Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

• ClinicalTrials.gov Identifier: NCT01466179
• Recruitment Status: Completed
• First Posted: November 6, 2011
• Results First Posted: January 22, 2015
• Last Update Posted: August 18, 2017
• Sponsor: Amgen Research (Munich) GmbH
• Information provided by (Responsible Party): Amgen Research (Munich) GmbH

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Lymphoblastic Leukemia
• Intervention: Biological: Blinatumomab
• Enrollment: 225

Participant Flow

Recruitment Details	This study was open to adult patients with relapsed / refractory B-precursor acute lymphoblastic leukemia (ALL). The study protocol originally used a Simon 2-stage design and was subsequently expanded to include a third stage. Protocol amendment 4 added an additional cohort of participants for central nervous system evaluations.
Pre-assignment Details	Two hundred twenty-five participants enrolled in the study overall. Results below include data for 189 participants enrolled in the first 3 stages of the study (the primary analysis set). An additional 36 participants enrolled in the Additional Evaluation Cohort are not reported here as the study is ongoing and data collection has not completed.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Period Title: Overall Study
Started	189 [1]
Completed	10 [2]
Not Completed	179
Reason Not Completed
Ongoing in core study	2
Physician Decision	46
Progressive disease	43
Adverse Event	32
Disease relapse	23
Lack of Efficacy	14
Death	7
Withdrawal by Subject	7
Protocol Violation	2
Other	3
[1] Participants enrolled during the first 3 stages of the study; [2] Completed 5 cycles of treatment; Data as of the time of the data cut-off date (10 October 2013).

Baseline Characteristics

Arm/Group Title		Blinatumomab
Arm/Group Description		Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Baseline Participants		189
Baseline Analysis Population Description		Primary Analysis Set
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	189 participants
		39.0; (18 to 79)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
18 to < 35 years		90
35 to < 55 years		46
55 to < 65 years		28
≥ 65 years		25
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	189 participants
	Female	70 37.0%
	Male	119 63.0%
Race/Ethnicity, Customized [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
White		145
Asian		6
Black or African American		7
American Indian or Alaska native		1
Native Hawaiian or other Pacific Islander		1
Other		9
Not recorded		20
		[1] Measure Description: Race was not permitted to be collected in France
Disease stage entry criteria met [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
Primary refractory		16
Relapse ≤ 12 months of allogeneic HSCT		39
Entering first salvage; first remission ≤ 12 mo		23
Entering second or greater salvage therapies		108
No criteria met		3
		[1] Measure Description: HSCT = hematopoietic stem cell transplantation
Number of prior relapses; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
0		16
1		107
2		46
>2		20
Prior allogeneic HSCT and prior relapses [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
Prior allogeneic HSCT		64
No prior alloHSCT, no prior relapse		16
No prior alloHSCT, 1 prior relapse		84
No prior alloHSCT, 2 prior relapses		22
No prior alloHSCT, > 2 prior relapses		3
		[1] Measure Description: alloHSCT = allogeneic hematopoietic stem cell transplantation
Number of prior salvage therapies; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
No prior salvage therapy		38
1 prior salvage therapy		77
2 prior salvage therapies		42
> 2 prior salvage therapies		32
Time since initial diagnosis; Median (Full Range); Unit of measure: Months
	Number Analyzed	189 participants
		16.59; (1.9 to 249.0)
Time since last relapse [1]; Median (Full Range); Unit of measure: Months
	Number Analyzed	189 participants
		1.38; (0.1 to 56.8)
		[1] Measure Description: Reported for 173 participants with a prior relapse (the other16 participants were primary refractory with no prior relapses).
Baseline bone marrow blast category [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	189 participants
< 10%		1
10% - < 50%		43
≥ 50%		145
		[1] Measure Description: Bone marrow blasts were assessed by local and central laboratories; reported data are based on maximum central and local laboratory assessments.

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description	Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR): bone marrow blasts ≤ 5%; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μL, and absolute neutrophil count (ANC) > 1,000/μL Complete Remission With Partial Hematological Recovery (CRh*): bone marrow blasts ≤ 5%; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μL, and ANC > 500/μL.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

The Primary Analysis Set (PAS), defined as participants from the first 3 stages of the study who received any infusion of blinatumomab.

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	42.9; (35.7 to 50.2)

2. Secondary Outcome

Title	Time to Hematological Relapse (Duration of Response)
Description	Time to hematological relapse was measured for participants in remission during the core study (the time from the first infusion through 30 days after the last infusion), from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death. Hematological relapse is defined as: proportion of blasts in bone marrow > 5% after documented CR/CRh* or; blasts in peripheral blood after documented CR/CRh*. Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.
Time Frame	Up to the data cut-off date of 10 October 2013; median observation time was 8.0 months.

Outcome Measure Data

Analysis Population Description

Participants who reached complete remission or complete remission with partial hematological recovery during the core study.

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	82
Median (95% Confidence Interval); Unit of Measure: months
	6.7 [1]; (5.1 to NA)

[1]

Not estimable due to the number of events during the observation period.

3. Secondary Outcome

Title	Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission
Description	Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT.
Time Frame	Up to the data cut-off date of 10 October 2013. Maximum duration on study was 17.8 months.

Outcome Measure Data

Analysis Population Description

Participants who reached complete remission or complete remission with partial hematological recovery during the first 2 cycles of treatment.

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	81
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	39.5; (28.8 to 51.0)

4. Secondary Outcome

Title	Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment
Description	Complete Remission was defined by the following criteria: bone marrow blasts ≤ 5%; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μL, and absolute neutrophil count (ANC) > 1,000/μL
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	33.3; (26.7 to 40.5)

5. Secondary Outcome

Title	Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description	Complete Remission With Partial Hematological Recovery was defined by the following criteria: bone marrow blasts ≤ 5%; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μL, and ANC > 500/μL.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.5; (5.7 to 14.6)

6. Secondary Outcome

Title	Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment
Description	Partial Remission is defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	2.6; (0.9 to 6.1)

7. Secondary Outcome

Title	Relapse-free Survival
Description	Relapse-free survival was assessed for participants who achieved a complete remission or complete remission with partial hematological recovery during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.
Time Frame	Up to the data cut-off date of 10 October 2013; median observation time was 8.9 months.

Outcome Measure Data

Analysis Population Description

Participants who reached complete remission or complete remission with partial hematological recovery during the core study

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	82
Median (95% Confidence Interval); Unit of Measure: months
	5.9; (4.8 to 8.3)

8. Secondary Outcome

Title	Event-free Survival
Description	Event-free survival was calculated from the start date of blinatumomab infusion until the date of bone marrow aspiration at which hematological relapse was first detected, or the date of diagnosis on which the hematological or extramedullary relapse was documented or the date of start of any new therapy for ALL (excluding HSCT), or the date of death, whichever was earlier. Participants who did not achieve complete remission or complete remission with partial hematological recovery during the core study were evaluated as having an event on Day 1. Participants in remission who did not experience hematological relapse, did not receive a new therapy for ALL (excluding HSCT), and did not die were censored on the date of the last available bone marrow aspiration or on the last date of survival follow-up visit, whichever was later. Event free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.
Time Frame	Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Median (95% Confidence Interval); Unit of Measure: months
	0.0; (0.0 to 1.0)

9. Secondary Outcome

Title	Overall Survival
Description	Overall survival was measured for all participants from the time the participant received the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan Meier method.
Time Frame	Up to the data cut-off date of 10 October 2013; median observation time was 9.8 months.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Median (95% Confidence Interval); Unit of Measure: months
	6.1; (4.2 to 7.5)

10. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events
Description	Adverse events (AEs) were evaluated for severity according to the the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. An AE was considered "serious" if it resulted in death, was life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant incapacity or substantial disruption to conduct normal life functions, is a congenital anomaly or birth defect or is a medically important condition. Progressive disease was not an adverse event, per the protocol, unless it was more severe than expected for the patient. Therefore, many deaths due to progressive disease were not counted as adverse events.
Time Frame	From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 42.2 days.

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS), defined as all patients who received any infusion of blinatumomab.

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Unit of Measure: participants
Any adverse event (AE)	188
Adverse events of at least CTC grade 3	155
Treatment-related adverse events	166
Related adverse events of at least CTC grade 3	105
Serious adverse events	121
Serious adverse events of at least CTC grade 3	105
Related serious adverse events	69
AEs leading to interruption of blinatumomab	63
AEs leading to discontinuation of blinatumomab	34
Related AE leading to treatment discontinuation	18
AEs leading to death	28
Related AEs leading to death	3

11. Secondary Outcome

Title	100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
Description	The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in remission (CR/CRh*) following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Patients alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of patients having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods.
Time Frame	From the date of allogeneic HSCT until the data cut-off date of 10 October 2013; median observation time was 7.4 months.

Outcome Measure Data

Analysis Population Description

Participants who received an allogeneic HSCT while in remission induced by blinatumomab treatment.

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	32
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	11.3; (0.0 to 23.4)

12. Secondary Outcome

Title	Serum Blinatumomab Concentration at Steady State
Description	The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the start of the IV infusion or dose step for cycle 1 and cycle 2, respectively. Serum concentrations of blinatumomab were measured using a validated bioassay. The lower limit of quantitation (LLOQ) = 50.0 pg/mL.
Time Frame	Samples were taken before treatment start and on Days 3, 8, 10, 15, 22, and 29 after infusion start during Cycles 1 and 2.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Data Set (PKS) defined as all patients who received any infusion of blinatumomab and had at least one PK sample collected unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption or sampling information was missing.

Arm/Group Title	Cycle 1: Blinatumomab 9 μg/Day	Cycle 1: Blinatumomab 28 μg/Day	Cycle 2: Blinatumomab 28 μg/Day
Arm/Group Description:	Participants receiving 9 μg/day blinatumomab by continuous intravenous (CIV) infusion during Cycle 1.	Participants receiving 28 μg/day blinatumomab by continuous intravenous (CIV) infusion during Cycle 1.	Participants receiving 28 μg/day blinatumomab by continuous intravenous (CIV) infusion during Cycle 2.
Overall Number of Participants Analyzed	132	160	88
Mean (Standard Deviation); Unit of Measure: pg/mL
	211 (258)	621 (502)	731 (444)

13. Secondary Outcome

Title	Serum Cytokine Peak Levels
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using enzyme-linked immunosorbent assays or cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the limit of quantification (LOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured. Serum IL-4 levels were below detection limit (< 20 pg/mL) at all time points in all participants studied.
Time Frame	Serum samples were collected on Days 1 and 8 at 2 hours and 6 hours after treatment start, and on Day 2 (24 hours) and Day 3 (48 hours) of each treatment cycle and on Days 9 and 10 after dose step.

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Data Set (PDS): All patients who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected. N indicates the number of participants with available data at each time point.

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Mean (Standard Deviation); Unit of Measure: pg/mL
IFN-Ɣ: Cycle 1 Week 1 (N=184)	93.1 (409)
IFN-Ɣ: Cycle 1 Week 2 (N=175)	27.4 (83.1)
IFN-Ɣ: Cycle 2 Week 1 (N=95)	22.8 (45.8)
IFN-Ɣ: Cycle 3 Week 1 (N=41)	21.6 (27.6)
IL-10: Cycle 1 Week 1 (N=184)	589 (822)
IL-10: Cycle 1 Week 2 (N=175)	95.7 (136)
IL-10: Cycle 2 Week 1 (N=95)	397 (633)
IL-10: Cycle 3 Week 1 (N=41)	428 (941)
IL-2: Cycle 1 Week 1 (N=184)	24.7 (44.6)
IL-2: Cycle 1 Week 2 (N=175)	10.8 (5.21)
IL-2: Cycle 2 Week 1 (N=95)	11 (5.17)
IL-2: Cycle 3 Week 1 (N=41)	10.3 (2.03)
IL-6: Cycle 1 Week 1 (N=184)	826 (2390)
IL-6: Cycle 1 Week 2 (N=175)	234 (681)
IL-6: Cycle 2 Week 1 (N=95)	315 (952)
IL-6: Cycle 3 Week 1 (N=41)	69.2 (114)
TNF-α: Cycle 1 Week 1 (N=184)	30 (125)
TNF-α: Cycle 1 Week 2 (N=175)	10.3 (3.33)
TNF-α: Cycle 2 Week 1 (N=95)	12.1 (15)
TNF-α: Cycle 3 Week 1 (N=41)	12 (7.79)

14. Secondary Outcome

Title	Percentage of Participants With a Best Response of Blast Free Hypoplastic or Aplastic Bone Marrow Within 2 Cycles of Treatment
Description	Blast Free Hypoplastic or Aplastic Bone Marrow was defined as: bone marrow blasts ≤ 5%; no evidence of disease; insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or absolute neutrophil count (ANC) ≤ 500/μL
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.0; (5.3 to 14.0)

15. Secondary Outcome

Title	Best Response During the Core Study
Description	Complete Remission (CR): bone marrow blasts ≤ 5%; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μL, and absolute neutrophil count (ANC) > 1,000/μL Complete Remission With Partial Hematological Recovery (CRh*): bone marrow blasts ≤ 5%; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μL, and ANC > 500/μL Blast Free Hypoplastic or Aplastic Bone Marrow: bone marrow blasts ≤ 5%; no evidence of disease; insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or ANC ≤ 500/μL Partial Remission: • bone marrow blasts 6% to 25% with at least a 50% reduction from Baseline.
Time Frame	From the first dose of blinatumomab until 30 days after the end of the last infusion during the core study, or until the data cut-off date of 10 October 2013; a maximum of 7.5 months.

Outcome Measure Data

Analysis Population Description

Primary analysis set

Arm/Group Title	Blinatumomab
Arm/Group Description:	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
Overall Number of Participants Analyzed	189
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Remission (CR/CRh*)	43.4; (36.2 to 50.8)
Complete Remission	35.4; (28.6 to 42.7)
Complete remission with only partial hematological	7.9; (4.5 to 12.8)
Blast free hypoplastic or aplastic bone marrow	9.0; (5.3 to 14.0)
Partial remission	2.6; (0.9 to 6.1)

Adverse Events

Time Frame	From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 42.2 days.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The the initial dose was 9 μg/day for the first seven days of treatment, escalated to 28 μg/day starting from Week 2 of treatment.
All-Cause Mortality
	Blinatumomab
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Blinatumomab
	Affected / at Risk (%)
Total	121/189 (64.02%)
Blood and lymphatic system disorders
Anaemia † 1	1/189 (0.53%)
Disseminated intravascular coagulation † 1	1/189 (0.53%)
Febrile neutropenia † 1	16/189 (8.47%)
Leukocytosis † 1	2/189 (1.06%)
Lymphopenia † 1	1/189 (0.53%)
Neutropenia † 1	7/189 (3.70%)
Pancytopenia † 1	2/189 (1.06%)
Cardiac disorders
Atrial fibrillation † 1	1/189 (0.53%)
Bradycardia † 1	1/189 (0.53%)
Cardiac failure † 1	1/189 (0.53%)
Cardiac failure congestive † 1	2/189 (1.06%)
Sinus bradycardia † 1	1/189 (0.53%)
Supraventricular tachycardia † 1	1/189 (0.53%)
Ventricular fibrillation † 1	1/189 (0.53%)
Congenital, familial and genetic disorders
Aplasia † 1	1/189 (0.53%)
Eye disorders
Diplopia † 1	1/189 (0.53%)
Gastrointestinal disorders
Abdominal pain † 1	1/189 (0.53%)
Colitis † 1	1/189 (0.53%)
Diarrhoea † 1	1/189 (0.53%)
Enteritis † 1	1/189 (0.53%)
Gastrointestinal haemorrhage † 1	2/189 (1.06%)
Pancreatitis † 1	1/189 (0.53%)
General disorders
Asthenia † 1	2/189 (1.06%)
Chest pain † 1	2/189 (1.06%)
Device occlusion † 1	2/189 (1.06%)
Disease progression † 1	3/189 (1.59%)
Fatigue † 1	1/189 (0.53%)
Hypothermia † 1	1/189 (0.53%)
Medical device complication † 1	3/189 (1.59%)
Mucosal inflammation † 1	1/189 (0.53%)
Multi-organ failure † 1	1/189 (0.53%)
Oedema peripheral † 1	1/189 (0.53%)
Pyrexia † 1	11/189 (5.82%)
Immune system disorders
Cytokine release syndrome † 1	1/189 (0.53%)
Hypersensitivity † 1	2/189 (1.06%)
Infections and infestations
Abdominal infection † 1	1/189 (0.53%)
Aspergillus infection † 1	2/189 (1.06%)
BK virus infection † 1	1/189 (0.53%)
Bacterial sepsis † 1	2/189 (1.06%)
Bronchopneumonia † 1	1/189 (0.53%)
Bronchopulmonary aspergillosis † 1	1/189 (0.53%)
Candida infection † 1	1/189 (0.53%)
Cellulitis † 1	2/189 (1.06%)
Cholecystitis infective † 1	1/189 (0.53%)
Device related infection † 1	7/189 (3.70%)
Enterobacter infection † 1	1/189 (0.53%)
Enterococcal bacteraemia † 1	2/189 (1.06%)
Enterococcal infection † 1	2/189 (1.06%)
Enterococcal sepsis † 1	2/189 (1.06%)
Epididymal infection † 1	1/189 (0.53%)
Erysipelas † 1	1/189 (0.53%)
Escherichia sepsis † 1	2/189 (1.06%)
Fungal infection † 1	2/189 (1.06%)
Fusarium infection † 1	2/189 (1.06%)
Gastrointestinal infection † 1	2/189 (1.06%)
Herpes zoster † 1	1/189 (0.53%)
Infection † 1	4/189 (2.12%)
Kidney infection † 1	1/189 (0.53%)
Klebsiella infection † 1	1/189 (0.53%)
Leuconostoc infection † 1	1/189 (0.53%)
Lower respiratory tract infection † 1	1/189 (0.53%)
Lung infection † 1	1/189 (0.53%)
Neutropenic sepsis † 1	2/189 (1.06%)
Pathogen resistance † 1	1/189 (0.53%)
Pilonidal cyst † 1	1/189 (0.53%)
Pneumonia † 1	9/189 (4.76%)
Pneumonia fungal † 1	2/189 (1.06%)
Pneumonia klebsiella † 1	1/189 (0.53%)
Pneumonia respiratory syncytial viral † 1	1/189 (0.53%)
Pseudomonal bacteraemia † 1	1/189 (0.53%)
Pseudomonas infection † 1	1/189 (0.53%)
Pulmonary sepsis † 1	1/189 (0.53%)
Rhinitis † 1	1/189 (0.53%)
Rhinovirus infection † 1	1/189 (0.53%)
Sepsis † 1	9/189 (4.76%)
Septic shock † 1	3/189 (1.59%)
Sinusitis † 1	1/189 (0.53%)
Sinusitis fungal † 1	1/189 (0.53%)
Staphylococcal bacteraemia † 1	4/189 (2.12%)
Staphylococcal infection † 1	2/189 (1.06%)
Staphylococcal sepsis † 1	2/189 (1.06%)
Streptococcal sepsis † 1	1/189 (0.53%)
Urinary tract infection † 1	1/189 (0.53%)
Urosepsis † 1	1/189 (0.53%)
Viral haemorrhagic cystitis † 1	1/189 (0.53%)
Viral infection † 1	1/189 (0.53%)
Injury, poisoning and procedural complications
Accidental overdose † 1	2/189 (1.06%)
Femoral neck fracture † 1	1/189 (0.53%)
Hip fracture † 1	1/189 (0.53%)
Overdose † 1	5/189 (2.65%)
Post lumbar puncture syndrome † 1	1/189 (0.53%)
Subdural haematoma † 1	1/189 (0.53%)
Toxicity to various agents † 1	1/189 (0.53%)
Investigations
Alanine aminotransferase increased † 1	1/189 (0.53%)
Aspartate aminotransferase increased † 1	1/189 (0.53%)
Blood alkaline phosphatase increased † 1	2/189 (1.06%)
Blood bilirubin increased † 1	3/189 (1.59%)
Blood creatinine increased † 1	1/189 (0.53%)
Blood lactate dehydrogenase increased † 1	1/189 (0.53%)
C-reactive protein increased † 1	2/189 (1.06%)
Neutrophil count decreased † 1	1/189 (0.53%)
Platelet count decreased † 1	1/189 (0.53%)
White blood cell count decreased † 1	1/189 (0.53%)
Metabolism and nutrition disorders
Fluid overload † 1	1/189 (0.53%)
Hyperglycaemia † 1	1/189 (0.53%)
