Trial Outcomes & Findings for Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL (NCT NCT04524455)

Last Updated: 2024-04-08

Results Overview

Investigators determined whether an adverse event (AE) qualified as a DLT per pre-specified protocol defined criteria. An AE was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

17 participants

Primary outcome timeframe

Cohort 1: Up to 67 days; Cohort 2a: Up to 56 days

Results posted on

2024-04-08

Participant Flow

This study was conducted at 22 centers in Australia, Austria, France, Germany, Italy, Netherlands, Spain, United Kingdom, and the United States between 02 October 2020 to 24 January 2023.

Participant milestones

Participant milestones
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) Blinatumomab continuous intravenous infusion (cIV) was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered intravenously (IV) at 240 mg, starting on Cycle 1 Day 11 (C1D11) and dosed every 4 weeks (Q4W) thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.
Overall Study STARTED	8	9
Overall Study Participants Who Received Blinatumomab	8	8
Overall Study Participants Who Received AMG 404	8	8
Overall Study COMPLETED	4	3
Overall Study NOT COMPLETED	4	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) Blinatumomab continuous intravenous infusion (cIV) was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered intravenously (IV) at 240 mg, starting on Cycle 1 Day 11 (C1D11) and dosed every 4 weeks (Q4W) thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.
Overall Study Death	3	3
Overall Study Decision by Sponsor	0	2
Overall Study Withdrawal of Consent From Study	1	0
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

Blinatumomab in Combination With AMG 404 for the Treatment of Adults With Relapsed or Refractory B Cell Precursor ALL

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=9 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Total n=17 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=99 Participants	8 Participants n=107 Participants	14 Participants n=206 Participants
Age, Categorical >=65 years	2 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants
Age, Continuous	52.9 Years STANDARD_DEVIATION 18.0 • n=99 Participants	39.3 Years STANDARD_DEVIATION 15.7 • n=107 Participants	45.7 Years STANDARD_DEVIATION 17.7 • n=206 Participants
Sex: Female, Male Female	2 Participants n=99 Participants	4 Participants n=107 Participants	6 Participants n=206 Participants
Sex: Female, Male Male	6 Participants n=99 Participants	5 Participants n=107 Participants	11 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	4 Participants n=107 Participants	4 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=99 Participants	5 Participants n=107 Participants	13 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race/Ethnicity, Customized Asian	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants
Race/Ethnicity, Customized White	6 Participants n=99 Participants	6 Participants n=107 Participants	12 Participants n=206 Participants
Race/Ethnicity, Customized Other	0 Participants n=99 Participants	2 Participants n=107 Participants	2 Participants n=206 Participants

PRIMARY outcome

Timeframe: Cohort 1: Up to 67 days; Cohort 2a: Up to 56 days

Population: DLT Analysis Set: included DLT-evaluable participants in the Safety Analysis Set. A participant was DLT-evaluable if the participant had completed DLT-evaluable period which begins with the first AMG 404 dose and includes 28 days after the second AMG 404 dose is administered or experienced a DLT any time during the DLT-evaluable period.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=3 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=7 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	0 Participants	0 Participants	—	—	—	—

PRIMARY outcome

Timeframe: Median (min, max) overall duration from first dose until 30 days after last dose is: 83.4 (40.2, 274.1) days

Population: Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404.

A TEAE was defined as any AE starting on or after first dose of blinatumomab or AMG 404. The investigator used clinical judgment to assess causal relationship. A serious AE (SAE) was defined as any AE that: * results in death, * immediately life-threatening, * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * is a congenital anomaly/birth defect, and/or * other medically important serious AE. AEs of interest (EOIs) for blinatumomab included capillary leak syndrome, cytokine release syndrome, decreased immunoglobulins, elevated liver enzyme, embolic and thrombotic events, immunogenicity, infections, infusion reactions without considering duration, leukoencephalopathy, progressive multifocal leukoencephalopathy, neurologic events, neutropenia and febrile neutropenia, pancreatitis, and tumor lysis syndrome. EOIs for AMG 404 included non-infectious diarrhea and hemorrhages.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs) TEAEs	8 Participants	8 Participants	—	—	—	—
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs) Serious TEAEs	6 Participants	7 Participants	—	—	—	—
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs) Blinatumomab-related TEAEs	8 Participants	6 Participants	—	—	—	—
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs) AMG 404-related TEAEs	3 Participants	4 Participants	—	—	—	—
Number of Participants Who Experienced Treatment-Emergent AEs (TEAEs) EOIs	8 Participants	8 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Within the first 2 cycles: Up to approximately 86 days; across all cycles: Up to approximately 274 days

Population: Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404.

Hematological remissions were defined by the following criteria: CR: * Less than 5% blasts in the bone marrow (BM) * No evidence of disease * Full recovery of peripheral blood (PB) counts: * Platelets \> 100 000/μl * Absolute neutrophil count (ANC) \> 1000/μl CR with only CRh: * Less than 5% blasts in the BM * No evidence of disease * Partial recovery of PB counts: * Platelets \> 50 000/μl and * ANC \> 500/μl Percentage of participants with CR/CRh were summarized along with corresponding 95% exact confidence interval (CI) using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Percentage of Participants Who Achieved Complete Remission (CR) or CR With Partial Hematological Recovery (CRh) (CR/CRh) Within the First 2 Cycles	37.5 Percentage of Participants Interval 8.5 to 75.5	62.5 Percentage of Participants Interval 24.5 to 91.5	—	—	—	—
Percentage of Participants Who Achieved Complete Remission (CR) or CR With Partial Hematological Recovery (CRh) (CR/CRh) Across All Cycles	37.5 Percentage of Participants Interval 8.5 to 75.5	62.5 Percentage of Participants Interval 24.5 to 91.5	—	—	—	—

SECONDARY outcome

Timeframe: Within the first 2 cycles: Up to approximately 86 days; across all cycles: Up to approximately 274 days

Population: Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404.

Hematological remissions were defined by the following criteria: CR: * Less than 5% blasts in the BM * No evidence of disease * Full recovery of PB counts: * Platelets \> 100 000/μl * ANC \> 1000/μl Percentage of participants with CR were summarized along with corresponding 95% exact CI using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Percentage of Participants Who Achieved CR Within the First 2 Cycles	25.0 Percentage of Participants Interval 3.2 to 65.1	50.0 Percentage of Participants Interval 15.7 to 84.3	—	—	—	—
Percentage of Participants Who Achieved CR Across All Cycles	25.0 Percentage of Participants Interval 3.2 to 65.1	50.0 Percentage of Participants Interval 15.7 to 84.3	—	—	—	—

SECONDARY outcome

Timeframe: Up to approximately 274 days

Population: Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404. Includes only participants who achieved CR within the first 2 cycles of treatment.

Duration of CR was calculated from the date CR was first achieved within the first 2 cycles until the earliest date of disease assessment indicating a relapse event or death due to any cause, whichever occurred first. Months were calculated as days from date of CR to event/censor date, divided by 30.5. Median time to event and 95% CI was summarized using the Kaplan-Meier (KM) method.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=2 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=4 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Median Duration of CR in Participants Who Achieved CR Within First 2 Cycles	NA Months Interval 4.4 to Median and upper CI not reached.	NA Months Interval 1.6 to Median and upper CI not reached.	—	—	—	—

SECONDARY outcome

Timeframe: Up to approximately 274 days

Duration of CR/CRh was calculated from the date CR/CRh was first achieved within the first 2 cycles until the earliest date of disease assessment indicating a relapse event or death due to any cause, whichever occurred first. Months were calculated as days from date of CR/CRh to event/censor date, divided by 30.5. Median time to event and 95% CI was summarized using the KM method.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=3 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=5 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Median Duration of CR/CRh in Participants Who Achieved CR/CRh Within First 2 Cycles	NA Months Interval 4.4 to Median and upper CI not reached.	NA Months Interval 1.6 to Median and upper CI not reached.	—	—	—	—

SECONDARY outcome

Timeframe: Cohort 1: C1D1 and D8 (predose, 2 to 24 h postdose), and D11, D18 and D29; C2D1 (predose, 2 to 24 h postdose) and D29. Cohort 2a: C1D3 and D10 (predose, 2 to 48 h postdose), and D29, D30 and D31; C2D1 (predose, 2 to 24 h postdose), D13 and D29

Population: PK Analysis Set: Defined as all participants in the Safety Analysis Set who have at least 1 PK sample collected. Includes only participants with available data at each timepoint.

Pharmacokinetic (PK) parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=7 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day n=3 Participants Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day n=7 Participants Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day n=5 Participants Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Steady-state Concentrations (Css) of Blinatumomab	152 pg/mL Standard Deviation 70.2	676 pg/mL Standard Deviation 478	779 pg/mL Standard Deviation 210	210 pg/mL Standard Deviation 177	638 pg/mL Standard Deviation 274	626 pg/mL Standard Deviation 228

SECONDARY outcome

Timeframe: Cohort 1: C1D11 (predose, end of infusion to 48 h postdose), D18, D29, and D39 (predose and end of infusion). Cohort 2a: C1D1 (predose, end of infusion to 168 h postdose), D12 and D29 (predose and end of infusion)

Population: PK Analysis Set: Defined as all participants in the Safety Analysis Set who have at least 1 PK sample collected. Includes only participants with available data at each timepoint.

PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Maximum Observed Concentration (Cmax) of AMG 404	70.2 mg/mL Standard Deviation 18.7	175 mg/mL Standard Deviation 53.5	—	—	—	—

SECONDARY outcome

Population: PK Analysis Set: Defined as all participants in the Safety Analysis Set who have at least 1 PK sample collected. Includes only participants with available data at each timepoint.

PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Time to Cmax (Tmax) of AMG 404	2.5 Hours Interval 0.45 to 25.0	1.5 Hours Interval 0.5 to 2.8	—	—	—	—

SECONDARY outcome

Population: PK Analysis Set: Defined as all participants in the Safety Analysis Set who have at least 1 PK sample collected. Includes only participants with available data at each timepoint.

PK parameters were estimated using standard non-compartmental approaches and summarized by dose level as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=7 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Area Under the Plasma Concentration-time Curve From Time 0 to 28 Days Post Infusion (AUC0-28d) of AMG 404	750 day·mg/mL Standard Deviation 269	1920 day·mg/mL Standard Deviation 660	—	—	—	—

SECONDARY outcome

Timeframe: Up to approximately 274 days

Population: Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404. Includes only participants with available data.

Only samples testing positive for anti-blinatumomab binding antibodies were to be tested for neutralizing antibodies (NAbs) as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Number of Participants With Incidences of Anti-Blinatumomab Antibodies Binding Antibody Positive at Anytime	0 Participants	0 Participants	—	—	—	—
Number of Participants With Incidences of Anti-Blinatumomab Antibodies NAb Positive at Anytime	0 Participants	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Up to approximately 274 days

Population: Safety Analysis Set: defined as all participants who were enrolled and received at least 1 dose of blinatumomab and AMG 404. Includes only participants with available data.

Only samples testing positive for anti-AMG 404 binding antibodies were to be tested for NAbs as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Cohort 1: Blinatumomab + AMG 404 (240 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 1 to 7, then at 28 μg/day thereafter. Each cycle consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 2a: Blinatumomab + AMG 404 (480 mg) n=8 Participants Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9, then at 28 μg/day thereafter. Cycle 1 consisted of 44 days and included a 14-day blinatumomab treatment-free interval between Days 31 and 44. Each cycle thereafter consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter. Participants could receive up to 5 cycles.	Cohort 1; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 240 mg, starting on C1D11 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 9 μg/Day Blinatumomab cIV was administered at 9 μg/day on Days 3 to 9. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 1: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day on Days 10 to 30. Cycle 1 consisted of 44 days. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.	Cohort 2a; Cycle 2: Blinatumomab 28 μg/Day Blinatumomab cIV was administered at 28 μg/day. Cycle 2 consisted of 42 days and included a 14-day blinatumomab treatment-free interval between Days 29 and 42. The treatment-free interval could be prolonged by up to 7 days if deemed necessary by the investigator. AMG 404 was administered IV at 480 mg, starting on C1D1 and dosed Q4W thereafter.
Number of Participants With Incidences of Anti-AMG 404 Antibodies Binding Antibody Positive at Anytime	0 Participants	0 Participants	—	—	—	—

Adverse Events

Cohort 1: Blinatumomab + AMG 404 (240 mg)

Serious events: 6 serious events

Other events: 8 other events

Deaths: 3 deaths

Cohort 2a: Blinatumomab + AMG 404 (480 mg)

Serious events: 7 serious events

Other events: 8 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER