Clinical trial NCT03480438: Treatment of Older Patients With B-precursor ALL With Sequential Dose Reduced Chemotherapy and Blinatumomab
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: B-Precursor ALL
Lead sponsor: Goethe University
Sponsor class: OTHER
First posted: 2018-03-29
Enrollment: 52
Sex: ALL
Minimum age (years): 56
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Hematologic and MRD response after induction therapy
timeFrame: after induction therapy (up to 8 weeks)
Secondary outcomes:
measure: Overall Survival
timeFrame: 1 year after start of therapy
measure: Adverse Events
timeFrame: continuously until end-of-core-study (week 43)
measure: MRD response after induction and consolidation
timeFrame: after induction and consolidation (up to 35 weeks)
measure: Time to MRD relapse
timeFrame: continuously until end of maintenance therapy (up to 27 months)
measure: Continuous complete remission
timeFrame: 1 year after start of therapy
measure: Relapse free survival
timeFrame: 1 year after start of therapy
measure: Event-free survival
timeFrame: 1 year after start of therapy
measure: Relapse localisation
timeFrame: In case of relapse, continuously until end of maintenance therapy (up to 27 months)
measure: Quality of life
timeFrame: until end of maintenance therapy (up to 27 months)
measure: Treatment deviation 1
timeFrame: until end of treatment (up to 39 weeks)
measure: Treatment deviation 2
timeFrame: until end of treatment (up to 39 weeks)
measure: Treatment deviation 3
timeFrame: until end of treatment (up to 39 weeks)
measure: Treatment deviation 4
timeFrame: until end of treatment (up to 39 weeks)
measure: Treatment deviation 5
timeFrame: until end of treatment (up to 39 weeks)
Other outcomes:
measure: Hospitalisation time
timeFrame: until end of treatment (up to 39 weeks)
measure: Infusion pump systems
timeFrame: until end of treatment (up to 39 weeks)
measure: Ambulatory care services
timeFrame: until end of treatment (up to 39 weeks)
measure: Biologic markers
timeFrame: continuously until end of consolidation therapy (up to 35 weeks)
Locations:
city: Frankfurt (Main)
country: Germany
facility: University Hospital of Frankfurt (Main)
state: Hessen
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Berlin
country: Germany
facility: Charité - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig
city: Bremen
country: Germany
facility: Klinikum Bremen Mitte
city: Essen
country: Germany
facility: Evangelisches Krankenhaus Essen-Werden
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle
city: Hamburg
country: Germany
facility: Uniklinik Hamburg Eppendorf
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: München
country: Germany
facility: Klinikum Großhadern
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
city: Würzburg
country: Germany
facility: Uniklinik Würzburg
Study officials:
affiliation: Johann Wolfgang Goethe University Hospital
name: Nicola Goekbuget, MD
role: STUDY_DIRECTOR
References: