Clinical trial NCT03109093: Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia
Official title: A Multicenter, Single-arm Study to Assess the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (Blast Successor Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: ALL, Recurrent, Adult
Keywords: ALL
acute lymphoblastic leukemia
MRD positive
minimal residual disease
blinatumomab
Lead sponsor: Goethe University
Sponsor class: OTHER
First posted: 2017-04-12
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is designed to confirm the efficacy, safety, and tolerability of blinatumomab in patients with MRD of B- precursor ALL in complete hematological remission including patients with relapse after SCT. The study aims to expand experience generated in previous trials in patients with MRD positive ALL with a focus on additional specific questions.

Detailed description: Transfer of patients to alloHSCT after one cycle or after a subsequent cycle is considered as per protocol discontinuation and as premature treatment discontinuation.

In case of hematological or extramedullary relapse, the study treatment will be permanently discontinued.

There will be a safety follow-up visit at 30 days after end of the last infusion. There will be efficacy follow-up until 18 months after treatment start. In patients scheduled for SCT the 30-day safety-visit may be performed at the latest time point possible before initiation of subsequent treatment.

Eligibility criteria: Inclusion Criteria:

1. Patients with CD19 positive B-precursor ALL in complete hematological remission defined as less than 5% blasts in bone marrow after at least three intense chemotherapy blocks (e.g., GMALL induction I-II/consolidation I).
2. Presence of minimal residual disease (MRD) after an interval of at least 8 days from last systemic chemo-therapy

   * at a level of ≥10-4 - \<10-3 (molecular failure or molecular relapse) in an assay with a minimum sensitivity of 10-4 documented after an interval of at least 2 weeks from last systemic chemotherapy OR
   * at levels below 10-4 documented after an interval of at least 2 weeks from last systemic chemotherapy:

     * Positive \<10-4, non quantifiable (MolNE1) OR
     * Positive \<10-4 (MolNE2) OR
   * Presence of minimal residual disease (MRD), non quantifiable (MolNE3).
3. For evaluation of MRD patients must have at least one molecular marker based on individual rearrangements of immunoglobulin, TCR-genes or other suitable genes evaluated by the reference laboratory of the trial
4. Bone marrow function as defined below:

   * ANC (Neutrophils) \>= 1,000/µL
   * Platelets \>= 50,000/µL (transfusion permitted)
   * HB level \>= 9g/dl (transfusion permitted)
5. Renal and hepatic function as defined below:

   * AST (GOT), ALT (GPT), and AP \< 5 x upper limit of normal (ULN)
   * Total bilirubin \< 1.5 x ULN (unless related to Gilbert's Meulengracht disease)
   * Creatinine \< 1.5x ULN
   * Creatinine clearance \>= 60 mL/min (e.g. calculated according Cockroft\&Gault)
6. Negative HIV test, negative hepatitis B (HbsAg) and hepatitis C virus (anti-HCV) test
7. Negative pregnancy test in women of childbearing potential
8. ECOG Performance Status 0 or 1
9. Age \>=18 years
10. Ability to understand and willingness to sign a written informed consent
11. Signed and dated written informed consent is available
12. Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion Criteria:

1. Ph/BCR-ABL positive ALL
2. Presence of circulating blasts or current extramedullary involvement by ALL
3. History or presence of clinically relevant CNS pathology (e.g. seizure, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome or psychosis)
4. Current detection of ALL blast cells in cerebro-spinal fluid
5. History of or active relevant autoimmune disease
6. Systemic cancer chemotherapy within 2 weeks prior to study treatment (except for intrathecal prophylaxis)
7. Radiotherapy within 4 weeks prior to study treatment
8. Live vaccination within 2 weeks before the start of study treatment
9. Autologous hematopoietic stem cell transplantation (SCT) within six weeks prior to study treatment
10. Allogeneic SCT within 12 weeks before the start of study treatment
11. Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
12. Any systemic therapy against GvHD within 2 weeks before start of study treatment
13. Therapy with monoclonal antibodies (rituximab, alemtuzumab) within 4 weeks prior to study treatment
14. Treatment with any investigational product within four weeks prior to study treatment
15. Previous treatment with blinatumomab or other anti-CD19-therapy
16. Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
17. History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified therapy with the exception of:

    * 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
18. Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator
19. Nursing women
20. Woman of childbearing potential and is not willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment.
21. Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment

Primary outcomes:
measure: MRD response after one cycle
timeFrame: after one cycle of treatment (up to 43 days)
Secondary outcomes:
measure: Continuous complete remission
timeFrame: 18 months following initiation of blinatumomab
measure: Hematological relapse-free survival
timeFrame: 18 months following initiation of blinatumomab
measure: Overall survival
timeFrame: 18 months following initiation of blinatumomab
measure: Relapse localisations
timeFrame: In Case of Relapse, continuously until End of Follow-Up (up to 18 Months)
measure: Biological evaluation of hematological and extramedullary relapse
timeFrame: In Case of Relapse, continuously until End of Follow-Up (up to 18 Months)
measure: Serious Adverse Event (SAE) incidence
timeFrame: continuously until End of Safety-Follow-Up (up to 26 weeks)
measure: MRD response after two cycles
timeFrame: after two cycles of treatment (up to 85 days)
measure: complete MRD response after two cycles
timeFrame: after two cycles of treatment (up to 85 days)
measure: duration of MRD response
timeFrame: 18 months following initiation of blinatumomab
measure: Time to MRD response
timeFrame: MRD determination after each cycle of treatment (up to 24 weeks)
measure: GvHD
timeFrame: until End of Safety-Follow-Up (up to 26 weeks)
measure: treatment related mortality after subsequent SCT
timeFrame: after subsequent SCT (at day 100 and later)
measure: treatment related mortality
timeFrame: continuously until End of Follow-Up (up to 18 Months)
measure: Quality of Life
timeFrame: until End of Follow-Up (up to 18 Months)
Other outcomes:
measure: Treatment deviation1
timeFrame: until end of treatment (up to 22 weeks)
measure: Treatment deviation2
timeFrame: until end of treatment (up to 22 weeks)
measure: Treatment deviation3
timeFrame: until end of treatment (up to 22 weeks)
measure: Treatment deviation4
timeFrame: until end of treatment (up to 22 weeks)
measure: Treatment deviation5
timeFrame: until end of treatment (up to 22 weeks)
measure: Treatment deviation6
timeFrame: until end of treatment (up to 22 weeks)
measure: Treatment deviation7
timeFrame: until end of treatment (up to 22 weeks)
measure: Hospitalisation days
timeFrame: until end of treatment (up to 22 weeks)
Locations:
city: Frankfurt (Main)
country: Germany
facility: University Hospital of Frankfurt (Main)
state: Hessen
city: Berlin
country: Germany
facility: Charité - Campus Benjamin Franklin
city: Dresden
country: Germany
facility: Uniklinik Dresden
city: Düsseldorf
country: Germany
facility: Uniklinik Düsseldorf
city: Essen
country: Germany
facility: Univeristätsklinikum Essen
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Hamburg
country: Germany
facility: Uniklinik Hamburg Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Uniklinik Heidelberg
city: Kiel
country: Germany
facility: UKSH-Kiel
city: Leipzig
country: Germany
facility: Universitätsklinik Leipzig
city: Mannheim
country: Germany
facility: Klinikum Mannheim
city: Marburg
country: Germany
facility: Universitätsklinkum Gießen und Marburg
city: München
country: Germany
facility: Klinikum Großhadern
city: Münster
country: Germany
facility: Uniklinik Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg Nord
city: Regensburg
country: Germany
facility: Uniklinik Regensburg
city: Stuttgart
country: Germany
facility: Robert - Bosch - Krankenhaus
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen
city: Ulm
country: Germany
facility: Universitätsklinkum Ulm
city: Würzburg
country: Germany
facility: Uniklinik Würzburg
Study officials:
affiliation: GMALL-Study-Group
name: Nicola Goekbuget, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gökbuget N, et al . Interim Results of a Multicenter, Single-Arm Study to Assess Blinatumomab in Adult Patients (pts) with Minimal Residual Disease (MRD) of B-Precursor (BCP) Acute Lymphoblastic Leukemia (GMALL-MOLACT1-BLINA). Blood (2020) 136 (Supplement 1): 39-40.