Hypokalaemia † 1	2/189 (1.06%)
Tumour lysis syndrome † 1	1/189 (0.53%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/189 (1.06%)
Arthritis † 1	1/189 (0.53%)
Back pain † 1	1/189 (0.53%)
Bone pain † 1	2/189 (1.06%)
Fistula † 1	1/189 (0.53%)
Muscular weakness † 1	2/189 (1.06%)
Myopathy † 1	1/189 (0.53%)
Pain in extremity † 1	1/189 (0.53%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia † 1	2/189 (1.06%)
Acute lymphocytic leukaemia † 1	2/189 (1.06%)
B precursor type acute leukaemia † 1	1/189 (0.53%)
Chloroma † 1	1/189 (0.53%)
Lymphoma † 1	1/189 (0.53%)
Nervous system disorders
Aphasia † 1	2/189 (1.06%)
Ataxia † 1	3/189 (1.59%)
Cerebral haemorrhage † 1	1/189 (0.53%)
Cognitive disorder † 1	3/189 (1.59%)
Convulsion † 1	2/189 (1.06%)
Dizziness † 1	1/189 (0.53%)
Dysaesthesia † 1	1/189 (0.53%)
Dysarthria † 1	1/189 (0.53%)
Encephalopathy † 1	5/189 (2.65%)
Headache † 1	4/189 (2.12%)
Hemiparesis † 1	1/189 (0.53%)
Nervous system disorder † 1	1/189 (0.53%)
Neurological symptom † 1	1/189 (0.53%)
Neurotoxicity † 1	3/189 (1.59%)
Paraesthesia † 1	1/189 (0.53%)
Poor quality sleep † 1	1/189 (0.53%)
Tremor † 1	5/189 (2.65%)
Trigeminal nerve disorder † 1	1/189 (0.53%)
Psychiatric disorders
Agitation † 1	1/189 (0.53%)
Confusional state † 1	5/189 (2.65%)
Delirium febrile † 1	1/189 (0.53%)
Mental status changes † 1	1/189 (0.53%)
Restlessness † 1	1/189 (0.53%)
Renal and urinary disorders
Bladder perforation † 1	1/189 (0.53%)
Renal failure † 1	1/189 (0.53%)
Renal failure acute † 1	1/189 (0.53%)
Reproductive system and breast disorders
Scrotal oedema † 1	1/189 (0.53%)
Respiratory, thoracic and mediastinal disorders
Respiratory distress † 1	1/189 (0.53%)
Respiratory failure † 1	3/189 (1.59%)
Skin and subcutaneous tissue disorders
Erythema multiforme † 1	1/189 (0.53%)
Hyperhidrosis † 1	1/189 (0.53%)
Rash vesicular † 1	1/189 (0.53%)
Skin lesion † 1	1/189 (0.53%)
Surgical and medical procedures
Catheter placement † 1	2/189 (1.06%)
Central venous catheter removal † 1	1/189 (0.53%)
Resuscitation † 1	1/189 (0.53%)
Vascular disorders
Capillary leak syndrome † 1	1/189 (0.53%)
Embolism † 1	1/189 (0.53%)
Femoral artery occlusion † 1	1/189 (0.53%)
Hypotension † 1	2/189 (1.06%)
Hypovolaemic shock † 1	1/189 (0.53%)
Subclavian vein thrombosis † 1	1/189 (0.53%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Blinatumomab
	Affected / at Risk (%)
Total	186/189 (98.41%)
Blood and lymphatic system disorders
Anaemia † 1	37/189 (19.58%)
Febrile neutropenia † 1	38/189 (20.11%)
Leukopenia † 1	19/189 (10.05%)
Neutropenia † 1	26/189 (13.76%)
Thrombocytopenia † 1	21/189 (11.11%)
Cardiac disorders
Sinus tachycardia † 1	11/189 (5.82%)
Tachycardia † 1	11/189 (5.82%)
Eye disorders
Vision blurred † 1	12/189 (6.35%)
Gastrointestinal disorders
Abdominal distension † 1	11/189 (5.82%)
Abdominal pain † 1	31/189 (16.40%)
Abdominal pain upper † 1	10/189 (5.29%)
Constipation † 1	39/189 (20.63%)
Diarrhoea † 1	34/189 (17.99%)
Nausea † 1	46/189 (24.34%)
Vomiting † 1	25/189 (13.23%)
General disorders
Asthenia † 1	17/189 (8.99%)
Chest pain † 1	19/189 (10.05%)
Chills † 1	29/189 (15.34%)
Fatigue † 1	28/189 (14.81%)
Oedema † 1	11/189 (5.82%)
Oedema peripheral † 1	49/189 (25.93%)
Pain † 1	14/189 (7.41%)
Pyrexia † 1	106/189 (56.08%)
Immune system disorders
Cytokine release syndrome † 1	22/189 (11.64%)
Infections and infestations
Upper respiratory tract infection † 1	10/189 (5.29%)
Investigations
Alanine aminotransferase increased † 1	23/189 (12.17%)
Aspartate aminotransferase increased † 1	20/189 (10.58%)
Blood bilirubin increased † 1	12/189 (6.35%)
Immunoglobulins decreased † 1	17/189 (8.99%)
Weight increased † 1	16/189 (8.47%)
Metabolism and nutrition disorders
Decreased appetite † 1	19/189 (10.05%)
Hyperglycaemia † 1	23/189 (12.17%)
Hypokalaemia † 1	44/189 (23.28%)
Hypomagnesaemia † 1	25/189 (13.23%)
Hypophosphataemia † 1	13/189 (6.88%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	18/189 (9.52%)
Back pain † 1	25/189 (13.23%)
Bone pain † 1	18/189 (9.52%)
Muscle spasms † 1	10/189 (5.29%)
Muscular weakness † 1	14/189 (7.41%)
Myalgia † 1	17/189 (8.99%)
Pain in extremity † 1	20/189 (10.58%)
Nervous system disorders
Dizziness † 1	25/189 (13.23%)
Headache † 1	63/189 (33.33%)
Tremor † 1	33/189 (17.46%)
Psychiatric disorders
Anxiety † 1	14/189 (7.41%)
Insomnia † 1	29/189 (15.34%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	35/189 (18.52%)
Dyspnoea † 1	16/189 (8.47%)
Epistaxis † 1	11/189 (5.82%)
Skin and subcutaneous tissue disorders
Petechiae † 1	11/189 (5.82%)
Rash † 1	22/189 (11.64%)
Vascular disorders
Hypertension † 1	12/189 (6.35%)
Hypotension † 1	21/189 (11.11%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 16.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

Results Point of Contact

• Name/Title: Study Director
• Organization: Amgen Inc.
• Phone: 866-572-6436

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.

Gokbuget N, Kantarjian HM, Bruggemann M, Stein AS, Bargou RC, Dombret H, Fielding AK, Heffner L, Rigal-Huguet F, Litzow M, O'Brien S, Zugmaier G, Gao S, Nagorsen D, Forman SJ, Topp MS. Molecular response with blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Adv. 2019 Oct 22;3(20):3033-3037. doi: 10.1182/bloodadvances.2019000457.

Zhu M, Kratzer A, Johnson J, Holland C, Brandl C, Singh I, Wolf A, Doshi S. Blinatumomab Pharmacodynamics and Exposure-Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Pharmacol. 2018 Feb;58(2):168-179. doi: 10.1002/jcph.1006. Epub 2017 Sep 18.

Barlev A, Lin VW, Katz A, Hu K, Cong Z, Barber B. Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data. Adv Ther. 2017 Jan;34(1):148-155. doi: 10.1007/s12325-016-0447-x. Epub 2016 Nov 21.

Zhu M, Wu B, Brandl C, Johnson J, Wolf A, Chow A, Doshi S. Blinatumomab, a Bispecific T-cell Engager (BiTE((R))) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications. Clin Pharmacokinet. 2016 Oct;55(10):1271-1288. doi: 10.1007/s40262-016-0405-4.

Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foa R, Litzow M, Ribera JM, Rambaldi A, Schiller G, Bruggemann M, Horst HA, Holland C, Jia C, Maniar T, Huber B, Nagorsen D, Forman SJ, Kantarjian HM. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015 Jan;16(1):57-66. doi: 10.1016/S1470-2045(14)71170-2. Epub 2014 Dec 16. Erratum In: Lancet Oncol. 2015 Apr;16(4):e158.

• Responsible Party: Amgen Research (Munich) GmbH
• ClinicalTrials.gov Identifier: NCT01466179
• Other Study ID Numbers: MT103-211; 2011-002257-61 ( EudraCT Number )
• First Submitted: October 28, 2011
• First Posted: November 6, 2011
• Results First Submitted: December 21, 2014
• Results First Posted: January 22, 2015
• Last Update Posted: August 18, 2017