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Mithramycin for Children and Adults With Solid Tumors or Ewing Sarcoma

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ClinicalTrials.gov Identifier: NCT01610570
Recruitment Status : Terminated (Study was closed to enrollment before dose level one was completed.)
First Posted : June 4, 2012
Results First Posted : February 15, 2016
Last Update Posted : March 2, 2018
Sponsor:
Information provided by (Responsible Party):
Brigitte Widemann, M.D., National Institutes of Health Clinical Center (CC)

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Ewing Sarcoma
Sarcoma
Intervention Drug: Mithramycin
Enrollment 8

Recruitment Details  
Pre-assignment Details The study was closed to enrollment before dose level I was completed and hence no patients were enrolled on other dose levels.
Arm/Group Title Phase I Dose Level -1 Phase 1 Dose Level 1 Phase 1 Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description

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

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

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

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.
Period Title: Ph I >/= 12 mo. Children & Adolescents
Started 0 2 0 0
Completed 0 2 0 0
Not Completed 0 0 0 0
Period Title: Ph II >/= 18yrs of Age at Enrollment
Started 0 0 0 6
Completed 0 0 0 6
Not Completed 0 0 0 0
Period Title: Ph II >/= 12 mo. & </=17yrs
Started 0 0 0 0
Completed 0 0 0 0
Not Completed 0 0 0 0
Arm/Group Title Phase I Dose Level -1 Phase 1 Dose Level 1 Phase I Dose Level 2 Phase 2 Total
Hide Arm/Group Description 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 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 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 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 of all reporting groups
Overall Number of Baseline Participants 0 2 0 6 8
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants 2 participants 0 participants 6 participants 8 participants
<=18 years
2
 100.0%
0
   0.0%
2
  25.0%
Between 18 and 65 years
0
   0.0%
6
 100.0%
6
  75.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 0 participants 2 participants 0 participants 6 participants 8 participants
12.5  (0) 23.8  (5.3) 21.0  (6.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants 2 participants 0 participants 6 participants 8 participants
Female
0
   0.0%
3
  50.0%
3
  37.5%
Male
2
 100.0%
3
  50.0%
5
  62.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants 2 participants 0 participants 6 participants 8 participants
Hispanic or Latino
1
  50.0%
0
   0.0%
1
  12.5%
Not Hispanic or Latino
1
  50.0%
6
 100.0%
7
  87.5%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants 2 participants 0 participants 6 participants 8 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
2
 100.0%
6
 100.0%
8
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 0 participants 2 participants 0 participants 6 participants 8 participants
2
 100.0%
6
 100.0%
8
 100.0%
1.Primary Outcome
Title Maximum Tolerated Dose (MTD) of Mithramycin
Hide Description 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.
Time Frame Cycle 1 of therapy (or 28 days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level -1 Phase I Dose Level 1 Phase I Dose Level 2
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
2.Primary Outcome
Title Number of Participants With Serious and Non-serious Adverse Events
Hide Description 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.
Time Frame 95 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase I Dose Level -1 Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 0 2 0 6
Measure Type: Count of Participants
Unit of Measure: Participants
2
 100.0%
6
 100.0%
3.Secondary Outcome
Title Objective Response Rate (Complete Response (CR) + Partial Response (PR))
Hide Description 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.
Time Frame 1-2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This is a phase II objective, thus phase I groups are not shown here.
Arm/Group Title Phase II - Expansion Phase
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 6
Measure Type: Number
Unit of Measure: participants
Complete response (CR) 0
Partial response (PR) 0
4.Secondary Outcome
Title Time to Progression (TTP)
Hide Description 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.
Time Frame At date of progression, an average of 56 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 0 0 6
Measure Type: Number
Unit of Measure: Days
Patient #1 56
Patient #2 56
Patient #3 126
Patient #5 54
Patient #7 56
Patient #8 56
5.Secondary Outcome
Title Count of Participants With NR0B1 Expression in Tumor Biopsies
Hide Description Biopsies were to be obtained in adult patients who have disease that could be safely biopsied.
Time Frame Pre-treatment and day 4 (+/- 1 day)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This outcome measure was not done because none of the adult patients on this study had disease that was deemed accessible.
Arm/Group Title Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)
Hide Description 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.
Time Frame ≥4 weeks from baseline
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 0 0 6
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response
0
   0.0%
Partial Response
0
   0.0%
Progressive Disease
6
 100.0%
Stable Disease
0
   0.0%
7.Secondary Outcome
Title Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria
Hide Description 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.
Time Frame ≥4 weeks from baseline
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description:
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.
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.
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.
Overall Number of Participants Analyzed 0 0 6
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response
0
   0.0%
Partial Response
0
   0.0%
Progressive Disease
6
 100.0%
Stable Disease
0
   0.0%
8.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods
Hide Description 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.
Time Frame 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
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 & Phase II Expansion Phase
Hide Arm/Group Description:
Dose levels 13.0 and 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.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: ng/mL
17.8  (4.6)
9.Secondary Outcome
Title Half-Life (HL) of Mithramycin
Hide Description 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.
Time Frame 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
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 & Phase II Expansion Phase
Hide Arm/Group Description:
Dose levels 13.0 and 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.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: hours
6.8  (2.3)
10.Secondary Outcome
Title Area Under the Curve Extrapolated to Infinity (AUCinf)
Hide Description 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.
Time Frame 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
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 & Phase II Expansion Phase
Hide Arm/Group Description:
Dose levels 13.0 and 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.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: h*ng/mL
1544  (754)
11.Secondary Outcome
Title Area Under the Curve for the Dosing Interval (AUCtau)
Hide Description AUCtau is AUC for the dosing interval. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method.
Time Frame 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
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 & Phase II Expansion Phase
Hide Arm/Group Description:
Dose levels 13.0 and 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.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: h*ng/mL
394  (94)
12.Secondary Outcome
Title Clearance at Steady State (CLss)
Hide Description 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.
Time Frame 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
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 & Phase II Expansion Phase
Hide Arm/Group Description:
Dose levels 13.0 and 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.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: L/h
1.9  (0.8)
13.Secondary Outcome
Title Volume of Distribution at Steady State (Vss)
Hide Description 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.
Time Frame 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
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Hide Analysis Population Description
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.
Arm/Group Title Phase I Dose Level 1 & Phase II Expansion Phase
Hide Arm/Group Description:
Dose levels 13.0 and 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.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: L
293  (88)
14.Other Pre-specified Outcome
Title Number of Participants With Dose Limiting Toxicity (DLT)
Hide Description 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.
Time Frame Cycle 1 of therapy (or 28 days)
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Hide Analysis Population Description
Hepatotoxicity
Arm/Group Title Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
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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.
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.
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.
Overall Number of Participants Analyzed 2 0 6
Measure Type: Count of Participants
Unit of Measure: Participants
2
 100.0%
0
0
   0.0%
Time Frame 95 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Phase I Dose Level -1 Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Hide Arm/Group Description 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. 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. 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. 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.
All-Cause Mortality
Phase I Dose Level -1 Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/0      0/2 (0.00%)      0/0      0/6 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Phase I Dose Level -1 Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/0      2/2 (100.00%)      0/0      1/6 (16.67%)    
General disorders         
Fever  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Investigations         
Alanine aminotransferase increased  1  0/0  2/2 (100.00%)  0/0  1/6 (16.67%)  1
Aspartate aminotransferase increased  1  0/0  2/2 (100.00%)  0/0  1/6 (16.67%)  1
Vascular disorders         
Hypotension  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase I Dose Level -1 Phase I Dose Level 1 Phase I Dose Level 2 Phase II - Expansion Phase
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/0      2/2 (100.00%)      0/0      6/6 (100.00%)    
Blood and lymphatic system disorders         
Anemia  1  0/0  1/2 (50.00%)  2 0/0  2/6 (33.33%)  7
Congenital, familial and genetic disorders         
Congenital, familial and genetic disorders - Other, difficulty concentrating  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Gastrointestinal disorders         
Abdominal pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Bloating  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Constipation  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  2
Gastrointestinal disorders - Other, acid reflux  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Nausea  1  0/0  0/2 (0.00%)  0/0  5/6 (83.33%)  6
Vomiting  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
General disorders         
Facial pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Fatigue  1  0/0  1/2 (50.00%)  1 0/0  4/6 (66.67%)  6
Fever  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  3
Flu like symptoms  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
General disorders and administration site conditions - Other, fluid retention  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Localized edema  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Non-cardiac chest pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  3
General disorders and administration site conditions - Other  1 [1]  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  2
General disorders and administration site conditions - Other, oral thrush  1  0/0  1/2 (50.00%)  1 0/0  1/6 (16.67%)  1
General disorders and administration site conditions - Other, body aches  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
General disorders and administration site conditions - Other, malaise  1  0/0  1/2 (50.00%)  1 0/0  0/6 (0.00%) 
Investigations         
Alanine aminotransferase increased  1  0/0  1/2 (50.00%)  4 0/0  6/6 (100.00%)  32
Alkaline phosphatase increased  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  2
Aspartate aminotransferase increased  1  0/0  1/2 (50.00%)  3 0/0  6/6 (100.00%)  28
Lymphocyte count decreased  1  0/0  2/2 (100.00%)  6 0/0  6/6 (100.00%)  25
Neutrophil count decreased  1  0/0  1/2 (50.00%)  1 0/0  2/6 (33.33%)  2
Platelet count decreased  1  0/0  0/2 (0.00%)  0/0  4/6 (66.67%)  8
White blood cell decreased  1  0/0  1/2 (50.00%)  3 0/0  4/6 (66.67%)  9
Metabolism and nutrition disorders         
Anorexia  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Hyperglycemia  1  0/0  0/2 (0.00%)  0/0  5/6 (83.33%)  11
Hyperkalemia  1  0/0  1/2 (50.00%)  1 0/0  1/6 (16.67%)  4
Hypermagnesemia  1  0/0  2/2 (100.00%)  3 0/0  3/6 (50.00%)  7
Hypoalbuminemia  1  0/0  1/2 (50.00%)  2 0/0  3/6 (50.00%)  10
Hypocalcemia  1  0/0  1/2 (50.00%)  2 0/0  5/6 (83.33%)  6
Hypoglycemia  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Hypokalemia  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  2
Hyponatremia  1  0/0  1/2 (50.00%)  1 0/0  2/6 (33.33%)  2
Hypophosphatemia  1  0/0  1/2 (50.00%)  2 0/0  5/6 (83.33%)  12
Metabolism and nutrition disorders - Other, LDH elevated  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Metabolism and nutrition disorders - Other, indigestion  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Musculoskeletal and connective tissue disorders         
Arthralgia  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Back pain  1  0/0  0/2 (0.00%)  0/0  3/6 (50.00%)  3
Bone pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Chest wall pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Flank pain  1  0/0  1/2 (50.00%)  1 0/0  0/6 (0.00%) 
Generalized muscle weakness  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Joint range of motion decreased lumbar spine  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Musculoskeletal and connective tissue disorder - Other, hand numbness  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Myalgia  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Neck pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Pain in extremity  1  0/0  1/2 (50.00%)  1 0/0  4/6 (66.67%)  4
Musculoskeletal and connective tissue disorder - Other, jaw numbness  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Nervous system disorders         
Dizziness  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Dysgeusia  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Headache  1  0/0  0/2 (0.00%)  0/0  3/6 (50.00%)  6
Paresthesia  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Psychiatric disorders         
Agitation  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Insomnia  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  2
Renal and urinary disorders         
Proteinuria  1  0/0  0/2 (0.00%)  0/0  3/6 (50.00%)  8
Reproductive system and breast disorders         
Scrotal pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Testicular pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  2
Respiratory, thoracic and mediastinal disorders         
Cough  1  0/0  1/2 (50.00%)  1 0/0  1/6 (16.67%)  1
Dyspnea  1  0/0  1/2 (50.00%)  1 0/0  0/6 (0.00%) 
Epistaxis  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  2
Hiccups  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Nasal congestion  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  2
Sore throat  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  3
Skin and subcutaneous tissue disorders         
Photosensitivity  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Skin and subcutaneous tissue disorders - Other, peri-scapular pain  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Skin and subcutaneous tissue disorders - Other, rash  1  0/0  0/2 (0.00%)  0/0  1/6 (16.67%)  1
Vascular disorders         
Flushing  1  0/0  0/2 (0.00%)  0/0  2/6 (33.33%)  2
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
[1]
Decreased breath sounds LLL
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Brigitte Widemann
Organization: National Cancer Institute
Phone: 301-496-7387
Responsible Party: Brigitte Widemann, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01610570     History of Changes
Other Study ID Numbers: 120135
12-C-0135
First Submitted: May 31, 2012
First Posted: June 4, 2012
Results First Submitted: November 25, 2015
Results First Posted: February 15, 2016
Last Update Posted: March 2, 2018