The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/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
Scientific title
An Open-Label Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia
Secondary ID [1] 0 0
2010-020768-40
Secondary ID [2] 0 0
C18083/2046
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
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


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Recommended Phase II Dose (RP2D) of Bendamustine - 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.
Timepoint [1] 0 0
Induction Cycle (21- to 35-day cycle)
Primary outcome [2] 0 0
Overall Response Rate (ORR) - 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.
Timepoint [2] 0 0
Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Secondary outcome [1] 0 0
Best Overall Tumor Response Rate - 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.
Timepoint [1] 0 0
At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Secondary outcome [2] 0 0
Best Overall Tumor Response Rate, by Phase - 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.
Timepoint [2] 0 0
At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Secondary outcome [3] 0 0
Duration of Response (DOR) - 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.
Timepoint [3] 0 0
At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Secondary outcome [4] 0 0
Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4)
Timepoint [4] 0 0
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.
Secondary outcome [5] 0 0
Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4)
Timepoint [5] 0 0
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.
Secondary outcome [6] 0 0
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)
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
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)
Timepoint [7] 0 0
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.

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.

Key
Minimum age
1 Year
Maximum age
20 Years
Gender
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Teva Investigational Site 300 - Herston
Recruitment hospital [2] 0 0
Teva Investigational Site 301 - Parkville
Recruitment hospital [3] 0 0
Teva Investigational Site 302 - Randwick
Recruitment postcode(s) [1] 0 0
- Herston
Recruitment postcode(s) [2] 0 0
- Parkville
Recruitment postcode(s) [3] 0 0
- Randwick
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Michigan
Country [6] 0 0
United States of America
State/province [6] 0 0
Mississippi
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Oregon
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Tennessee
Country [12] 0 0
United States of America
State/province [12] 0 0
Texas
Country [13] 0 0
United States of America
State/province [13] 0 0
Washington
Country [14] 0 0
United States of America
State/province [14] 0 0
Wisconsin
Country [15] 0 0
Belarus
State/province [15] 0 0
Minsk
Country [16] 0 0
Brazil
State/province [16] 0 0
Barretos-SP
Country [17] 0 0
Brazil
State/province [17] 0 0
Caxias do Sul
Country [18] 0 0
Brazil
State/province [18] 0 0
Curitiba-PR
Country [19] 0 0
Brazil
State/province [19] 0 0
Porto Alegre
Country [20] 0 0
Brazil
State/province [20] 0 0
Sao Paulo-SP
Country [21] 0 0
Brazil
State/province [21] 0 0
Sao Paulo
Country [22] 0 0
Canada
State/province [22] 0 0
Toronto
Country [23] 0 0
Israel
State/province [23] 0 0
Jerusalem
Country [24] 0 0
Israel
State/province [24] 0 0
Petach Tikva
Country [25] 0 0
Israel
State/province [25] 0 0
Ramat Gan
Country [26] 0 0
Korea, Republic of
State/province [26] 0 0
Seoul
Country [27] 0 0
Mexico
State/province [27] 0 0
Guadalajara
Country [28] 0 0
Mexico
State/province [28] 0 0
Mexico City
Country [29] 0 0
Mexico
State/province [29] 0 0
Monterrey
Country [30] 0 0
New Zealand
State/province [30] 0 0
Auckland
Country [31] 0 0
Poland
State/province [31] 0 0
Bialystok
Country [32] 0 0
Poland
State/province [32] 0 0
Lublin
Country [33] 0 0
Poland
State/province [33] 0 0
Warszawa
Country [34] 0 0
Russian Federation
State/province [34] 0 0
Moscow
Country [35] 0 0
Russian Federation
State/province [35] 0 0
St. Petersburg
Country [36] 0 0
Singapore
State/province [36] 0 0
Singapore

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Teva Branded Pharmaceutical Products, R&D Inc.
Address
Country

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/show/NCT01088984
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.
Public notes

Contacts
Principal investigator
Name 0 0
Sponsor's Medical Expert
Address 0 0
Cephalon
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications