Clinical trial NCT02412306: Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Official title: A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia
Keywords: Amgen
Lead sponsor: Amgen
Sponsor class: INDUSTRY
Collaborators: name: Amgen Astellas Biopharma K.K.
First posted: 2015-04-09
Enrollment: 66
Sex: ALL
Minimum age (years): 0
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: The Phase 1b part will investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab to determine the maximum tolerated dose (MTD) in both adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL. The Phase 2 part will assess the safety and efficacy of the recommended dose level of blinatumomab identified in the Phase 1b portion of the study in the adult study population.

In June 2017 protocol amendment 4 extended the study to include an expansion cohort of approximately 65 participants to investigate the safety of blinatumomab in participants who did not participate in Phase 1b or Phase 2 of the study. Adult and pediatric patients in the expansion cohort may receive up to 5 cycles of investigational blinatomumab and may receive commercial blinatomumab after a minimum of 2 cycles of the investigational drug.

Eligibility criteria: Adult Subjects Key Inclusion Criteria:

* Age ≥ 18 years old at enrollment
* Subjects with Philadelphia-negative B-precursor ALL, with any of the following:

  * Relapsed or refractory after first line therapy with first remission duration ≤ 12 months; or
  * Relapsed or refractory after first salvage therapy; or
  * Relapsed or refractory within 12 months of allogeneic hematopoietic stem cell transplant (alloHSCT)
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
* Greater than 5% blasts in bone marrow

Pediatric Subjects Key Inclusion Criteria:

* Age \< 18 years old at enrollment
* Relapsed/refractory disease, defined as one of the following:

  * second or later bone marrow relapse;
  * any marrow relapse after alloHSCT; or
  * Refractory to other treatments:

    * For subjects in first relapse: failure to achieve a complete response (CR) following a full standard reinduction chemotherapy regimen
    * For subjects who have not achieved a first remission: failure to achieve remission following a full standard induction regimen
* Greater than 5% blasts in bone marrow
* Karnofsky performance status ≥ 50% for subjects ≥ 16 years
* Lansky performance status ≥ 50% for subjects \< 16 years

Key Exclusion Criteria

* Subjects with Burkitt´s Leukemia according to World Health Organization (WHO) classification
* History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis; with the exception of well-controlled CNS leukemia
* Active ALL in the CNS or testes
* Current autoimmune disease or history of autoimmune disease with potential CNS involvement
* Autologous HSCT within 6 weeks prior to start of blinatumomab treatment
* AlloHSCT within 12 weeks prior to start of blinatumomab treatment
* Any active acute Graft-versus-Host Disease (GvHD) grade 2-4 according to Glucksberg criteria or active chronic GvHD requiring systemic treatment

Primary outcomes:
measure: Phase 1b: Number of Participants With Dose-limiting Toxicities
timeFrame: Days 1 to 14
measure: 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
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
timeFrame: From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 55.6 (25, 140) and 28.0 (8, 56) days in the adult and pediatric expansion cohorts, respectively.
Secondary outcomes:
measure: 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
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment
timeFrame: The first 2 cycles of treatment, 12 weeks
measure: Phase 1b and Phase 2: Duration of Response
timeFrame: 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.
measure: Phase 1b and Phase 2: Relapse-free Survival
timeFrame: 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.
measure: Phase 1b and Phase 2: Overall Survival
timeFrame: 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.
measure: Phase 2: Best Overall Response Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission
timeFrame: Median (min, max) follow-up time was 26.7 (3.0, 28.5) months.
measure: Phase 2: 100-Day Mortality After Allogeneic HSCT
timeFrame: 100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5)
measure: Phase 1b and Phase 2: Number of Participants With TEAEs
timeFrame: 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.
measure: Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State
timeFrame: 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).
measure: Phase 1b and Phase 2: Systemic Clearance of Blinatumomab
timeFrame: 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).
measure: Phase 1b and Phase 2: Terminal Half-life of Blinatumomab
timeFrame: Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion
measure: Phase 1b and Phase 2: Volume of Distribution of Blinatumomab
timeFrame: Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion
measure: Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies
timeFrame: Day 1 before first dose; cycles 1 and 2 day 29, 6 hours after end of infusion; 30 days after last dose.
measure: Phase 1b and Phase 2: Interleukin-2 Concentration
timeFrame: Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start
measure: Phase 1b and Phase 2: Interleukin-6 Concentration
timeFrame: Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start
measure: Phase 1b and Phase 2: Interleukin-10 Concentration
timeFrame: Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start
measure: Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration
timeFrame: Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start
measure: Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration
timeFrame: Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start
measure: Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
measure: Expansion Cohort Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment
timeFrame: Within the first 2 cycles of treatment, 12 weeks
Other outcomes:
Locations:
city: Nagoya-shi
country: Japan
facility: National Hospital Organization Nagoya Medical Center
state: Aichi
city: Nagoya-shi
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Fukuoka-shi
country: Japan
facility: Kyushu University Hospital
state: Fukuoka
city: Maebashi-shi
country: Japan
facility: Gunmaken Saiseikai Maebashi Hospital
state: Gunma
city: Sapporo-shi
country: Japan
facility: Sapporo Hokuyu Hospital
state: Hokkaido
city: Kobe-shi
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Yokohama-shi
country: Japan
facility: Kanagawa Childrens Medical Center
state: Kanagawa
city: Nagasaki-shi
country: Japan
facility: Nagasaki University Hospital
state: Nagasaki
city: Niigata-shi
country: Japan
facility: Niigata Cancer Center Hospital
state: Niigata
city: Okayama-shi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Osaka-shi
country: Japan
facility: Osaka City General Hospital
state: Osaka
city: Osaka-shi
country: Japan
facility: Osaka Metropolitan University Hospital
state: Osaka
city: Saitama-shi
country: Japan
facility: Saitama Childrens Medical Center
state: Saitama
city: Shimotsuke-shi
country: Japan
facility: Jichi Medical University Hospital
state: Tochigi
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Setagaya-ku
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Horibe K, Morris JD, Tuglus CA, Dos Santos C, Kalabus J, Anderson A, Goto H, Ogawa C. A phase 1b study of blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Int J Hematol. 2020 Aug;112(2):223-233. doi: 10.1007/s12185-020-02907-9. Epub 2020 Jun 20.
citation: Kiyoi H, Morris JD, Oh I, Maeda Y, Minami H, Miyamoto T, Sakura T, Iida H, Tuglus CA, Chen Y, Dos Santos C, Kalabus J, Anderson A, Hata T, Nakashima Y, Kobayashi Y. Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia. Cancer Sci. 2020 Apr;111(4):1314-1323. doi: 10.1111/cas.14322. Epub 2020 Feb 11.
citation: Kobayashi Y, Oh I, Miyamoto T, Lee WS, Iida H, Minami H, Maeda Y, Jang JH, Yoon SS, Yeh SP, Tran Q, Morris J, Franklin J, Kiyoi H. Efficacy and safety of blinatumomab: Post hoc pooled analysis in Asian adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Asia Pac J Clin Oncol. 2022 Jun;18(3):311-318. doi: 10.1111/ajco.13609. Epub 2021 Jun 29.
citation: Goto H, Ogawa C, Iida H, Horibe K, Oh I, Takada S, Maeda Y, Minami H, Nakashima Y, Morris JD, Kormany W, Chen Y, Miyamoto T. Safety and Efficacy of Blinatumomab in Japanese Adult and Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Final Results from an Expansion Cohort. Acta Haematol. 2022;145(6):592-602. doi: 10.1159/000525835. Epub 2022 Jul 5.