E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with relapsed / refractory B-precursor ALL |
|
E.1.1.1 | Medical condition in easily understood language |
Acute lymphoblastic leukemia- a cancer of the blood and marrow. |
|
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 | 19.0 |
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 |
|
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 evaluate efficacy of blinatumomab in patients with relapsed/refractory B-precursor ALL. |
|
E.2.2 | Secondary objectives of the trial |
- To evaluate safety of blinatumomab in patients with relapsed/refractory B-precursor ALL
- To evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab
- To evaluate CNS symptoms and explore potential predictive factors for CNS events associated with blinatumomab |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with Ph-negative B-precursor ALL, with any of the following:
- relapsed or refractory with first remission duration less than or equal to 12 months in first salvage or
- relapsed or refractory after first salvage therapy or
- relapsed or refractory within 12 months of allogeneic HSCT
2. 10% or more blasts in bone marrow
3. In case of clinical signs of additional extramedullary disease: measurable disease (at least one lesion ≥ 1.5 cm)
4. ECOG performance status ≤ 2
5. Age ≥ 18 years
6. Ability to understand and willingness to sign a written informed consent
7. Signed and dated written informed consent is available |
|
E.4 | Principal exclusion criteria |
1. Patients with Ph-positive ALL
2. Patients with Burkitt´s Leukemia according to WHO classification
3. History or presence of clinically relevant CNS pathology as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis
4. Active ALL in the CNS or testes
5. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
6. Autologous HSCT within six weeks prior to start of blinatumomab treatment
7. Allogeneic HSCT within three months prior to start of blinatumomab treatment
8. Any active acute GvHD, or active chronic GvHD Grade 2 – 4 (see Appendix 2 and Appendix 3)
9. Any systemic therapy against GvHD within two weeks prior to start of blinatumomab treatment
10. Cancer chemotherapy within two weeks prior to start of blinatumomab treatment (intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab treatment)
11. Radiotherapy within two weeks prior to start of blinatumomab treatment
12. Immunotherapy (e.g., rituximab) within four weeks prior to start of blinatumomab treatment
13. Any investigational anti-leukemic product within four weeks prior to start of blinatumomab treatment
14. Treatment with any other IMP after signature of informed consent
15. Eligibility for allogeneic HSCT at the time of enrollment (as defined by disease status, performance status and availability of donor)
16. Known hypersensitivity to immunoglobulins or to any other component of the IMP formulation
17. Abnormal laboratory values as defined below:
a. AST (SGOT) and/or ALT (SGPT) and/or AP ≥ 5 x ULN
b. Total bilirubin ≥ 1.5 x ULN (unless related to Gilbert´s or Meulengracht disease)
c. Creatinine ≥ 1.5 ULN or Creatinine clearance < 50 ml/min (calculated)
d. Hb ≤ 9 g/dl (transfusion allowed)
18. History of malignancy other than ALL within five years prior to start of blinatumomab treatment with the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix
19. Active uncontrolled infection, any other concurrent disease or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator
20. Infection with HIV or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis
C virus (anti-HCV positive)
21. Pregnant or nursing women
22. Women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least three months thereafter. Male patients not willing to ensure not to beget a child during participation in the study and at least three months thereafter
23. Previous treatment with blinatumomab |
|
E.5 End points |
E.5.1 | Primary end point(s) |
CR (Complete response/remission) + CRh* (Complete response/remission with partial recovery of peripheral blood counts) rate within two cycles of treatment with blinatumomab. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At screening and at the end of each treatment cycle a bone marrow aspiration/biopsy will be performed to evaluate the efficacy of blinatumomab.
Following the last treatment cycle, there will be efficacy follow-up visits at three, six, nine, 12, 18 and 24 months after treatment start for patients who did not undergo allogeneic HSCT |
|
E.5.2 | Secondary end point(s) |
1. Time to hematological relapse
2. Proportion of patients eligible for allogeneic HSCT who undergo the procedure after treatment with blinatumomab
3. CR rate within two cycles of treatment with blinatumomab
4. CRh* rate within two cycles of treatment with blinatumomab
5. PR rate within two cycles of treatment with blinatumomab
6. Relapse-free survival
7. Event-free survival
8. Overall survival
9. Overall incidence and severity of AEs
10. 100-day mortality after allogeneic HSCT
11. Pharmacokinetic parameters: steady state concentration of blinatumomab
12. Serum cytokine concentrations
Exploratory endpoints
1. Rate of MRD response within two cycles of treatment with blinatumomab
2. Rate of MRD complete response within two cycles of treatment with blinatumomab
3. Quantification and characterization of peripheral blood lymphocyte subsets
4. Neurological exam abnormalities and changes from baseline |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Assessment at the end of each treatment cycle (and optionally at day 15 of the first cycle) and during efficacy follow up (until 24 months after treatment start at most)
2. Until patient´s last follow up (until 3 years after treatment start at most)
3.-5. At the end of the first and second treatment cycle and optionally at day 15 of the first cycle
6.-8. Throughout entire study, until three years after treatment start at most
9. 100 days after HSCT, if applicable
10.-11. At baseline and during the first two treatment cycles
Exploratory endpoints
1.-2. At the end of each treatment cycle (and optionally at day 15 of the first cycle)
3. At baseline, during the first two treatment cycles, and during efficacy follow-up (2 years after treatment start at most)
4. Stage 4 of study |
|
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 | 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 | 25 |
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 |
France |
Germany |
Italy |
Spain |
United Kingdom |
United States |
|
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
|
The end of trial is defined as the time point of the last visit (including phone/mail follow-up with the patient´s physician in the follow-up period) of the last patient in the study. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |