Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia

ALL, Recurrent, Adult Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03109093
• Other study ID #: GMALL-MOLACT1-BLINA
• Secondary ID: 2015-000733-76
• Status: Completed
• Phase: Phase 2
• Start date: March 15, 2017
• Est. completion date: March 10, 2023

Study information

• Verified date: March 2023
• Source: Goethe University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 83
• Est. completion date: March 10, 2023
• Est. primary completion date: August 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• ALL, Recurrent, Adult
• Leukemia
• Leukemia, Lymphoid
• Neoplasm, Residual
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Blinatumomab
Patients will receive blinatumomab at a dose of 28 µg/day as continuous intravenous infusion at constant flow rate for four weeks, followed by a two-week infusion free interval, defined as one treatment cycle. Up to of four cycles will be performed. In case of defined toxicities, the dose of blinatumomab may be reduced to 9µg/day. Patients with an MRD relapse may qualify to receive additional treatment with blinatumomab.

Locations

Country	Name	City	State
Germany	Charité - Campus Benjamin Franklin	Berlin
Germany	Uniklinik Dresden	Dresden
Germany	Uniklinik Düsseldorf	Düsseldorf
Germany	Univeristätsklinikum Essen	Essen
Germany	University Hospital of Frankfurt (Main)	Frankfurt (Main)	Hessen
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Universitätsmedizin Göttingen	Göttingen
Germany	Uniklinik Hamburg Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Uniklinik Heidelberg	Heidelberg
Germany	UKSH-Kiel	Kiel
Germany	Universitätsklinik Leipzig	Leipzig
Germany	Klinikum Mannheim	Mannheim
Germany	Universitätsklinkum Gießen und Marburg	Marburg
Germany	Klinikum Großhadern	München
Germany	Uniklinik Münster	Münster
Germany	Klinikum Nürnberg Nord	Nürnberg
Germany	Uniklinik Regensburg	Regensburg
Germany	Robert - Bosch - Krankenhaus	Stuttgart
Germany	Universitätsklinik Tübingen	Tübingen
Germany	Universitätsklinkum Ulm	Ulm
Germany	Uniklinik Würzburg	Würzburg

Sponsors (1)

Lead Sponsor	Collaborator
Goethe University

Country where clinical trial is conducted

Germany, 

References & Publications (1)

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Treatment deviation1	Incidence of dose reductions	until end of treatment (up to 22 weeks)
Other	Treatment deviation2	incidence of treatment interruptions	until end of treatment (up to 22 weeks)
Other	Treatment deviation3	days of interruption	until end of treatment (up to 22 weeks)
Other	Treatment deviation4	withdrawals	until end of treatment (up to 22 weeks)
Other	Treatment deviation5	total delivered dose	until end of treatment (up to 22 weeks)
Other	Treatment deviation6	total days of treatment	until end of treatment (up to 22 weeks)
Other	Treatment deviation7	realisation rate calculated as scheduled total dose/delivered total dose	until end of treatment (up to 22 weeks)
Other	Hospitalisation days	Number of hospitalisation days	until end of treatment (up to 22 weeks)
Primary	MRD response after one cycle	Proportion of patients who achieve complete MRD response after one cycle of treatment with blinatumomab in patients with and without prior SCT	after one cycle of treatment (up to 43 days)
Secondary	Continuous complete remission	Probability of continuous complete remission (remission duration) at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	18 months following initiation of blinatumomab
Secondary	Hematological relapse-free survival	Probability of hematological relapse-free survival rate at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	18 months following initiation of blinatumomab
Secondary	Overall survival	Probability of overall survival at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	18 months following initiation of blinatumomab
Secondary	Relapse localisations	Frequency of different relapse localisations in proportion to total hematological relapses (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	In Case of Relapse, continuously until End of Follow-Up (up to 18 Months)
Secondary	Biological evaluation of hematological and extramedullary relapse	Biological evaluation of hematological and extramedullary relapses including CD19 expression (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	In Case of Relapse, continuously until End of Follow-Up (up to 18 Months)
Secondary	Serious Adverse Event (SAE) incidence	Overall incidence and severity of adverse events in patients with and without prior SCT (CTCAE 4.0) (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	continuously until End of Safety-Follow-Up (up to 26 weeks)
Secondary	MRD response after two cycles	Proportion of patients who achieve MRD response after one or two cycles of treatment with Blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	after two cycles of treatment (up to 85 days)
Secondary	complete MRD response after two cycles	Proportion of patients who achieve complete MRD response after two cycles of treatment with blinatumomab in patients with and without prior SCT (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	after two cycles of treatment (up to 85 days)
Secondary	duration of MRD response	Probability of continuous MRD response and complete MRD response and duration of MRD response at 18 months following initiation of blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	18 months following initiation of blinatumomab
Secondary	Time to MRD response	Time to MRD response measured by time-point of first achievement (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	MRD determination after each cycle of treatment (up to 24 weeks)
Secondary	GvHD	Evaluation of GvHD as part of AE documentation and according to Glucksberg Criteria, grade and localisation. (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	until End of Safety-Follow-Up (up to 26 weeks)
Secondary	treatment related mortality after subsequent SCT	Evaluation of overall survival, remission duration, relapse-free survival and treatment related mortality (at day 100 and later) in patients with SCT in complete remission after blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	after subsequent SCT (at day 100 and later)
Secondary	treatment related mortality	Evaluation of overall survival, remission duration, relapse-free survival and treatment related mortality in patients without SCT in complete remission after blinatumomab (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	continuously until End of Follow-Up (up to 18 Months)
Secondary	Quality of Life	Measurement of Quality of Life with EORTC instruments (EORTC QLQ C30 and EQ-5D) at different time-points during treatment (Separate analysis of all outcome parameters in patients with MRD above 10-4, 10-4-10-3 and patients with MRD below 10-4 or non-quantifiable MRD)	until End of Follow-Up (up to 18 Months)