0/0 • 95 days	50.0% 1/2 • Number of events 2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 7 • 95 days
Metabolism and nutrition disorders Anorexia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Musculoskeletal and connective tissue disorders Arthralgia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Aspartate aminotransferase increased	— 0/0 • 95 days	50.0% 1/2 • Number of events 3 • 95 days	— 0/0 • 95 days	100.0% 6/6 • Number of events 28 • 95 days
Musculoskeletal and connective tissue disorders Back pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	50.0% 3/6 • Number of events 3 • 95 days
Gastrointestinal disorders Bloating	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Musculoskeletal and connective tissue disorders Bone pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Musculoskeletal and connective tissue disorders Chest wall pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Congenital, familial and genetic disorders Congenital, familial and genetic disorders - Other, difficulty concentrating	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Gastrointestinal disorders Constipation	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
Respiratory, thoracic and mediastinal disorders Cough	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Nervous system disorders Dizziness	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Nervous system disorders Dysgeusia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Respiratory, thoracic and mediastinal disorders Dyspnea	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	0.00% 0/6 • 95 days
Respiratory, thoracic and mediastinal disorders Epistaxis	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
General disorders Facial pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
General disorders Fatigue	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	66.7% 4/6 • Number of events 6 • 95 days
General disorders Fever	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 3 • 95 days
Musculoskeletal and connective tissue disorders Flank pain	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	0.00% 0/6 • 95 days
General disorders Flu like symptoms	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Vascular disorders Flushing	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
Gastrointestinal disorders Gastrointestinal disorders - Other, acid reflux	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
General disorders General disorders and administration site conditions - Other, fluid retention	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Musculoskeletal and connective tissue disorders Generalized muscle weakness	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Nervous system disorders Headache	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	50.0% 3/6 • Number of events 6 • 95 days
Respiratory, thoracic and mediastinal disorders Hiccups	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Metabolism and nutrition disorders Hyperglycemia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	83.3% 5/6 • Number of events 11 • 95 days
Metabolism and nutrition disorders Hyperkalemia	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 4 • 95 days
Metabolism and nutrition disorders Hypermagnesemia	— 0/0 • 95 days	100.0% 2/2 • Number of events 3 • 95 days	— 0/0 • 95 days	50.0% 3/6 • Number of events 7 • 95 days
Metabolism and nutrition disorders Hypoalbuminemia	— 0/0 • 95 days	50.0% 1/2 • Number of events 2 • 95 days	— 0/0 • 95 days	50.0% 3/6 • Number of events 10 • 95 days
Metabolism and nutrition disorders Hypocalcemia	— 0/0 • 95 days	50.0% 1/2 • Number of events 2 • 95 days	— 0/0 • 95 days	83.3% 5/6 • Number of events 6 • 95 days
Metabolism and nutrition disorders Hypoglycemia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Metabolism and nutrition disorders Hypokalemia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
Metabolism and nutrition disorders Hyponatremia	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
Metabolism and nutrition disorders Hypophosphatemia	— 0/0 • 95 days	50.0% 1/2 • Number of events 2 • 95 days	— 0/0 • 95 days	83.3% 5/6 • Number of events 12 • 95 days
Psychiatric disorders Insomnia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
Musculoskeletal and connective tissue disorders Joint range of motion decreased lumbar spine	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
General disorders Localized edema	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Lymphocyte count decreased	— 0/0 • 95 days	100.0% 2/2 • Number of events 6 • 95 days	— 0/0 • 95 days	100.0% 6/6 • Number of events 25 • 95 days
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, LDH elevated	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, hand numbness	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Musculoskeletal and connective tissue disorders Myalgia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Respiratory, thoracic and mediastinal disorders Nasal congestion	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
Gastrointestinal disorders Nausea	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	83.3% 5/6 • Number of events 6 • 95 days
Musculoskeletal and connective tissue disorders Neck pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Neutrophil count decreased	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 2 • 95 days
General disorders Non-cardiac chest pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
General disorders Pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 3 • 95 days
Musculoskeletal and connective tissue disorders Pain in extremity	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	66.7% 4/6 • Number of events 4 • 95 days
Nervous system disorders Paresthesia	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Skin and subcutaneous tissue disorders Photosensitivity	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations Platelet count decreased	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	66.7% 4/6 • Number of events 8 • 95 days
Renal and urinary disorders Proteinuria	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	50.0% 3/6 • Number of events 8 • 95 days
Reproductive system and breast disorders Scrotal pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, peri-scapular pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Respiratory, thoracic and mediastinal disorders Sore throat	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	33.3% 2/6 • Number of events 3 • 95 days
Reproductive system and breast disorders Testicular pain	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 2 • 95 days
Gastrointestinal disorders Vomiting	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Investigations White blood cell decreased	— 0/0 • 95 days	50.0% 1/2 • Number of events 3 • 95 days	— 0/0 • 95 days	66.7% 4/6 • Number of events 9 • 95 days
General disorders General disorders and administration site conditions - Other	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 2 • 95 days
General disorders General disorders and administration site conditions - Other, oral thrush	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
General disorders General disorders and administration site conditions - Other, body aches	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
General disorders General disorders and administration site conditions - Other, malaise	— 0/0 • 95 days	50.0% 1/2 • Number of events 1 • 95 days	— 0/0 • 95 days	0.00% 0/6 • 95 days
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, jaw numbness	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, indigestion	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, rash	— 0/0 • 95 days	0.00% 0/2 • 95 days	— 0/0 • 95 days	16.7% 1/6 • Number of events 1 • 95 days

Additional Information

Dr. Brigitte Widemann

National Cancer Institute

Phone: 301-496-7387

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place