Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL) (BLAST)
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Confirmatory 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)|
- Percentage of Participants With a Minimal Residual Disease (MRD) Response Within the First Treatment Cycle [ Time Frame: During the first cycle (6 weeks) ]
At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory.
Complete MRD response is defined as no polymerase chain reaction (PCR) amplification of individual rearrangements of immunoglobulin (Ig)- or T-cell receptor (TCR)-genes detected after completion of the first cycle.
- Hematological Relapse-free Survival (RFS) [ Time Frame: 18 months ]
Hematological RFS was measured from first dose of blinatumomab until the first assessment of documented relapse (either hematological or extramedullary), secondary leukemia, or death due to any cause. Participants without a documented relapse, or death due to any cause were censored at the time of their last hematological assessment. Participants who received chemotherapy for relapsed or persistent MRD or for any other reason after treatment with blinatumomab, or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse, or death occurred were censored at the start of chemotherapy or HSCT, respectively.
Hematological relapse was defined as unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological, microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia (whichever occurred first).
The 18-month Kaplan-Meier estimate of hematological RFS is reported.
- Overall Survival [ Time Frame: Until the data cut-off date of 05 August 2015; median time on study was 18.3 months. ]Overall survival was measured from the first treatment with blinatumomab until death due to any cause. Participants who did not die were censored at their last contact date.
- 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant [ Time Frame: 100 days after HSCT, as of the data cut-off date of 05 August 2015 ]The mortality rate within 100 days after allogeneic HSCT was defined as the Kaplan-Meier estimate of the percentage of participants dying within 100 days after the day of the first allogeneic HSCT.
- Time to Hematological Relapse [ Time Frame: Until the data cut-off date of 05 August 2015; median time on study was 18.3 months. ]Time to hematological relapse was measured from the start of treatment with blinatumomab until hematological or extramedullary relapse. Participants who died or received HSCT or post-blinatumomab chemotherapy after treatment with blinatumomab were censored at their last hematological assessment prior to death or HSCT or post-blinatumomab chemotherapy (whichever occurred first).
- Duration of Complete MRD Response [ Time Frame: Until the data cut-off date of 05 August 2015; median time on study was 18.3 months. ]
The duration of MRD response was analyzed as the time from onset of MRD negativity until MRD or hematological relapse or date of last confirmation of negative MRD status. Participants who received chemotherapy or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse were censored at the start of chemotherapy or HSCT, respectively.
MRD relapse is defined as the reappearance of individual rearrangements of Ig- or TCR-genes ≥ lower limit of quantification (LLOQ) for at least 1 individual marker measured by an assay with a sensitivity of minimum 10^-4. Hematological relapse is defined as the unequivocal detection of > 5% leukemia cells in bone marrow as measured by cytological or microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia.
- Change in MRD Level From Baseline to End of Cycle 1 in Non-MRD Responders [ Time Frame: Baseline and end of cycle 1 (6 weeks) ]MRD level was measured by polymerase chain reaction (PCR) performed on bone marrow and assessed by the central laboratory. An MRD level of 10^-n corresponds to residual leukemia cells at a frequency of 1 per 10ⁿ bone marrow cells.
- Number of Participants With Adverse Events [ Time Frame: From the first dose of blinatumomab until 30 days after last dose. Adverse events are reported up to the data cut-off date of 05 August 2015; the median treatment duration was 55 days. ]
Adverse events (AEs) were evaluated for severity according to the the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, as follows:
Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death.
The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.
An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.
- Change From Baseline in EORTC-QLQ-C30 Scales [ Time Frame: Subjects are assessed at Screening Visit (Baseline), at day 29 of each treatment cycle, at Day 30 Safety Follow-Up Visit and during mandated Efficacy Follow-Up Visits occurring at month 3, 6, 9, 12, 18 and 24 after treatment start. ]
The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact).
For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms.
The maximum changes from baseline to cycles 1 through 4 and to the end of the core study are reported.
- Change From Baseline in EuroQoL 5-Dimension (EQ-5D) Scales [ Time Frame: Subjects are assessed at Screening Visit (Baseline), at day 29 of each treatment cycle, at Day 30 Safety Follow-Up Visit and during mandated Efficacy Follow-Up Visits occurring at month 3, 6, 9, 12, 18 and 24 after treatment start. ]The EQ-5D is a self-administered questionnaire which captures 3 basic types of information: a descriptive profile (health state index) and the overall health rating using a visual analog scale. The health state index measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression on scales from no problems (score = 1), some problems (score = 2), to extreme problems (score = 3). For each dimension the mean change from baseline was calculated at the end of each treatment cycle and at the end of study. The maximum observed change from baseline during cycles 1 to 4 and the change from baseline at the end of study are reported for each dimension.
- Resource Utilization [ Time Frame: 5 years ]
|Study Start Date:||November 2010|
|Estimated Study Completion Date:||January 2019|
|Primary Completion Date:||February 2014 (Final data collection date for primary outcome measure)|
Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate of 15 μg/m²/day over 28 days followed by an infusion-free period of 14 days for up to 4 cycles of treatment.
Continuous intravenous infusion
The detection of minimal residual disease (MRD) after induction therapy and/or consolidation therapy is an independent prognostic factor for poor outcome of adult ALL. No standard treatments are available for patients with MRD-positive B-precursor ALL. Blinatumomab (MT103) 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. The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab (MT103) is effective, safe and tolerable in the treatment of ALL patients with minimal residual disease.
Participants will receive up to four 4-week cycles of intravenous blinatumomab treatment followed by an infusion-free period of 14 days. A safety follow-up will be performed 30 days after the end of the last infusion and efficacy follow-ups will occur until 24 months after treatment start. Participants will be followed for up to 5 years after the start of treatment for survival.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01207388
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|Principal Investigator:||Ralf Bargou, MD||Medizinische Klinik und Poliklinik II, Würzburg|
|Principal Investigator:||Nicola Gökbuget, MD||Klinikum der Goethe Universität Frankfurt|