Treatment of Older Patients With B-precursor ALL With Sequential Dose Reduced Chemotherapy and Blinatumomab

B-Precursor ALL Clinical Trial

— EWALL-BOLD  

Official title:

Phase II Trial for the Treatment of Older Patients With Newly Diagnosed CD19 Positive, Ph/BCR-ABL Negative B-precursor Acute Lymphoblastic Leukemia With Sequential Dose Reduced Chemotherapy and Blinatumomab (EWALL-BOLD)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03480438
• Other study ID #: EWALL-BOLD
• Status: Recruiting
• Phase: Phase 2
• Start date: June 1, 2018
• Est. completion date: January 1, 2024

Study information

• Verified date: March 2023
• Source: Goethe University
• Contact: Nicola Goekbuget, MD
• Phone: +49 (0)69 - 6301
• Email: goekbuget[@]em.uni-frankfurt
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial proposed here attempts to reduce induction chemotherapy to phase I of standard induction in patients with B-precursor ALL. Induction phase II will be replaced by blinatumomab. The initial treatment phase is followed by sequential chemotherapy and further blinatumomab cycles.

Description:

Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T-cell activation and a cytotoxic T-cell response against CD19 expressing cells. In Phase II-III clinical trials 43-69 % of the patients treated with blinatumomab in relapsed/refractory ALL with poor prognostic features, achieved a complete hematologic remission and around 80 % of these obtained a molecular remission as well. Blinatumomab thus has demonstrated significant antileukemic activity in relapsed/refractory adult ALL. The ultimate goal for optimised management of adult ALL is to integrate targeted compounds with known single-drug activity into first-line treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: January 1, 2024
• Est. primary completion date: September 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 56 Years to 74 Years

Eligibility

Inclusion Criteria:

1. Patients with newly diagnosed CD19 positive B-precursor ALL

2. Greater than 25 % blasts in bone marrow

3. Eastern Cooperative Oncology Group (ECOG) performance status <= 2

4. Charlson comorbidity score <= 2

5. Age > 55 and < 75 years at the time of informed consent

6. Renal and hepatic function as defined below:

• AST (SGOT), ALT(SGPT) and AP < 5x upper limit of normal (UNL) (unless related to leukemic liver infiltration by investigator assessment)
• Total bilirubin < 1.5x ULN (unless related to Gilbert's Meulengracht disease)
• Creatinine < 1.5x ULN
• Creatinine clearance >= 50 mL/min (e.g. calculated according Cockroft & Gault)

7. Negative pregnancy test in women of childbearing potential

8. Ability to understand and willingness to sign a written informed consent

9. For Germany: Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion Criteria:

1. Antileukemic pretreatment (GMALL prephase with dexamethasone and cyclophosphamide allowed)

2. 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 2 years before enrollment and felt to be at low risk for recurrence by the treating physician including
• 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

3. History or presence of clinically relevant (per investigator's assessment) 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

4. Active ALL in the CNS confirmed by CSF analysis) or testes (clinical diagnosis) or other extramedullary involvement; non-bulky lymph node (< 7.5 cm diameter) involvement will be accepted

5. Current autoimmune disease or history of autoimmune disease with potential CNS involvement

6. Known exclusion criteria to recommended chemotherapy

7. Known positivity of HIV, hepatitis B (HbsAG) or hepatitis C virus (anti-HCV)

8. Subject received prior anti-CD19 therapy

9. Live vaccination within 2 weeks before the start of study treatment

10. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation: Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing

11. 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

12. 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

13. 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 would pose a risk to subject safety of interfere with the study evaluation, procedures or completion

14. Woman of childbearing potential and is not willing to use a highly effective method of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment

15. Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving protocol-specified therapy and for at least an additional 3 months after the last dose of protocol-specified therapy.

Related Conditions & MeSH terms

• B-Precursor ALL

Intervention

Drug:
• Blinatumomab
Patients will receive standard of care chemotherapy before blinatumomab, between blinatumomab cycles and after blinatumomab.

Locations

Country	Name	City	State
Germany	Uniklinik RWTH Aachen	Aachen
Germany	Charité - Campus Benjamin Franklin	Berlin
Germany	Vivantes Klinikum Neukölln	Berlin
Germany	Städtisches Klinikum Braunschweig	Braunschweig
Germany	Klinikum Bremen Mitte	Bremen
Germany	Evangelisches Krankenhaus Essen-Werden	Essen
Germany	University Hospital of Frankfurt (Main)	Frankfurt (Main)	Hessen
Germany	Universitätsklinikum Halle	Halle (Saale)
Germany	Uniklinik Hamburg Eppendorf	Hamburg
Germany	Evangelisches Krankenhaus Hamm	Hamm
Germany	Städtisches Klinikum Karlsruhe	Karlsruhe
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Gemeinschaftsklinikum Mittelrhein	Koblenz
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Klinikum Großhadern	München
Germany	Klinikum rechts der Isar der TU München	München
Germany	Klinikum Oldenburg	Oldenburg
Germany	Universitätsklinik Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	Helios Klinikum Wuppertal	Wuppertal
Germany	Uniklinik Würzburg	Würzburg

Sponsors (1)

Lead Sponsor	Collaborator
Goethe University

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hospitalisation time	Number of hospitalisation days	until end of treatment (up to 39 weeks)
Other	Infusion pump systems	Use of infusion pump systems	until end of treatment (up to 39 weeks)
Other	Ambulatory care services	Use of ambulatory care services	until end of treatment (up to 39 weeks)
Other	Biologic markers	Measurement of biologic markers in bone marrow and peripheral blood throughout induction and consolidation therapy	continuously until end of consolidation therapy (up to 35 weeks)
Primary	Hematologic and MRD response after induction therapy	Proportion of patients achieving a complete hematologic remission and a complete molecular remission (MRD response or complete MRD response) after induction therapy defined as one cycle of chemotherapy and one cycle of blinatumomab	after induction therapy (up to 8 weeks)
Secondary	Overall Survival	Probability of overall survival at 1 year after start of therapy	1 year after start of therapy
Secondary	Adverse Events	Rate and grade of adverse events (AE) according to CTC-AE in induction phase I, blinatumomab induction and during blinatumomab cycle I, II and III	continuously until end-of-core-study (week 43)
Secondary	MRD response after induction and consolidation	Proportion of patients who achieve a MRD response or a complete MRD response after induction consolidation	after induction and consolidation (up to 35 weeks)
Secondary	Time to MRD relapse	Time to MRD relapse after prior achievement of MRD response or complete MRD response	continuously until end of maintenance therapy (up to 27 months)
Secondary	Continuous complete remission	Probability of continuous complete remission at 1 year	1 year after start of therapy
Secondary	Relapse free survival	Probability of relapse free survival at 1 year	1 year after start of therapy
Secondary	Event-free survival	Probability of event-free survival at 1 year	1 year after start of therapy
Secondary	Relapse localisation	Proportion of different relapse localisation in relation to total number of relapses	In case of relapse, continuously until end of maintenance therapy (up to 27 months)
Secondary	Quality of life	Quality of life measures (EORTC=European Organisation for Research and Treatment of Cancer standard scales) at different time-points during induction and consolidation; this is a multidimensional questionnaire with different scales per item such als functional scale, global health status and symptoms. Details are outlined in respective manuals (https://qol.eortc.org/manuals/)	until end of maintenance therapy (up to 27 months)
Secondary	Treatment deviation 1	Rate of treatment interruptions	until end of treatment (up to 39 weeks)
Secondary	Treatment deviation 2	Duration of treatment interruptions	until end of treatment (up to 39 weeks)
Secondary	Treatment deviation 3	Dose reductions	until end of treatment (up to 39 weeks)
Secondary	Treatment deviation 4	Mitigation strategies	until end of treatment (up to 39 weeks)
Secondary	Treatment deviation 5	Rate of withdrawals	until end of treatment (up to 39 weeks)

External Links

•   Trial register of the Kompetenznetz Leukaemie