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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01088984
Registration number
NCT01088984
Ethics application status
Date submitted
16/03/2010
Date registered
18/03/2010
Date last updated
23/05/2016
Titles & IDs
Public title
Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia
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Scientific title
An Open-Label Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia
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Secondary ID [1]
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2010-020768-40
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Secondary ID [2]
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C18083/2046
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Leukemia
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Bendamustine
Experimental: Bendamustine - Bendamustine 90 or 120 mg/m^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (maximum of 12 total cycles), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Treatment: Drugs: Bendamustine
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Recommended Phase II Dose (RP2D) of Bendamustine
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Assessment method [1]
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RP2D was determined by a traditional 3+3 dose escalation design, with the following restrictions: only doses of 60, 90, 120, and 150 mg/m^2 were explored, and escalation to 150 mg/m^2 would only occur if the 120 mg/m^2 dose was deemed safe and pharmacokinetic data indicate subtherapeutic exposure as compared with adults. The first cohort was administered bendamustine at the 90 mg/m^2 dose; de-escalation to the 60 mg/m^2 dose would only occur if the starting dose led to dose-limiting toxicity (DLT) in 2 or more participants. A DLT was defined as any study drug-related nonhematologic adverse event (AE) that was grade 4 for toxicity by National Cancer Institute's Common Toxicity Criteria for AEs, version 4. In addition, grade 3 or above allergic reaction or skin rash were considered DLTs. Hematologic AEs were not considered DLTs. The dose level at which at least 2 of 3 or 2 of 6 participants had a DLT was considered as exceeding the RP2D. The RP2D was the dose 1 step below that level.
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Timepoint [1]
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Induction Cycle (21- to 35-day cycle)
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Primary outcome [2]
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Overall Response Rate (ORR)
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Assessment method [2]
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ORR was calculated as follows: number of participants in the primary analysis set achieving a best overall response of complete remission without platelet recovery (CRp) or complete remission (CR), divided by the number of participants in the primary analysis set. The most positive response for each patient during the study was counted. The 95% CI was calculated using binomial parameter exact method. Response was determined by the investigator, and evaluated per Jeha et al, 2006: A CR required no evidence of circulating blasts or extramedullary disease, an M1 marrow (= 5% bone marrow blasts), and recovery of peripheral counts (platelets = 100 × 10^9/L and absolute neutrophil count = 1.0 × 10^9/L). A CR without platelet recovery (CRp) required all of the criteria for a CR with the exception of platelet recovery.
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Timepoint [2]
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Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles
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Secondary outcome [1]
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Best Overall Tumor Response Rate
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Assessment method [1]
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Biological activity of bendamustine was defined as achieving a best response of partial response (PR), CRp, or CR. Rate was calculated as follows: number of participants in the primary analysis set achieving a best overall response of PR, CRp, or CR, divided by the number of participants in the primary analysis set. The most positive response for each patient during the study was counted. The 95% CI was calculated using binomial parameter exact method. Response was determined by the investigator, and evaluated per Jeha et al, 2006: A PR had to meet the following criteria: complete disappearance of circulating blasts and an M2 marrow (= 5% and = 25% bone marrow blasts) and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. See Outcome Measure 2 for full definitions for CRp and CR.
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Timepoint [1]
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At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
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Secondary outcome [2]
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Best Overall Tumor Response Rate, by Phase
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Assessment method [2]
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Biological activity of bendamustine was defined as achieving a best response of partial response (PR), CRp, or CR. Rate was calculated as follows: number of participants in the primary analysis set achieving a best overall response of PR, CRp, or CR, divided by the number of participants in the primary analysis set. The most positive response for each patient during the study was counted. The 95% CI was calculated using binomial parameter exact method. Response was determined by the investigator, and evaluated per Jeha et al, 2006: A PR had to meet the following criteria: complete disappearance of circulating blasts and an M2 marrow (= 5% and = 25% bone marrow blasts) and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. See Outcome Measure 2 for full definitions for CRp and CR.
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Timepoint [2]
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At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
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Secondary outcome [3]
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Duration of Response (DOR)
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Assessment method [3]
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DOR was determined for the participants with CR or CRp in the primary analysis set, defined as the time from first achieving remission to the time when progression was diagnosed, the participant died, or the participant started receiving new antineoplastic therapy. Data from participants who do not progress were censored at the last valid assessments. Median DOR and its 95% confidence interval was determined based on the Kaplan-Meier method. Data from participants who received a transplant were censored at the time of the transplant.
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Timepoint [3]
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At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
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Secondary outcome [4]
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Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4)
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Assessment method [4]
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Timepoint [4]
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Cycle 1, Day 1: before infusion, immediately following the infusion, and 3, 6, 10(±2), and 24 hours after the start of infusion. The 24-hour postinfusion sample was obtained before the start of the infusion on Day 2.
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Secondary outcome [5]
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Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4)
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Assessment method [5]
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Timepoint [5]
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Cycle 1, Day 1: before infusion, immediately following the infusion, and 3, 6, 10(±2), and 24 hours after the start of infusion. The 24-hour postinfusion sample was obtained before the start of the infusion on Day 2.
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Secondary outcome [6]
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Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until the Last Measurable Plasma Concentration (AUC0-t) for Bendamustine and Its Metabolites (M3 and M4)
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Assessment method [6]
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Timepoint [6]
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Cycle 1, Day 1: before infusion, immediately following the infusion, and 3, 6, 10(±2), and 24 hours after the start of infusion. The 24-hour postinfusion sample was obtained before the start of the infusion on Day 2.
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Secondary outcome [7]
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Area Under the Plasma Drug Concentration by Time Curve From Time 0 Until 24 Hours After Study Drug Administration (AUC0-24) for Bendamustine and Its Metabolites (M3 and M4)
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Assessment method [7]
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Timepoint [7]
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Cycle 1, Day 1: before infusion, immediately following the infusion, and 3, 6, 10(±2), and 24 hours after the start of infusion. The 24-hour postinfusion sample was obtained before the start of the infusion on Day 2.
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Eligibility
Key inclusion criteria
Key
- The patient has histologically proven acute lymphocytic leukemia (ALL) or acute
myeloid leukemia (AML) that has relapsed or is refractory to the last regimen, and the
patient is without alternative curative therapy.
- The patient's last myelosuppression therapy ended at least 2 weeks before the first
dose of study drug.
- Nonhematologic acute toxic effects of prior therapy have resolved to grade 2 or less
according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE).
- The patient has adequate liver function with bilirubin values less than or equal to
1.5 times the upper limit of normal (ULN) and aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) values less than or equal to 5 times the
age-appropriate ULN.
- The patient has adequate renal function with serum creatinine values less than 2 times
ULN.
- The patient has Karnofsky or Lansky performance status of 60 or greater. Patients
older than 16 years of age will be scored according to the Karnofsky scale and
patients 16 years of age or younger will be scored according to the Lansky scale.
- The patient may have had hematopoietic stem cell transplantation.
- Women of childbearing potential (not surgically sterile) must use a medically accepted
method of contraception and must agree to continue use of this method for the duration
of treatment and for 30 days after the end of treatment.
- Men not surgically sterile or who are capable of producing offspring must practice
abstinence or use a barrier method of birth control, and must agree to continue use of
this method for the duration of treatment and for 30 days after the end of treatment.
- The patient must be willing and able to comply with study restrictions and to remain
at the clinic for the required duration during the study period, and willing to return
to the clinic for the follow-up evaluation as specified in this protocol.
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Minimum age
1
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Maximum age
20
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- The patient has any active, uncontrolled systemic infection, severe concurrent
disease, or symptomatic untreated central nervous system (CNS) involvement.
- The patient has evidence of active graft versus host disease.
- The patient has a known human immunodeficiency virus (HIV) infection.
- The patient has active hepatitis B or hepatitis C infection.
- The patient is a pregnant or lactating woman. Any women becoming pregnant during the
study will be withdrawn from the study immediately.
- The patient has any serious uncontrolled medical or psychological disorder that would
impair the ability of the patient to receive study drug.
- The patient has any condition that places the patient at unacceptable risk or
confounds the ability of the investigators to interpret study data.
- The patient has received any other investigational agent within 30 days of study
entry.
- The patient has known hypersensitivity to bendamustine or mannitol.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/08/2010
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/08/2011
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Sample size
Target
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Accrual to date
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Final
43
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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Teva Investigational Site 300 - Herston
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Recruitment hospital [2]
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Teva Investigational Site 301 - Parkville
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Recruitment hospital [3]
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Teva Investigational Site 302 - Randwick
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Recruitment postcode(s) [1]
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- Herston
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Recruitment postcode(s) [2]
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- Parkville
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Recruitment postcode(s) [3]
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- Randwick
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Recruitment outside Australia
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United States of America
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State/province [1]
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California
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United States of America
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Florida
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United States of America
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Maryland
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United States of America
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Massachusetts
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United States of America
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Michigan
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United States of America
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Mississippi
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United States of America
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Missouri
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United States of America
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New York
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Oregon
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United States of America
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Pennsylvania
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United States of America
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Tennessee
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United States of America
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Texas
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Washington
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United States of America
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Wisconsin
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Country [15]
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Belarus
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State/province [15]
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Minsk
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Country [16]
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Brazil
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Barretos-SP
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Brazil
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Caxias do Sul
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Brazil
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Curitiba-PR
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Brazil
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Porto Alegre
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Brazil
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Sao Paulo-SP
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Brazil
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Sao Paulo
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Canada
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Toronto
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Israel
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Jerusalem
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Israel
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Petach Tikva
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Israel
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Ramat Gan
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Korea, Republic of
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Seoul
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Mexico
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Guadalajara
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Mexico
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Mexico City
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Mexico
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Monterrey
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New Zealand
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Auckland
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Poland
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Bialystok
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Poland
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Lublin
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Poland
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Warszawa
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Russian Federation
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Moscow
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Russian Federation
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St. Petersburg
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Country [36]
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Singapore
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State/province [36]
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Singapore
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Teva Branded Pharmaceutical Products R&D, Inc.
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
The primary objective of phase 1 of this study is to establish the recommended phase II dose
(RP2D). The primary objective of phase 2 of this study is to evaluate the safety and efficacy
of bendamustine at the recommended pediatric dose for the treatment of pediatric patients
with relapsed or refractory acute leukemia.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01088984
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Trial related presentations / publications
Fraser C, Brown P, Megason G, Ahn HS, Cho B, Kirov I, Frankel L, Aplenc R, Bensen-Kennedy D, Munteanu M, Weaver J, Harker-Murray P. Open-label bendamustine monotherapy for pediatric patients with relapsed or refractory acute leukemia: efficacy and tolerability. J Pediatr Hematol Oncol. 2014 May;36(4):e212-8. doi: 10.1097/MPH.0000000000000021.
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Public notes
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Contacts
Principal investigator
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Sponsor's Medical Expert
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Address
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Cephalon
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01088984
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