E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pediatric and adolescent patients with B-precursor ALL in second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments. |
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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 | 18.0 |
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 |
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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 |
The first part (Phase I) is to determine the recommended Phase II dose of blinatumomab. The Phase II Part is to assess the efficacy of blinatumomab. |
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E.2.2 | Secondary objectives of the trial |
Phase I Part:
- To assess the safety of different dose levels of blinatumomab in different age groups
- To assess pharmacokinetics of different dose levels of blinatumomab in different age groups
- To assess the anti-leukemia activity of blinatumomab
- To assess the development of anti-drug antibodies (ADA) to blinatumomab
- To describe changes in pharmacodynamic markers following treatment with blinatumomab at differing dose levels
Phase II Part:
- To assess the safety of blinatumomab
- To assess the development of ADA to blinatumomab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Morphologic and immunophenotypic evidence of B-precursor ALL (pro B-, pre B-, common ALL) with > 25% blasts in bone marrow (M3) at study enrolment.
2. Age < 18 years at enrollment [only children age 2-17 will be enrolled prior to the identification of the recommended Phase II dose].
3. Relapsed/refractory disease:
• Second or later bone marrow relapse,
• Any marrow relapse after allogeneic HSCT, or
• Refractory to other treatments:
- Patients in first relapse must have failed to achieve a CR following full standard reinduction chemotherapy regimen of at least 4 weeks duration
- Patients who have not achieved a first remission must have failed a full standard induction regimen
4. Karnofsky performance status ≥ 50% for patients ≥ 16 years and Lansky Performance Status (LPS) of ≥ 50% for patients < 16 years
5. Organ function requirements: Patients must have
a. Creatinine clearance ≥ 70 mL/min/1.73 m2 or a normal serum creatinine based on age/gender prior to day 1
b. Adequate liver function defined as:
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age OR direct bilirubin ≤ 1.5 mg/DL prior to day 1
ALT (SGPT) ≤ 135 IU/L at least once during screening
6. Patient and/or his/her legal representative have reviewed the patient information/informed consent form and have had their questions answered and have given written informed consent
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E.4 | Principal exclusion criteria |
1. Active acute or extensive chronic GvHD
2. Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment
3. Evidence for current CNS involvement by ALL (CNS 2, CNS 3) or testicular involvement by ALL [patients with CNS relapse at the time of M3 relapse are not eligible for the Phase I part but are eligible for the Phase II part of the study, if CNS is successfully treated prior to enrollment]. Two successive CSF evaluations at least one week apart following completion of CNS therapy that are CNS1 are required
4. History of relevant CNS pathology or current relevant CNS pathology (seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder)
5. History of autoimmune disease with potential CNS involvement or current autoimmune disease
6. Any HSCT within 3 months prior to blinatumomab treatment
7. Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (except for intrathecal chemotherapy and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids)
8. Chemotherapy related toxicities that haven’t resolved to ≤ Grade 2
9. Radiotherapy within 2 weeks prior to blinatumomab treatment
10. Immunotherapy (e.g. rituximab, alemtuzumab) within 6 weeks prior to blinatumomab treatment
11. Any investigational product within 4 weeks prior to study entry
12. Previous treatment with blinatumomab.
13. Known hypersensitivity to immune globulins or to any other component of the study drug formulation
14. Presence of HAMA reactivity (in patients with prior exposure to murine antibodies or proteins)
15. Active malignancy other than ALL
16. 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.
17. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)
18. Pregnant or nursing female adolescent patients
19. Post-menarchal female adolescent patients or male adolescent patients not willing to use an effective form of contraception during treatment phase of the study and at least 3 months thereafter
20. Placed into an institution due to juridical or regulatory ruling |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I Part:
- Maximal tolerable dose defined by ≤ 1 of 6 patients experiencing dose limiting toxicity (DLT) or maximal administered dose (MAD)
Phase II Part:
- Rate of complete remission (CR) within the first 2 cycles |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I Part:
In the Phase I part of the study, safety will be assessed by the occurence of dose limiting toxicity (DLT) within the first 28 days of treatment (cycle 1).
Phase II Part:
In the Phase II part of the study, efficacy will be assessed by measurement of complete blood count (CBC) and evaluation of a bone marrow will be assessed at D15 of the first cycle and at the end of the infusion period (D29, can be delayed until Day 42) of every cycle. |
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E.5.2 | Secondary end point(s) |
Phase I Part:
1. Overall incidence and severity of adverse events
2. Quantification and characterization of pharmacokinetic parameters over time in selected patients
3. Rate of complete remission (CR) within first 2 cycles
4. Time to hematological relapse
5. CR duration
6. Overall survival (OS)
7. Relapse free survival
8. Proportion of patients who develop ADA at any time
9. Quantification and characterization of cytokine serum concentrations
Phase II Part:
1. Overall incidence and severity of adverse events
2. Proportion of patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with blinatumomab
3. Time to hematological relapse
4. CR duration
5. Overall survival (OS)
6. Relapse free survival
7. Proportion of patients who develop ADA at any time
Exploratory Endpoints (Phase I + II)
1. Rate of MRD response
2. Rate of complete MRD response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I Part:
1. Continously
2. D1, 3, 8, 15, 22, 29 (cycle 1 + 2)
3.-7. Efficacy will be assessed by measurement of complete blood count (CBC) and evaluation of a bone marrow aspiration at D15 of the first cycle and at the end of the infusion period (D29, can be delayed until Day 42) of each cycle.
8. End of every cycle
9. D1, 2, 3
Phase II Part:
1.-2. Continously
3.-6. as for 3.-7. Phase I Part
7. End of every cycle
Exploratory Endpoints (Phase I + II)
as for 3.-7. Phase I Part |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Canada |
France |
Germany |
Italy |
Netherlands |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of the trial is defined as the last protocol mandated evaluation for the last patient in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |