E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric and Adolescent Subjects with Relapsed and/or Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) |
|
E.1.1.1 | Medical condition in easily understood language |
Acute Lymphoblastic Leukemia – a cancer of the blood and marrow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066109 |
E.1.2 | Term | Precursor B-lymphoblastic leukemia acute |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
|
E.2.2 | Secondary objectives of the trial |
To describe key efficacy outcomes, including
1. incidence of complete response (CR) within 2 cycles of blinatumomab
2. minimal residual disease (MRD) remission within 2 cycles of blinatumomab
3. relapse free survival (RFS)
4. overall survival (OS)
5. incidence of alloHSCT
6. 100-day mortality after alloHSCT |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
|
E.4 | Principal 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 opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of treatment-emergent and treatment-related adverse events |
|
E.5.1.1 | 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 |
|
E.5.2 | Secondary end point(s) |
1. Incidence of CR within 2 cycles of blinatumomab
2. MRD remission within 2 cycles of blinatumomab
3. Relapse-free survival
4. Overall survival
5. Incidence of alloHSCT
6. 100-day mortality after alloHSCT |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. + 2. Assessment at the end of the first and second treatment cycle
3.+4.+5. Assessment throughout entire study
6. Assessment 100 days after alloHSCT |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
France |
Germany |
Italy |
Switzerland |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
the time when the last subject is assessed in the long-term survival portion of the study |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |