Leukemia
Conditions
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.
Interventions
DRUGBendamustine
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 20 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. | — |
| 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. |
| 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. | — |
| 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. | — |
| 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. |
Countries
Australia, Belarus, Brazil, Canada, Israel, Mexico, New Zealand, Poland, Russia, Singapore, South Korea, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 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. | 11 |
| Phase 2: Bendamustine 120 mg/m^2 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. | 32 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 | Death | 2 | 1 |
| Phase 1 | Disease Progression | 2 | 4 |
| Phase 1 | Other | 1 | 1 |
| Phase 2 | Death | 0 | 5 |
| Phase 2 | DIsease Progression | 0 | 25 |
| Phase 2 | Other | 0 | 1 |
| Phase 2 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1: Bendamustine 90 or 120 mg/m^2 | Phase 2: Bendamustine 120 mg/m^2 | Total |
|---|---|---|---|
| Age, Continuous | 8.7 years STANDARD_DEVIATION 4.31 | 9.3 years STANDARD_DEVIATION 4.93 | 9.2 years STANDARD_DEVIATION 4.74 |
| Age, Customized 12 to 20 years | 4 participants | 12 participants | 16 participants |
| Age, Customized 1 to 6 years | 4 participants | 10 participants | 14 participants |
| Age, Customized 7 to 11 years | 3 participants | 10 participants | 13 participants |
| Sex: Female, Male Female | 1 Participants | 12 Participants | 13 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 43 / 43 |
| serious Total, serious adverse events | 33 / 43 |
Outcome results
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.
Time frame: Assessed at each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Population: The primary analysis set for efficacy included all participants treated at the RP2D in Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Overall Response Rate (ORR) | 0 percentage of participants |
p-value: 1binomial parameter exact method
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.
Time frame: Induction Cycle (21- to 35-day cycle)
Population: All participants enrolled in Phase 1 of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Recommended Phase II Dose (RP2D) of Bendamustine | 120 mg/m^2 |
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)
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^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) | Bendamustine; n=1, 13 | 14998.00 ng*hr/mL | — |
| Phase 1: Bendamustine 90 or 120 mg/m^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) | Metabolite M3; n=0, 2 | NA ng*hr/mL | — |
| Phase 1: Bendamustine 90 or 120 mg/m^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) | Metabolite M4; n=0, 0 | NA ng*hr/mL | — |
| Phase 2: Bendamustine 120 mg/m^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) | Bendamustine; n=1, 13 | 12929.22 ng*hr/mL | Geometric Coefficient of Variation 50.46 |
| Phase 2: Bendamustine 120 mg/m^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) | Metabolite M3; n=0, 2 | 1336.89 ng*hr/mL | Geometric Coefficient of Variation 1.8 |
| Phase 2: Bendamustine 120 mg/m^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) | Metabolite M4; n=0, 0 | NA ng*hr/mL | — |
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)
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^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) | Bendamustine; n=5, 37 | 11174.86 ng*hr/mL | Geometric Coefficient of Variation 51.73 |
| Phase 1: Bendamustine 90 or 120 mg/m^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) | Metabolite M3; n=5, 36 | 697.09 ng*hr/mL | Geometric Coefficient of Variation 88.37 |
| Phase 1: Bendamustine 90 or 120 mg/m^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) | Metabolite M4; n=5, 37 | 43.80 ng*hr/mL | Geometric Coefficient of Variation 109.72 |
| Phase 2: Bendamustine 120 mg/m^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) | Bendamustine; n=5, 37 | 11046.32 ng*hr/mL | Geometric Coefficient of Variation 58.58 |
| Phase 2: Bendamustine 120 mg/m^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) | Metabolite M3; n=5, 36 | 701.19 ng*hr/mL | Geometric Coefficient of Variation 67.38 |
| Phase 2: Bendamustine 120 mg/m^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) | Metabolite M4; n=5, 37 | 72.78 ng*hr/mL | Geometric Coefficient of Variation 57.11 |
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.
Time frame: At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Population: The primary analysis set for efficacy included all participants treated at the RP2D in Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Best Overall Tumor Response Rate | 6 percentage of participants |
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.
Time frame: At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Population: The safety analysis set included all participants treated at any dose of bendamustine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Best Overall Tumor Response Rate, by Phase | 18 percentage of participants |
| Phase 2: Bendamustine 120 mg/m^2 | Best Overall Tumor Response Rate, by Phase | 6 percentage of participants |
| Total | Best Overall Tumor Response Rate, by Phase | 9 percentage of participants |
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.
Time frame: At each treatment cycle (21 to 35 days), for a maximum of 12 cycles
Population: No duration of remission (defined as CR or CRp) analysis was performed for participants in the primary analysis since none achieved remission.
Secondary
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) | Bendamustine; n=5, 37 | 5093.24 ng/mL | Geometric Coefficient of Variation 60.39 |
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M3; n=5, 36 | 311.70 ng/mL | Geometric Coefficient of Variation 92.98 |
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M4; n=5, 37 | 37.53 ng/mL | Geometric Coefficient of Variation 82.97 |
| Phase 2: Bendamustine 120 mg/m^2 | Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M4; n=5, 37 | 48.27 ng/mL | Geometric Coefficient of Variation 53.94 |
| Phase 2: Bendamustine 120 mg/m^2 | Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) | Bendamustine; n=5, 37 | 6401.80 ng/mL | Geometric Coefficient of Variation 52.9 |
| Phase 2: Bendamustine 120 mg/m^2 | Maximum Observed Plasma Drug Concentration (Cmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M3; n=5, 36 | 403.52 ng/mL | Geometric Coefficient of Variation 69.91 |
Secondary
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) | Bendamustine; n=5, 37 | 1.14 hours | Geometric Coefficient of Variation 10 |
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M3; n=5, 36 | 1.14 hours | Geometric Coefficient of Variation 10 |
| Phase 1: Bendamustine 90 or 120 mg/m^2 | Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M4; n=5, 37 | 1.14 hours | Geometric Coefficient of Variation 10 |
| Phase 2: Bendamustine 120 mg/m^2 | Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) | Bendamustine; n=5, 37 | 1.07 hours | Geometric Coefficient of Variation 9.49 |
| Phase 2: Bendamustine 120 mg/m^2 | Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M3; n=5, 36 | 1.07 hours | Geometric Coefficient of Variation 9.53 |
| Phase 2: Bendamustine 120 mg/m^2 | Time to Maximum Plasma Drug Concentration (Tmax) for Bendamustine and Its Metabolites (M3 and M4) | Metabolite M4; n=5, 37 | 1.07 hours | Geometric Coefficient of Variation 9.49 |