Clinical Study with the bispecific antibody Blinatumomab in pediatric and adolescent subjects with B-precursor Acute Lymphoblastic Leukemia (ALL) who did not respond to previous therapy or who relapsed after initial successful previous therapy

Phase 1

Conditions: Pediatric and Adolescent Subjects with Relapsed and/or Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
MedDRA version: 17.1Level: LLTClassification code 10000845Term: Acute lymphoblastic leukemiaSystem Organ Class: 100000004864
MedDRA version: 17.1Level: LLTClassification code 10063625Term: Acute lymphoblastic leukemia recurrentSystem Organ Class: 100000004864
MedDRA version: 17.1Level: LLTClassification code 10066109Term: Precursor B-lymphoblastic leukemia acuteSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-001700-21-FR

Lead Sponsor: Amgen Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 110

Inclusion Criteria

1. Morphologic and immunophenotypic evidence of CD19 positive B-precursor ALL (pro B-, pre B-, common ALL) with = 5% blasts in bone marrow (M2 and M3) at study enrollment
2. Age > 28 days and < 18 years at the time of informed consent/assent
3. 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:
o For patients in first relapse: failure to achieve a CR following a full standard reinduction chemotherapy regimen
o For patients who have not achieved a first remission: failure to achieve remission following a full standard induction regimen
• Subjects previously treated with blinatumomab may be eligible, if subject ended treatment for reason(s) other than disease progression or intolerability to blinatumomab
4. Subject’s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/ procedures being initiated
5. Subject does not qualify for, or cannot access other comparable or satisfactory alternative therapy for CD19 positive B-precursor ALL
6. Adequate liver function defined as:
• ALT (SGPT) < 5 x upper limit of normal (ULN) for age at least once during screening
Are the trial subjects under 18? yes
Number of subjects for this age range: 40
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Any active acute Graft-versus-Host Disease (GvHD) grade 2 to grade 4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
2. Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment (except for topical corticosteroids)
3. Active (overt) ALL in the CNS (confirmed by cerebrospinal fluid [CSF] analysis) or in testes
4. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis
- With the exception of CNS leukemia that is well controlled with intrathecal therapy
5. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
6. Cancer chemotherapy within 2 weeks prior to start of blinatumomab (except for tyrosine kinase inhibitors (TKI) and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids; intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab).
7. Chemotherapy related toxicities that haven’t resolved to = grade 2
8. Radiotherapy within 2 weeks prior to blinatumomab treatment
9. Immunotherapy (eg, rituximab) within 4 weeks prior to blinatumomab treatment
10. Currently receiving treatment in another investigational device or drug study, or less than 4 weeks since ending treatment on another investigational device or drug study(s). Other investigational procedures while participating in this study are excluded.
11. Subject has known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing
12. Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
13. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)
14. Subject is pregnant or breast feeding, or is planning to become pregnant within 3 months after the last dose of protocol-specified therapy
15. Adolescent female of childbearing potential and is not willing to use 2 highly effective forms of contraception while receiving blinatumomab and for an additional 3 months after the last dose of protocol-specified therapy
16. Male who has a female partner of childbearing potential and is not willing to use 2 highly effective forms of contraception while receiving blinatumomab and for an additional 3 months after the last dose of protocol-specified therapy
17. Male who has a pregnant partner, and is not willing to use a condom during sexual activity for 3 months after the last dose of protocol-specified therapy
18. Abnormal screening laboratory values as defined below:
• Serum creatinine = 1.5 x ULN for age
• Total bilirubin = 1.5 x ULN (unless related to Gilbert’s or Meulengracht disease)
19. Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject’s and Investigator’s knowledge
20. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To estimate the incidence of treatment-emergent and treatment-related adverse events during treatment with blinatumomab in pediatric and adolescent subjects with B-precursor acute lymphoblastic leukemia (ALL) in second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT (alloHSCT), or refractory to other treatments;Secondary Objective: To describe key efficacy outcomes, including <br>1. incidence of complete response (CR) within 2 cycles of blinatumomab<br>2. minimal residual disease (MRD) remission within 2 cycles of blinatumomab<br>3. relapse free survival (RFS)<br>4. overall survival (OS)<br>5. incidence of alloHSCT<br>6. 100-day mortality after alloHSCT;Primary end point(s): Incidence of treatment-emergent and treatment-related adverse events;Timepoint(s) of evaluation of this end point: Assessment throughout treatment period and 30 days after last dose (safety follow-up); primary analysis at the end of the second treatment cycle

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Incidence of CR within 2 cycles of blinatumomab<br>2. MRD remission within 2 cycles of blinatumomab<br>3. Relapse-free survival<br>4. Overall survival<br>5. Incidence of alloHSCT<br>6. 100-day mortality after alloHSCT;Timepoint(s) of evaluation of this end point: 1. + 2. Assessment at the end of the first and second treatment cycle<br>3.+4.+5. Assessment throughout entire study<br>6. Assessment 100 days after alloHSCT

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