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| ID | Type | Description | Link |
|---|---|---|---|
| 12-C-0135 |
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Study was closed to enrollment before dose level one was completed.
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Background:
- Mithramycin is a drug that was first tested as a cancer therapy in the 1960s. It acted against some forms of cancer, but was never accepted as a treatment. Research suggests that it may be useful against some solid tumors, particularly Ewing sarcoma. Researchers want to see if mithramycin can be used to treat solid tumors in children and adults. It will be tested in different groups of people, including those with a type of Ewing sarcoma that contains a chemical called Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1).
Objectives:
- To see if mithramycin is safe and effective against solid tumors and Ewing sarcoma in children and adults.
Eligibility:
Design:
BACKGROUND:
OBJECTIVES (PRIMARY):
ELIGIBILITY:
(greater than or equal to 12 months) and adolescents (less than or equal to 17 years) with recurrent or refractory measurable
extracranial Ewing sarcoma and the EWS-FLI1 fusion transcript will begin enrollment to the Phase II portion.
DESIGN:
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. The cohort at the recommended dose or maximum tolerated dose (MTD) will be expanded up to 12 patients, and attempts will be made to enroll 6 patients that are greater than or equal to 12 years of age and 6 patients that are < 12 years of age to gain experience with a broad age range of patients. A maximum of 18 evaluable patients will be enrolled on the phase I portion.
Phase II Portion: 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 EWS-FLI1 fusion transcript. Up to 24 evaluable patients will be enrolled on the phase II portion.
The Phase I and Phase II portions of the protocol will enroll patients simultaneously.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase I Dose Level -1 | Experimental | Dose Escalation Phase 9.0 mcg/kg.dose |
|
| Phase I Dose Level 1 | Experimental | Dose Escalation Phase 13.0 mcg/kg.dose |
|
| Phase I Dose Level 2 | Experimental | Dose Escalation Phase 17.5 mcg/kg.dose |
|
| Phase II - Expansion Phase | Experimental | Expansion phase 17.5 mcg/kg.dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Mithramycin | Drug | 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 Portion: 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Mithramycin | 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. | Cycle 1 of therapy (or 28 days) |
| Number of Participants With Serious and Non-serious Adverse Events | 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. | 95 days |
| Measure | Description | Time Frame |
|---|---|---|
| Objective Response Rate (Complete Response (CR) + Partial Response (PR)) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) | 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. |
weeks for nitrosoureas);
at least 3 half-lives must have elapsed since monoclonal antibody1;(https://members.childrensoncologygroup.org/Disc/devtherapeutics/default.asp for listing of monoclonal antibody half-lives.)
greater than or equal to 7 days must have elapsed from the last dose of biologic agents.
greater than or equal to 7 days since the completion of therapy with a growth factor
Recovered from acute toxicities of prior therapy to less than or equal to Grade 1; specifically
a) Hematologic and Coagulation Parameters
i. Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/mcL
ii. Platelets greater than or equal to 75,000/ mcL (transfusion independent)
iii. Hemoglobin greater than or equal to 8 g/dL (packed red blood cell (PRBC) transfusions permitted)
iv. Normal prothrombin time (PT)/partial thromboplastin time (PTT) with the exception of a lupus anticoagulant, which is permitted, may be corrected with Vitamin K administration or transfusion. Fibrinogen greater than or equal to the lower limit of normal.
b) Hepatic Function
i. Bilirubin (total) less than or equal to 1.5 times upper limit of normal (ULN)
ii. Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT) less than or equal to 3.0 times ULN
iii. Albumin > 2 g/dL
c) Renal Function
i. Creatinine clearance greater than or equal to 60 mL/min/1.73 m^2, or serum creatinine base on age and gender as follows:
Age (years) Maximum Serum Creatinine (mg/dL)
2 to < 6 0.8 0.8
6 to < 10 1 1
10 to < 13 1.2 1.2
13 to < 16 1.5 1.4
greater than or equal to 16 1.7 1.4
EXCLUSION CRITERIA:
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| Name | Affiliation | Role |
|---|---|---|
| Brigitte C Widemann, M.D. | National Cancer Institute (NCI) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18525458 | Background | Esiashvili N, Goodman M, Marcus RB Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol. 2008 Jun;30(6):425-30. doi: 10.1097/MPH.0b013e31816e22f3. | |
| 8022439 | Background | Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ, et al. The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994 Aug 4;331(5):294-9. doi: 10.1056/NEJM199408043310503. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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The study was closed to enrollment before dose level I was completed and hence no patients were enrolled on other dose levels.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| FG002 | Phase 1 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 |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ph I >/= 12 mo. Children & Adolescents |
| |||||||||||||
| Ph II >/= 18yrs of Age at Enrollment |
| |||||||||||||
| Ph II >/= 12 mo. & </=17yrs |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Tolerated Dose (MTD) of Mithramycin | 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. | 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. | Posted | Cycle 1 of therapy (or 28 days) |
|
95 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | General disorders | CTCAE (4.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Brigitte Widemann | National Cancer Institute | 301-496-7387 | widemanb@mail.nih.gov |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form: Phase I portion consent | Dec 24, 2014 | Nov 13, 2017 | ICF_000.pdf |
| ICF | No | No | Yes | Informed Consent Form: Phase II portion consent | Dec 24, 2014 | Nov 14, 2017 | ICF_001.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 16, 2016 | Dec 22, 2017 | Prot_SAP_002.pdf |
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| ID | Term |
|---|---|
| D012512 | Sarcoma, Ewing |
| D012509 | Sarcoma |
| D001859 | Bone Neoplasms |
| ID | Term |
|---|---|
| D012516 | Osteosarcoma |
| D018213 | Neoplasms, Bone Tissue |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
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| ID | Term |
|---|---|
| D008926 | Plicamycin |
| ID | Term |
|---|---|
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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|
| 1-2 months |
| Time to Progression (TTP) | 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. | At date of progression, an average of 56 days |
| Count of Participants With NR0B1 Expression in Tumor Biopsies | Biopsies were to be obtained in adult patients who have disease that could be safely biopsied. | Pre-treatment and day 4 (+/- 1 day) |
| Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) | 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. | ≥4 weeks from baseline |
| Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria | 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. | ≥4 weeks from baseline |
| Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods | 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. | 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 |
| Half-Life (HL) of Mithramycin | 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. | 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 |
| Area Under the Curve Extrapolated to Infinity (AUCinf) | 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. | 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 |
| Area Under the Curve for the Dosing Interval (AUCtau) | AUCtau is AUC for the dosing interval. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | 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 |
| Clearance at Steady State (CLss) | 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. | 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 |
| Volume of Distribution at Steady State (Vss) | 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. | 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 |
| Cycle 1 of therapy (or 28 days) |
| 1522903 | Background | Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992 Sep 10;359(6391):162-5. doi: 10.1038/359162a0. |
| 28735378 | Result | Grohar PJ, Glod J, Peer CJ, Sissung TM, Arnaldez FI, Long L, Figg WD, Whitcomb P, Helman LJ, Widemann BC. A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. Cancer Chemother Pharmacol. 2017 Sep;80(3):645-652. doi: 10.1007/s00280-017-3382-x. Epub 2017 Jul 22. |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | 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 |
| BG002 | 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 |
| BG003 | Phase 2 | 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. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | 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. |
| OG002 | 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. |
|
| Primary | Number of Participants With Serious and Non-serious Adverse Events | 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. | Posted | Count of Participants | Participants | 95 days |
|
|
|
| Secondary | Objective Response Rate (Complete Response (CR) + Partial Response (PR)) | 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. | This is a phase II objective, thus phase I groups are not shown here. | Posted | Number | participants | 1-2 months |
|
|
|
| Secondary | Time to Progression (TTP) | 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. | 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. | Posted | Number | Days | At date of progression, an average of 56 days |
|
|
|
| Secondary | Count of Participants With NR0B1 Expression in Tumor Biopsies | Biopsies were to be obtained in adult patients who have disease that could be safely biopsied. | This outcome measure was not done because none of the adult patients on this study had disease that was deemed accessible. | Posted | Pre-treatment and day 4 (+/- 1 day) |
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|
| Secondary | Number of Participants With a Change in Tumor Burden Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) | 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. | 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. | Posted | Count of Participants | Participants | ≥4 weeks from baseline |
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| Secondary | Number of Participants With a Change in Tumor Burden Measured by the World Health Organization (WHO) Criteria | 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. | 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. | Posted | Count of Participants | Participants | ≥4 weeks from baseline |
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| Secondary | Maximum Plasma Concentration (Cmax) of Mithramycin Using Non-Compartmental Methods | 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. | 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. | Posted | Mean | Standard Deviation | ng/mL | 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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| Secondary | Half-Life (HL) of Mithramycin | 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. | 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. | Posted | Mean | Standard Deviation | hours | 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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| Secondary | Area Under the Curve Extrapolated to Infinity (AUCinf) | 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. | 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. | Posted | Mean | Standard Deviation | h*ng/mL | 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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| Secondary | Area Under the Curve for the Dosing Interval (AUCtau) | AUCtau is AUC for the dosing interval. Analysis was performed using the Phoenix 6.3 with WinNonlin noncompartmental method. | 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. | Posted | Mean | Standard Deviation | h*ng/mL | 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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| Secondary | Clearance at Steady State (CLss) | 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. | 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. | Posted | Mean | Standard Deviation | L/h | 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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| Secondary | Volume of Distribution at Steady State (Vss) | 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. | 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. | Posted | Mean | Standard Deviation | L | 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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| Other Pre-specified | Number of Participants With Dose Limiting Toxicity (DLT) | 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. | Hepatotoxicity | Posted | Count of Participants | Participants | Cycle 1 of therapy (or 28 days) |
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|
|
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | 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. | 0 | 2 | 2 | 2 | 2 | 2 |
| EG002 | 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. | 0 | 0 | 0 | 0 | 0 | 0 |
| EG003 | 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. | 0 | 6 | 1 | 6 | 6 | 6 |
| Alanine aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Hypotension | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
|
| Agitation | Psychiatric disorders | CTCAE (4.0) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Alkaline phosphatase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Bloating | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Chest wall pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Congenital, familial and genetic disorders - Other, difficulty concentrating | Congenital, familial and genetic disorders | CTCAE (4.0) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Facial pain | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Fever | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Flu like symptoms | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Flushing | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
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| Gastrointestinal disorders - Other, acid reflux | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| General disorders and administration site conditions - Other, fluid retention | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Generalized muscle weakness | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Headache | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Hiccups | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Hyperglycemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hyperkalemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypermagnesemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypoalbuminemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypocalcemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypoglycemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypokalemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hyponatremia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypophosphatemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Insomnia | Psychiatric disorders | CTCAE (4.0) | Systematic Assessment |
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| Joint range of motion decreased lumbar spine | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Localized edema | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Lymphocyte count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Metabolism and nutrition disorders - Other, LDH elevated | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Musculoskeletal and connective tissue disorder - Other, hand numbness | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Neck pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Neutrophil count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Non-cardiac chest pain | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Pain | General disorders | CTCAE (4.0) | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Paresthesia | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Photosensitivity | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Platelet count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Proteinuria | Renal and urinary disorders | CTCAE (4.0) | Systematic Assessment |
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| Scrotal pain | Reproductive system and breast disorders | CTCAE (4.0) | Systematic Assessment |
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| Skin and subcutaneous tissue disorders - Other, peri-scapular pain | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Sore throat | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Testicular pain | Reproductive system and breast disorders | CTCAE (4.0) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| White blood cell decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
|
| General disorders and administration site conditions - Other | General disorders | CTCAE (4.0) | Systematic Assessment | Decreased breath sounds LLL |
|
| General disorders and administration site conditions - Other, oral thrush | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| General disorders and administration site conditions - Other, body aches | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| General disorders and administration site conditions - Other, malaise | General disorders | CTCAE (4.0) | Systematic Assessment |
|
| Musculoskeletal and connective tissue disorder - Other, jaw numbness | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
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| Metabolism and nutrition disorders - Other, indigestion | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
|
| Skin and subcutaneous tissue disorders - Other, rash | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
Not provided
Not provided
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009371 | Neoplasms by Site |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| Title | Measurements |
|---|---|
|
| Patient #5 |
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| Patient #7 |
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| Patient #8 |
|
| Title | Measurements |
|---|---|
|
| Stable Disease |
|
| Title | Measurements |
|---|---|
|
| Stable Disease |
|