NCT02412306

Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Completed Phase 1, PHASE2 Results posted Last updated 12 December 2022

What this trial tests

Phase 1, PHASE2 trial testing Blinatumomab in Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia in 66 participants. Completed in 4 July 2019.

Timeline

4 June 2015

Primary endpoint
6 February 2019

4 July 2019

Quick facts

Lead sponsor	Amgen
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	66
Start date	4 June 2015
Primary completion	6 February 2019
Estimated completion	4 July 2019
Sites	16 locations across Japan

Drugs / interventions tested

• Blinatumomab (blinatumomab) — full drug profile →

Conditions studied

• Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia — all drugs for Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia →

Sponsor

Amgen — full company profile →

Who can join

0 and older, any sex, with Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase 1b: Number of Participants With Dose-limiting Toxicities Primary · Days 1 to 14

Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management.

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	0
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	0

Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment Primary · Within the first 2 cycles of treatment, 12 weeks

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) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and 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\*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial rec

Group	Value	95% CI
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	38.1	18.1 – 61.6

Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment Secondary · Within the first 2 cycles of treatment, 12 weeks

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) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and 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\*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial rec

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	80.0	28.4 – 99.5

Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment Secondary · The first 2 cycles of treatment, 12 weeks

M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.

Group	Value	95% CI
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	55.6	21.2 – 86.3

Phase 1b and Phase 2: Duration of Response Secondary · Median (minimum [min], maximum [max]) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Duration of response was calculated from the date of bone marrow aspiration when response (CR/CRh\*) was detected for the first time during the first 2 cycles of treatment until the earlier of the following events: * the date of bone marrow aspiration at which hematological relapse or progressive disease (PD) was first detected, * the date of diagnosis on which the hematological or extra medullary relapse was documented, * the date of death if patient died due to PD * the date of end of induction phase if primary reason for treatment termination was hematological or extramedullary relapse. F

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	13.0	4.2 – 19.7
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	2.3	1.1 – 6.8
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	13.1	3.5 – 20.7

Phase 1b and Phase 2: Relapse-free Survival Secondary · Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Relapse-free survival (RFS) was defined for participants who achieved a response (CR/CRh\*) during the first 2 cycles of treatment. RFS was calculated from the date of bone marrow aspiration when response was detected for the first time to the date of bone marrow aspiration at which hematological relapse was first detected or the date of diagnosis on which the hematological or extra medullary relapse was documented or the date of death due to any cause, whichever was earlier. Participants who did not experience hematological relapse and did not die were censored on the date of the last availab

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	11.4	4.2 – 19.7
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	2.3	1.1 – 6.8
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	13.1	3.5 – 20.7

Phase 1b and Phase 2: Overall Survival Secondary · Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Overall survival (OS) was calculated from the start date of blinatumomab infusion in the first treatment cycle. All deaths were counted as events on the date of death. Participants still alive were censored on the last documented visit date or the date of the last phone contact when the participant was last known to have been alive. For participants who withdrew their informed consent, only information until the date of withdrawal was used in the analysis.

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	11.0	9.3 – 20.7
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	10.6	0.9 – NA
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	14.8	2.7 – 21.6

Phase 2: Best Overall Response Within 2 Cycles of Treatment Secondary · Within the first 2 cycles of treatment, 12 weeks

Best response was defined as one of the following: CR: ≤ 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood counts: Platelets \> 100,000/µl, and absolute neutrophil count (ANC) \> 1,000/µl CRh\*: ≤ 5% blasts in BM; No evidence of disease; Partial recovery of peripheral blood counts: Platelets \> 50,000/µl, and ANC \> 500/µl CRi: CR with incomplete count recovery without CRh\* Blast free hypoplastic or aplastic BM: ≤ 5 % blasts in BM; No evidence of disease; Insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or ANC ≤ 500/µl

Group	Value	95% CI
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	5
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	3
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	0
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	6

Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission Secondary · Median (min, max) follow-up time was 26.7 (3.0, 28.5) months.

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.

Group	Value	95% CI
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	81.0

Phase 2: 100-Day Mortality After Allogeneic HSCT Secondary · 100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5)

The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in any CR following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Participants still alive 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 participants having died up to 100 days after allogeneic HSCT estimated us

Group	Value	95% CI
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	11.8

Phase 1b and Phase 2: Number of Participants With TEAEs Secondary · From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 108 (56, 140), 56.0 (5, 84), and 56.0 (11, 115) days in adult phase 1b, adult phase 2 and pediatric phase 1b cohort respectively.

TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 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 bli

All TEAEs

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	5
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	9
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	21

TEAEs ≥ Grade 3

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	4
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	9
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	21

TEAEs ≥ Grade 4

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	2
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	7
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	14

Serious TEAEs (STEAEs)

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	0
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	1
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	7

TEAEs Leading to Blinatumomab Interruption

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	1
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	6
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	3

STEAEs Leading to Blinatumomab Interruption

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	0
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	0
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	0

TEAEs Leading to Blinatumomab Discontinuation

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	0
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	1
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	1

STEAEs Leading to Blinatumomab Discontinuation

Group	Value	95% CI
Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	0
Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	0
Phase 2: Blinatumomab 9/28 μg/Day (Adults)	1

Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State Secondary · After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).

The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 5 half-lives or after 24 hours from the start of continuous IV infusion. Cycle 1, day 2 values represent steady-state concentration after CIV with the initial dose of blinatumomab (9 µg/day for adults and 5 µg/m²/day for pediatric patients). All other time points were measured after the dose step to 28 µg/day (adults) / 15 µg/m²/day (pediatric participants).

Cycle 1 before dose step

Group	Value	95% CI
Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	191	± 90.8
Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	113	± 65.0
Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	135	± 41.7
Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)	107	± 42.7

Cycle 1 after dose step

Group	Value	95% CI
Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	948	± 488
Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	361	± 137
Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	907	± 403
Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)	361	± 137

Cycle 2

Group	Value	95% CI
Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	1150	± 575
Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	427	± 66.0
Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	1040	± 493
Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)	427	± 66.0

Cycle 3+

Group	Value	95% CI
Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	1420	± 685
Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	780	± NA
Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	1280	± 396

Adverse events — posted to ClinicalTrials.gov

Time frame: The median treatment duration for blinatumomab was 108 days for Adult Phase 1b Cohort, 56 days for Pediatric Phase 1b Cohort, 56 days for Adult Phase 2 Cohort, 55.6 days for Adult Expansion Cohort and 28 days for Pediatric Expansion Cohort. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1b: Blinatumomab 9/28 μg/Day (Adults)

Serious: 0/5 (0%)

Deaths: 5/5

Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)

Serious: 1/9 (11%)

Deaths: 7/9

Phase 2: Blinatumomab 9/28 μg/Day (Adults)

Serious: 7/21 (33%)

Deaths: 15/21

Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)

Serious: 2/14 (14%)

Deaths: 0/14

Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)

Serious: 3/17 (18%)

Deaths: 2/17

Serious adverse events (13 terms)

Reaction	System	Phase 1b: Blinatumomab 9/2…	Phase 1b: Blinatumomab 5/1…	Phase 2: Blinatumomab 9/28…	Expansion Cohort: Blinatum…	Expansion Cohort: Blinatum…
Neutrophil count decreased	Investigations	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—
Cytokine release syndrome	Immune system disorders	—	—	—	—	—
Bacteraemia	Infections and infestations	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—
Tumour lysis syndrome	Metabolism and nutrition disorders	—	—	—	—	—
Shock haemorrhagic	Vascular disorders	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—
Disease progression	General disorders	—	—	—	—	—
Multiple organ dysfunction syndrome	General disorders	—	—	—	—	—
Device related sepsis	Infections and infestations	—	—	—	—	—
Overdose	Injury, poisoning and procedural complications	—	—	—	—	—

Other adverse events (212 terms — click to expand)

Reaction	System	Phase 1b: Blinatumomab 9/2…	Phase 1b: Blinatumomab 5/1…	Phase 2: Blinatumomab 9/28…	Expansion Cohort: Blinatum…	Expansion Cohort: Blinatum…
Pyrexia	General disorders	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Cytokine release syndrome	Immune system disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Disseminated intravascular coagulation	Blood and lymphatic system disorders	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Malaise	General disorders	—	—	—	—	—
Hypogammaglobulinaemia	Immune system disorders	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—	—	—	—
Liver disorder	Hepatobiliary disorders	—	—	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Oedema	General disorders	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Activated partial thromboplastin time prolonged	Investigations	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—
Immunoglobulins decreased	Investigations	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—
Fluid retention	Metabolism and nutrition disorders	—	—	—	—	—
Hypocalcaemia	Metabolism and nutrition disorders	—	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—	—

Most-reported serious reactions: Neutrophil count decreased, Sepsis, Colitis, Cytokine release syndrome, Bacteraemia, Decreased appetite, Tumour lysis syndrome, Shock haemorrhagic.

Data from ClinicalTrials.gov NCT02412306 adverse events section.

Sponsor's own description

This is an open-label, combined 2-part multicenter study to evaluate the efficacy, safety, and tolerability of blinatumomab in adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. The landscape of bispecific T cell engager in cancer treatment.
   Zhou S, Liu M, Ren F, Meng X, et al · · 2021 · cited 172× · PMID 34039409 · DOI 10.1186/s40364-021-00294-9
2. Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies.
   Burt R, Warcel D, Fielding AK. · · 2019 · cited 51× · PMID 30380973 · DOI 10.1080/21645515.2018.1540828
3. Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review).
   Queudeville M, Ebinger M. · · 2021 · cited 43× · PMID 34201368 · DOI 10.3390/jcm10122544
4. Benefit-Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.
   Stein A, Franklin JL, Chia VM, Arrindell D, et al · · 2019 · cited 43× · PMID 30565020 · DOI 10.1007/s40264-018-0760-1
5. Pediatric Acute Lymphoblastic Leukemia Emerging Therapies-From Pathway to Target.
   Ivanov AV, Alecsa MS, Popescu R, Starcea MI, et al · · 2023 · cited 16× · PMID 36902091 · DOI 10.3390/ijms24054661
6. Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia.
   Kiyoi H, Morris JD, Oh I, Maeda Y, et al · · 2020 · cited 14× · PMID 31971321 · DOI 10.1111/cas.14322
7. Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia - role of blinatumomab.
   Queudeville M, Handgretinger R, Ebinger M. · · 2017 · cited 9× · PMID 28790849 · DOI 10.2147/ott.s103470
8. Efficacy and safety of blinatumomab: Post hoc pooled analysis in Asian adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.
   Kobayashi Y, Oh I, Miyamoto T, Lee WS, et al · · 2022 · cited 6× · PMID 34185953 · DOI 10.1111/ajco.13609