Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia

Leukemia Clinical Trial

Official title:

An Open-Label Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01088984
• Other study ID #: C18083/2046
• Secondary ID: 2010-020768-40
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 16, 2010
• Last updated: September 24, 2014
• Start date: August 2010
• Est. completion date: August 2011

Study information

• Verified date: March 2013
• Source: Teva Pharmaceutical Industries
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationBelarus: Ministry of HealthBrazil: Ministry of HealthCanada: Health CanadaIsrael: Israeli Health Ministry Pharmaceutical AdministrationMexico: Ministry of HealthSouth Korea: Korea Food and Drug Administration (KFDA)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: August 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 20 Years

Eligibility

Key Inclusion Criteria:

• 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 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

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia

Intervention

Drug:
• Bendamustine

Locations

Country	Name	City	State
Australia	Teva Investigational Site 300	Herston
Australia	Teva Investigational Site 301	Parkville
Australia	Teva Investigational Site 302	Randwick
Belarus	Teva Investigational Site 520	Minsk
Brazil	Teva Investigational Site 615	Barretos-SP
Brazil	Teva Investigational Site 616	Caxias do Sul
Brazil	Teva Investigational Site 613	Curitiba-PR
Brazil	Teva Investigational Site 612	Porto Alegre
Brazil	Teva Investigational Site 614	Porto Alegre
Brazil	Teva Investigational Site 610	Sao Paulo
Brazil	Teva Investigational Site 611	Sao Paulo
Brazil	Teva Investigational Site 617	Sao Paulo-SP
Canada	Teva Investigational Site 100	Toronto
Israel	Teva Investigational Site 501	Jerusalem
Israel	Teva Investigational Site 503	Petach Tikva
Israel	Teva Investigational Site 502	Ramat Gan
Korea, Republic of	Teva Investigational Site 330	Seoul
Korea, Republic of	Teva Investigational Site 331	Seoul
Korea, Republic of	Teva Investigational Site 332	Seoul
Korea, Republic of	Teva Investigational Site 333	Seoul
Mexico	Teva Investigational Site 603	Guadalajara
Mexico	Teva Investigational Site 600	Mexico City
Mexico	Teva Investigational Site 601	Mexico City
Mexico	Teva Investigational Site 602	Monterrey
New Zealand	Teva Investigational Site 303	Auckland
Poland	Teva Investigational Site 531	Bialystok
Poland	Teva Investigational Site 530	Lublin
Poland	Teva Investigational Site 532	Warszawa
Russian Federation	Teva Investigational Site 511	Moscow
Russian Federation	Teva Investigational Site 510	St. Petersburg
Singapore	Teva Investigational Site 320	Singapore
United States	Teva Investigational Site 8	Baltimore	Maryland
United States	Teva Investigational Site 16	Boston	Massachusetts
United States	Teva Investigational Site 3	Dallas	Texas
United States	Teva Investigational Site 9	Detroit	Michigan
United States	Teva Investigational Site 4	Fort Worth	Texas
United States	Teva Investigational Site 11	Hershey	Pennsylvania
United States	Teva Investigational Site 13	Houston	Texas
United States	Teva Investigational Site 1	Jackson	Mississippi
United States	Teva Investigational Site 5	Kansas City	Missouri
United States	Teva Investigational Site 19	Memphis	Tennessee
United States	Teva Investigational Site 6	Milwaukee	Wisconsin
United States	Teva Investigational Site 15	New York	New York
United States	Teva Investigational Site 17	Orange	California
United States	Teva Investigational Site 7	Philadelphia	Pennsylvania
United States	Teva Investigational Site 18	Portland	Oregon
United States	Teva Investigational Site 12	San Diego	California
United States	Teva Investigational Site 2	Seattle	Washington
United States	Teva Investigational Site 14	St. Louis	Missouri
United States	Teva Investigational Site 10	St. Petersburg	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products, R&D Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belarus,  Brazil,  Canada,  Israel,  Korea, Republic of,  Mexico,  New Zealand,  Poland,  Russian Federation,  Singapore, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Induction Cycle (21- to 35-day cycle)	Yes
Primary	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.	Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles	No
Secondary	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.	At each treatment cycle (21 to 35 days), for a maximum of 12 cycles	No
Secondary	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.	At each treatment cycle (21 to 35 days), for a maximum of 12 cycles	No
Secondary	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.	At each treatment cycle (21 to 35 days), for a maximum of 12 cycles	No
Secondary	Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4)		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.	No
Secondary	Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4)		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.	No
Secondary	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)		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.	No
Secondary	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)		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.	No