E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with relapsed and/or refractory B-precursor Acute lymphoblastic leukaemia |
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E.1.1.1 | Medical condition in easily understood language |
Adult patients with Acute lymphoblastic leukaemia - a cancer of the blood and marrow - which did not completely respond to treatment or has relapsed after first responding to therapy |
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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 | 19.1 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
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 |
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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 |
evaluate the effect of blinatumomab on overall survival (OS) when compared to standard of care (SOC) chemotherapy |
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E.2.2 | Secondary objectives of the trial |
• evaluate hematological response induced by blinatumomab when compared to SOC chemotherapy
• evaluate event free survival induced by blinatumomab when compared to SOC chemotherapy
• evaluate minimal residual disease (MRD) remissions induced by blinatumomab when compared to SOC chemotherapy
• estimate the effect of blinatumomab on patient reported outcomes, global health status/quality of life (QoL) using the EORTC QLQ-C30
• evaluate the incidence of allogeneic hematopoietic stem cell transplantation (alloHSCT) and 100-day mortality following HSCT in blinatumomab treated subjects when compared to SOC chemotherapy
• evaluate the safety of blinatumomab when compared to SOC chemotherapy
Exploratory:
• evaluate blinatumomab exposure-response relationships for efficacy and safety
• assess presence of ALL symptoms as measured by Acute Lymphoblastic Leukemia Symptom Scale (ALLSS)
• assess the potential for mutations in the tumor DNA to predict resistance to blinatumomab treatment |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects with Philadelphia negative B-precursor ALL, with any of the following:
- refractory to primary induction therapy or refractory to salvage therapy,
- in untreated first relapse with first remission duration <12 months
- in untreated second or greater relapse
- or relapse at any time after allogeneic HSCT
2. Subject has received intensive combination chemotherapy for the treatment of ALL for initial treatment or subsequent salvage therapy.
3. Greater than 5% blasts in the bone marrow
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
5. Age ≥ 18 years at the time of informed consent
6. Subject has provided informed consent or subject’s legally acceptable representative has provided informed consent when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent. |
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E.4 | Principal exclusion criteria |
1. History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
− Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician
− Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
− Adequately treated cervical carcinoma in situ without evidence of disease
− Adequately treated breast ductal carcinoma in situ without evidence of disease
− Prostatic intraepithelial neoplasia without evidence of prostate cancer.
2. Diagnosis of Burkitt´s Leukemia according to WHO classification
3. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis with the exception of history of CNS leukemia that is controlled with intrathecal therapy
4. Active ALL in the CNS (confirmed by CSF analysis) or testes (no clinical sign thereof)
5. Isolated extramedullary disease
6. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
7. Autologous HSCT within 6 weeks before the start of protocol-specified therapy
8. Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy
9. Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
10. Any systemic therapy against GvHD within 2 weeks before start of protocol-specified therapy
11. Known exclusion criteria to investigator choice of SOC chemotherapy (as per product insert).
12. Cancer chemotherapy within 2 weeks before start of protocol-specified therapy (intrathecal chemotherapy and dexamethasone are allowed until start of protocol-specified therapy). In addition, any subject whose organ toxicity (excluding hematologic) from prior ALL treatment has not resolved to no more than CTCAE grade 1
13. Radiotherapy within 2 weeks before the start of protocol-specified therapy
14. Immunotherapy (e.g., rituximab) within 4 weeks before start of protocol-specified therapy
15. Subject received prior anti-CD19 therapy
4.2.16 Abnormal screening laboratory values as defined below:
− AST (SGOT) and/or ALT (SGPT) and/or ALP ≥ 5 x upper limit of normal (ULN)
− Total bilirubin (TBL) ≥ 1.5 x ULN (unless related to Gilbert´s or Meulengracht disease)
− Creatinine ≥ 1.5 ULN or Creatinine clearance < 60 ml/min (calculated)
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. Subject is pregnant or breast feeding, or might become pregnant within 24 hours after the last dose of protocol-specified therapy
19. Woman of childbearing potential and is not willing to use 2 highly effective methods of contraception while receiving protocol-specified therapy and for an additional 24 h after the last dose of protocol-specified therapy.
20. Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study(s). Thirty days is calculated from Day 1 of protocol-specified therapy.
21. Other investigational procedures while participating in this study are excluded (expect for participation in optional sub-studies to this protocol).
22. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.
23. Subject previously has randomized into this study or previous treatment with blinatumomab.
24. 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 and Investigator’s knowledge.
25. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessment when the 330th death is reported in the clinical trial database, 12 months after the last subject is randomized if only 300 to 329 deaths have been reported, or when the 300th death is reported if the study duration exceeds 12 months from the last subject randomized. |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints (in order of hierarchical testing)
1. CR within 12 weeks of treatment initiation
2. CR/CRh*/CRi within 12 weeks of treatment initiation
3. Event Free Survival (EFS)
Secondary Efficacy Endpoints
4. Duration of CR
5. Duration of CR/CRh*/CRi
6. MRD remission (defined as MRD level below 10-4 by PCR or flow cytometry) within 12 weeks of treatment initiation
7. Time to a 10 point decrease from baseline in global health status and QoL scale using EORTC QLQ-C30, or EFS event
8. AlloHSCT with or without blinatumomab treatment
Secondary Safety Endpoints
9. Incidence of adverse events
10. 100-day mortality after alloHSCT
11. Incidence of anti-blinatumomab antibody formation
12. Changes in select vital sign and laboratory parameters
Exploratory Endpoints
13. Blinatumomab steady state concentration (Css)
14. ALLSS score at measured time points
15. Investigation for mutations in the tumor DNA to predict resistance to blinatumomab treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1+2: after 12 weeks; samples are taken at the end of cycles 1 and 2
3: at the time of relapse, death or EOS
4+5+15: throughout the study; samples are taken at the end of each cycle, at the safety follow-up visit and every 3 months during long-term follow-up
6: within 12 weeks of treatment initiation
7+12+14: troughout treatment and at the safety follow-up visit
8+9: throughout the study
10: 100 days after alloHSCT
11: before first dose, after cycle 2 and at the safety follow-up visit
13: day 1 and 15 of cycle 1
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
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 |
Australia |
Austria |
Belgium |
Bulgaria |
Canada |
Czech Republic |
France |
Germany |
Greece |
Ireland |
Israel |
Italy |
Korea, Republic of |
Mexico |
Poland |
Russian Federation |
Spain |
Taiwan |
Turkey |
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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End of study (primary completion): when the last subject is assessed or receives an intervention for the purposes of final collection of data for the primary endpoint.
End of study (end of trial): when the last subject is assessed or receives an intervention for evaluation in the study; including survival assessments.
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 24 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |