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

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01088984
• Collaborator: (none)
• Enrollment: 43
• Locations: 50
• Arm: 1
• Duration (Months): 12
• Patients Per Site: 0.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Bendamustine	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study of Bendamustine Hydrochloride for the Treatment of Pediatric Patients With Relapsed or Refractory Acute Leukemia
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Recommended Phase II Dose (RP2D) of Bendamustine [Induction Cycle (21- to 35-day cycle)]

   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.

2. Overall Response Rate (ORR) [Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles]

   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.

Secondary Outcome Measures

1. Best Overall Tumor Response Rate [At each treatment cycle (21 to 35 days), for a maximum of 12 cycles]

   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.

2. Best Overall Tumor Response Rate, by Phase [At each treatment cycle (21 to 35 days), for a maximum of 12 cycles]

   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.

3. Duration of Response (DOR) [At each treatment cycle (21 to 35 days), for a maximum of 12 cycles]

   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.

4. 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.]

5. 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.]

6. 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.]

7. 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.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Sponsor's Medical Expert, Cephalon

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01088984
• Other Study ID Numbers: C18083/2046; 2010-020768-40
• First Posted: Mar 18, 2010
• Last Update Posted: May 23, 2016
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Leukemia; Bendamustine Hydrochloride

Study Results

Participant Flow

Recruitment Details	Of the 46 patients screened, 43 patients at 24 centers from the United States, Australia, South Korea, Israel, Mexico, and Brazil met entry criteria and were considered eligible for enrollment. Of the 3 patients who were not enrolled, 2 patients died prior to study enrollment, and 1 patient was ineligible because inclusion criteria were not met.

Arm/Group Title	Bendamustine 90 mg/m^2	Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 90 mg/m^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an 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.
Period Title: Phase 1
STARTED	5	6
COMPLETED	0	0
NOT COMPLETED	5	6
Period Title: Phase 1
STARTED	0	32
COMPLETED	0	0
NOT COMPLETED	0	32

Baseline Characteristics

Arm/Group Title	Phase 1: Bendamustine 90 or 120 mg/m^2	Phase 2: Bendamustine 120 mg/m^2	Total
Arm/Group Description	Bendamustine 90 or 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Total of all reporting groups
Overall Participants	11	32	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.7 (4.31)	9.3 (4.93)	9.2 (4.74)
Age, Customized (participants) [Number]
1 to 6 years	4 36.4%	10 31.3%	14 32.6%
7 to 11 years	3 27.3%	10 31.3%	13 30.2%
12 to 20 years	4 36.4%	12 37.5%	16 37.2%
Sex: Female, Male (Count of Participants)
Female	1 9.1%	12 37.5%	13 30.2%
Male	10 90.9%	20 62.5%	30 69.8%

Outcome Measures

1. Primary Outcome

Title	Recommended Phase II Dose (RP2D) of Bendamustine
Description	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.
Time Frame	Induction Cycle (21- to 35-day cycle)

Outcome Measure Data

Analysis Population Description

All participants enrolled in Phase 1 of the study.

Arm/Group Title	Phase 1: Bendamustine 90 or 120 mg/m^2
Arm/Group Description	Bendamustine 90 or 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Measure Participants	11
Number [mg/m^2]	120

2. Primary Outcome

Title	Overall Response Rate (ORR)
Description	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.
Time Frame	Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Outcome Measure Data

Analysis Population Description

The primary analysis set for efficacy included all participants treated at the RP2D in Phase 2.

Arm/Group Title	Phase 2: Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1: Bendamustine 90 or 120 mg/m^2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	1-sided p-value is calculated against the null hypothesis of a response rate of 5%.
	Method	binomial parameter exact method
	Comments

3. Secondary Outcome

Title	Best Overall Tumor Response Rate
Description	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.
Time Frame	At each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Outcome Measure Data

Analysis Population Description

The primary analysis set for efficacy included all participants treated at the RP2D in Phase 2.

Arm/Group Title	Phase 2: Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	6 54.5%

4. Secondary Outcome

Title	Best Overall Tumor Response Rate, by Phase
Description	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.
Time Frame	At each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants treated at any dose of bendamustine.

Arm/Group Title	Phase 1: Bendamustine 90 or 120 mg/m^2	Phase 2: Bendamustine 120 mg/m^2	Total
Arm/Group Description	Bendamustine 90 or 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of a 21-day Induction Cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 90 or 120 mg/m^2 administered as an 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.
Measure Participants	11	32	43
Number (95% Confidence Interval) [percentage of participants]	18 163.6%	6 18.8%	9 20.9%

5. Secondary Outcome

Title	Duration of Response (DOR)
Description	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.
Time Frame	At each treatment cycle (21 to 35 days), for a maximum of 12 cycles

Outcome Measure Data

Analysis Population Description

No duration of remission (defined as CR or CRp) analysis was performed for participants in the primary analysis since none achieved remission.

Arm/Group Title	Phase 2: Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 120 mg/m^2 administered as an IV infusion over 60 minutes on Days 1 and 2 of each 21-day cycle (Cycles 2 through 12), with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.
Measure Participants	0

6. Secondary Outcome

Title	Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set included all participants who were in the safety analysis set (ie, those treated at any dose of bendamustine) who had valid pharmacokinetic data; n=number of participants with valid data for this assessment.

Arm/Group Title	Bendamustine 90 mg/m^2	Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 90 mg/m^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an 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.
Measure Participants	5	37
Bendamustine; n=5, 37	5093.24 (60.39)	6401.80 (52.90)
Metabolite M3; n=5, 36	311.70 (92.98)	403.52 (69.91)
Metabolite M4; n=5, 37	37.53 (82.97)	48.27 (53.94)

7. Secondary Outcome

Title	Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set included all participants who were in the safety analysis set (ie, those treated at any dose of bendamustine) who had valid pharmacokinetic data; n=number of participants with valid data for this assessment.

Arm/Group Title	Bendamustine 90 mg/m^2	Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 90 mg/m^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an 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.
Measure Participants	5	37
Bendamustine; n=5, 37	1.14 (10.00)	1.07 (9.49)
Metabolite M3; n=5, 36	1.14 (10.00)	1.07 (9.53)
Metabolite M4; n=5, 37	1.14 (10.00)	1.07 (9.49)

8. Secondary Outcome

Title	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)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set included all participants who were in the safety analysis set (ie, those treated at any dose of bendamustine) who had valid pharmacokinetic data; n=number of participants with valid data for this assessment.

Arm/Group Title	Bendamustine 90 mg/m^2	Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 90 mg/m^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an 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.
Measure Participants	5	37
Bendamustine; n=5, 37	11174.86 (51.73)	11046.32 (58.58)
Metabolite M3; n=5, 36	697.09 (88.37)	701.19 (67.38)
Metabolite M4; n=5, 37	43.80 (109.72)	72.78 (57.11)

9. Secondary Outcome

Title	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)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic analysis set included all participants who were in the safety analysis set (ie, those treated at any dose of bendamustine) who had valid pharmacokinetic data; n=number of participants with valid data for this assessment.

Arm/Group Title	Bendamustine 90 mg/m^2	Bendamustine 120 mg/m^2
Arm/Group Description	Bendamustine 90 mg/m^2 administered as an intravenous (IV) infusion over 60 minutes on Days 1 and 2 of a 21-day Induction cycle, with delays up to 2 weeks for neutrophil and platelet count recovery, for up to a 35-day cycle.	Bendamustine 120 mg/m^2 administered as an 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.
Measure Participants	5	37
Bendamustine; n=1, 13	14998.00 (NA)	12929.22 (50.46)
Metabolite M3; n=0, 2	NA (NA)	1336.89 (1.80)
Metabolite M4; n=0, 0	NA (NA)	NA (NA)

Adverse Events

Time Frame	Screening (Day -14 to Day-1) through end of treatment (up to 12 35-day cycles), plus 30 days.
Adverse Event Reporting Description	Participants were given both dosages for varying lengths and the adverse events were not reported according to which timepoint neither at which dosage events occurred.
Arm/Group Title	Bendamustine
Arm/Group Description	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.
All Cause Mortality
	Bendamustine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bendamustine
	Affected / at Risk (%)	# Events
Total	33/43 (76.7%)
Blood and lymphatic system disorders
Febrile neutropenia	12/43 (27.9%)	13
Leukocytosis	1/43 (2.3%)	1
Neutropenia	2/43 (4.7%)	2
Pancytopenia	2/43 (4.7%)	2
Thrombocytopenia	2/43 (4.7%)	2
Cardiac disorders
Cardiopulmonary failure	1/43 (2.3%)	1
Gastrointestinal disorders
Proctitis	1/43 (2.3%)	1
Vomiting	1/43 (2.3%)	1
General disorders
Chest pain	1/43 (2.3%)	1
Multi-organ failure	1/43 (2.3%)	2
Pyrexia	4/43 (9.3%)	7
Hepatobiliary disorders
Portal vein thrombosis	1/43 (2.3%)	1
Infections and infestations
Aspergillosis	2/43 (4.7%)	2
Bacteraemia	1/43 (2.3%)	1
Beta haemolytic streptococcal infection	1/43 (2.3%)	1
Capnocytophagia infection	1/43 (2.3%)	1
Cellulitis	1/43 (2.3%)	2
Febrile infection	1/43 (2.3%)	1
Fungal sepsis	1/43 (2.3%)	1
Herpes zoster	2/43 (4.7%)	3
Pharyngitis	1/43 (2.3%)	1
Pneumonia	1/43 (2.3%)	1
Septic shock	1/43 (2.3%)	1
Staphylococcal infection	1/43 (2.3%)	2
Investigations
Blood creatinine increased	1/43 (2.3%)	1
Electrocardiogram QT prolonged	1/43 (2.3%)	1
Metabolism and nutrition disorders
Hypercalcaemia	1/43 (2.3%)	1
Hyperglycaemia	1/43 (2.3%)	1
Hyperkalaemia	1/43 (2.3%)	1
Tumour lysis syndrome	1/43 (2.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/43 (2.3%)	3
Pain in extremity	1/43 (2.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	4/43 (9.3%)	4
Acute myeloid leukaemia	3/43 (7%)	3
B precursor type acute leukaemia	1/43 (2.3%)	1
Leukaemia	2/43 (4.7%)	4
Myeloid leukaemia	1/43 (2.3%)	1
T-cell type acute leukaemia	1/43 (2.3%)	1
Nervous system disorders
Depressed level of consciousness	2/43 (4.7%)	2
Headache	1/43 (2.3%)	1
Psychiatric disorders
Confusional state	1/43 (2.3%)	1
Renal and urinary disorders
Renal failure	1/43 (2.3%)	1
Renal impairment	2/43 (4.7%)	2
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/43 (4.7%)	2
Respiratory distress	1/43 (2.3%)	1
Respiratory failure	1/43 (2.3%)	1
Vascular disorders
Hypotension	1/43 (2.3%)	1
Peripheral artery aneurysm	1/43 (2.3%)	1
Other (Not Including Serious) Adverse Events
	Bendamustine
	Affected / at Risk (%)	# Events
Total	43/43 (100%)
Blood and lymphatic system disorders
Anaemia	28/43 (65.1%)	92
Febrile neutropenia	15/43 (34.9%)	19
Lymphopenia	3/43 (7%)	10
Neutropenia	5/43 (11.6%)	8
Pancytopenia	4/43 (9.3%)	5
Thrombocytopenia	14/43 (32.6%)	74
Gastrointestinal disorders
Abdominal pain	9/43 (20.9%)	13
Constipation	7/43 (16.3%)	8
Diarrhoea	14/43 (32.6%)	28
Gingival bleeding	3/43 (7%)	3
Nausea	20/43 (46.5%)	26
Vomiting	15/43 (34.9%)	31
General disorders
Catheter site pain	3/43 (7%)	3
Chest pain	4/43 (9.3%)	4
Chills	3/43 (7%)	3
Fatigue	7/43 (16.3%)	10
Mucosal inflammation	4/43 (9.3%)	4
Oedema peripheral	4/43 (9.3%)	10
Pain	3/43 (7%)	3
Pyrexia	21/43 (48.8%)	35
Infections and infestations
Bacteraemia	3/43 (7%)	3
Investigations
Alanine aminotransferase increased	5/43 (11.6%)	9
Aspartate aminotransferase increased	6/43 (14%)	11
Blood creatinine increased	5/43 (11.6%)	20
Blood potassium decreased	3/43 (7%)	13
Platelet count decreased	8/43 (18.6%)	41
Weight decreased	3/43 (7%)	6
Metabolism and nutrition disorders
Decreased appetite	9/43 (20.9%)	12
Fluid overload	3/43 (7%)	3
Hypercalcaemia	4/43 (9.3%)	14
Hyperglycaemia	5/43 (11.6%)	15
Hyperkalaemia	3/43 (7%)	5
Hypocalcaemia	6/43 (14%)	18
Hypokalaemia	9/43 (20.9%)	40
Hypomagnesaemia	8/43 (18.6%)	10
Hyponatraemia	6/43 (14%)	11
Hypophosphataemia	5/43 (11.6%)	15
Tumour lysis syndrome	4/43 (9.3%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	3/43 (7%)	3
Back pain	3/43 (7%)	5
Bone pain	3/43 (7%)	4
Pain in extremity	5/43 (11.6%)	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	4/43 (9.3%)	4
Acute myeloid leukaemia	3/43 (7%)	3
Nervous system disorders
Dizziness	3/43 (7%)	3
Headache	9/43 (20.9%)	12
Psychiatric disorders
Anxiety	3/43 (7%)	4
Respiratory, thoracic and mediastinal disorders
Cough	12/43 (27.9%)	13
Dyspnoea	5/43 (11.6%)	6
Epistaxis	6/43 (14%)	6
Productive cough	3/43 (7%)	4
Pulmonary oedema	3/43 (7%)	4
Rhinorrhoea	3/43 (7%)	3
Skin and subcutaneous tissue disorders
Dry skin	3/43 (7%)	4
Pruritus	4/43 (9.3%)	5
Rash	5/43 (11.6%)	7
Vascular disorders
Hypertension	12/43 (27.9%)	19
Hypotension	8/43 (18.6%)	18

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigator/Institution must submit proposed publication to Sponsor for review within a prespecified number of days before submission for publication. If Sponsor's review shows that potentially patentable subject matter would be disclosed, publication/public disclosure shall be delayed to enable Sponsor, or Sponsor's designees, to file necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.