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

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ClinicalTrials.gov Identifier: NCT02412306
Recruitment Status : Recruiting
First Posted : April 9, 2015
Last Update Posted : October 10, 2018
Sponsor:
Collaborator:
Amgen Astellas Biopharma K.K.
Information provided by (Responsible Party):
Amgen

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.

Condition or disease Intervention/treatment Phase
Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia Drug: Blinatumomab Phase 1 Phase 2

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. The expansion cohort is currently enrolling.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 122 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)
Actual Study Start Date : June 4, 2015
Estimated Primary Completion Date : July 27, 2019
Estimated Study Completion Date : August 5, 2019


Arm Intervention/treatment
Experimental: Blinatumomab
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 for adults was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Drug: Blinatumomab
Continuous intravenous infusion over four weeks per treatment cycle
Other Name: Blincyto®




Primary Outcome Measures :
  1. Primary Endpoint phase 1= Incidence of DLT (dose limiting toxicities) [ Time Frame: Primary outcome will be assessed within 12 weeks of treatment with blinatumomab ]
    Phase 1b Primary Endpoint Incidence of DLTs. DLTs are defined as greater or equal to grade 3 adverse event related to blinatumomab (CTCAE v4.0).

  2. Primary Endpoint phase 2 = CR/CRh* within 12 weeks of treatment with blinatumomab [ Time Frame: Within 12 weeks of treatment with blinatumomab ]
    Phase 2 Primary Endpoint CR/CRh* within 12 weeks of treatment with blinatumomab

  3. Incidence of treatment-emergent and treatment-related adverse events within the Expansion Cohort [ Time Frame: 30 (± 3) days after the last dose of IP ]
    Incidence of treatment-emergent and treatment-related adverse events reviewed at 30 (± 3) days after the last dose of blinatumomab.


Secondary Outcome Measures :
  1. Phase 1 the incidence and severity of adverse events [ Time Frame: within 12 weeks of blinatumomab treatment ]
    To determine the incidence and severity of adverse events as assessed by CTCAE v4.0

  2. Phase 1 the numer of subjects with complete remission [ Time Frame: Within 12 week of treatment with blinatumomab ]
    To determine the number of subjects with complete remission (CR/CR*h/CRi)

  3. Phase 1 time to hematological relapse [ Time Frame: up to 33 monts ]
    To determine time to hematological relapse (TTHR)

  4. Phase 1 overall survival (OS) [ Time Frame: up to 33 months ]
    Determine overall survival

  5. Phase 1 Relapse free survival (RFS) [ Time Frame: up to 33 months ]
    Determine Relapse free survival duration

  6. Phase 1 blinatumomab PK parameters [ Time Frame: within up to 30 weeks of treatment start ]
    To measure PK parameters (steady state concentrations and clearance of blinatumomab)

  7. Phase 1 serum cytokine concentrations [ Time Frame: within up to 30 weeks of treatment start ]
    To measure serum cytokine concentrations

  8. Phase 1 incidence of anti-blinatumomab antibody formation [ Time Frame: up to 34 weeks after treatment ]
    To determine incidence of anti-blinatumomab formation

  9. Phase 2 duration of response (TTHR) [ Time Frame: up to 33 months ]
    To measure Time to hematological relapse

  10. Phase 2 AlloHSCT after treatment with blinatumomab [ Time Frame: up to 33 months ]
    To determine the rate of Allogeneic HCST (alloHCST) treatment with blinatumomab

  11. Phase 2 the best overall response [ Time Frame: 12 weeks ]
    To determine the best overall response rate

  12. Phase 2 overall survival [ Time Frame: up to 33 months ]
    To determine the rate of overall survival (OS)

  13. Phase 2 rate of relapse free survival [ Time Frame: up to 33 months ]
    To determine the rate of relapse free survival (RFS)

  14. Phase 2 incidence and severity of advese events [ Time Frame: up to 33 months ]
    To determine incidence and severity of adverse events as measured by CTCAE v4.0

  15. Phase 2 the 100-day mortality after alloHSCT [ Time Frame: 100-days ]
    To determine the 100-day mortality rate after allogeneic hematopoietic stem cell transplant

  16. Phase 2 PK parameters [ Time Frame: up to 30 weeks ]
    To measure blinatumomab PK parameters (steady state concentration and clearance of blinatumomab)

  17. Phase 2 serum cytokine concentrations [ Time Frame: up to 30 weeks ]
    To measure serum cytokine concentrations

  18. Phase 2 anti-blinatumomab antibody formation [ Time Frame: up to 34 weeks after treatment start ]
    To determine incidence of anti-blinatumomab formation

  19. Phase 1 Duration of CR/CRh*/CRi [ Time Frame: up to 33 months ]
    To determine duration of complete remission

  20. Phase 2 Duration of CR/CRh*/CRi [ Time Frame: up to 33 months ]
    To determine duration of complete remission

  21. CR/CRh* within 12 weeks of treatment with blinatumomab in the Expansion Cohort [ Time Frame: Within 12 weeks of treatment with blinatumomab ]
    CR/CRh* within first 2 cycles of treatment with blinatumomab for adults and M1 remission within the first 2 cycles of treatment with blinatumomab in pediatric subjects.


Other Outcome Measures:
  1. Exploratory phase 1 rate of MRD response [ Time Frame: up to 33 months ]
    To determine MRD response

  2. Exploratory Phase 1 rate of Complete MRD response [ Time Frame: up to 33 months ]
    To determine rate of complete MRD response

  3. Exploratory phase 2 rate of complete MRD response [ Time Frame: up to 33 months ]
    To evaluate the rate of complete MRD response

  4. Exploratory phase 2 peripheral blood lymphocyte subsets [ Time Frame: up to 29 days after treatment start and week 34 (Safety followup visit) ]
    If counts have not recovered by Safety followup visit- lymphocyte subsets will be collected 6 months after Safety followup visit

  5. Exploratory phase 2 rate of neurological exam abnormalities and changes from baseling [ Time Frame: up to 33 months ]
    To evaluate the rate of neurological exam abnormalities and changes from baseline

  6. Exploratory phase 2 rate of MRD response [ Time Frame: up to 33 months ]
    To evaluate rate of MRD response

  7. Number of MRD Remission wihin the Expansion Cohort [ Time Frame: Within 12 weeks of starting blinatumomab ]
    MRD remission within 2 cycles of blinatumomab



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02412306


Contacts
Contact: Amgen Call Center 866-572-6436 medinfo@amgen.com

Locations
Japan
Research Site Recruiting
Nagoya-shi, Aichi, Japan, 460-0001
Research Site Recruiting
Nagoya-shi, Aichi, Japan, 466-8560
Research Site Recruiting
Fukuoka-shi, Fukuoka, Japan, 812-8582
Gunmaken Saiseikai Maebashi Hospital Recruiting
Maebashi-shi, Gunma, Japan, 371-0821
Principal Investigator: Toru Sakura         
Research Site Recruiting
Maebashi-shi, Gunma, Japan, 371-0821
Research Site Completed
Sapporo-shi, Hokkaido, Japan, 003-0006
Research Site Recruiting
Kobe-shi, Hyogo, Japan, 650-0017
Research Site Recruiting
Yokohama-shi, Kanagawa, Japan, 232-8555
Research Site Recruiting
Nagasaki-shi, Nagasaki, Japan, 852-8501
Research Site Completed
Niigata-shi, Niigata, Japan, 951-8566
Research Site Recruiting
Okayama-shi, Okayama, Japan, 700-8558
Research Site Completed
Osaka-shi, Osaka, Japan, 534-0021
Research Site Recruiting
Osaka-shi, Osaka, Japan, 545-8586
Research Site Completed
Saitama-shi, Saitama, Japan, 330-8777
Research Site Recruiting
Shimotsuke-shi, Tochigi, Japan, 329-0498
Research Site Recruiting
Chuo-ku, Tokyo, Japan, 104-0045
Research Site Completed
Setagaya-ku, Tokyo, Japan, 157-8535
Sponsors and Collaborators
Amgen
Amgen Astellas Biopharma K.K.
Investigators
Study Director: MD Amgen

Additional Information:
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02412306     History of Changes
Other Study ID Numbers: 20130265
First Posted: April 9, 2015    Key Record Dates
Last Update Posted: October 10, 2018
Last Verified: October 2018

Keywords provided by Amgen:
Amgen

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Blinatumomab
Antibodies, Bispecific
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs