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

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

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.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: Bendamustine

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Bendamustine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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.
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.
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.
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.

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: March 16, 2010
• First Submitted That Met QC Criteria: March 16, 2010
• First Posted (Estimate): March 18, 2010

Study Record Updates

• Last Update Posted (Estimate): May 23, 2016
• Last Update Submitted That Met QC Criteria: April 21, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Bendamustine Hydrochloride
• Other Study ID Numbers: C18083/2046; 2010-020768-40 (EudraCT Number)