Primary Objective: • To evaluate the safety and tolerability of subcutaneous (SC) blinatumomab dose administrations Secondary Objectives: * To determine pharmacokinetics (PK) with continuous intravenous (cIV) and SC administrations * To estimate the maximum tolerated dose (MTD) tested for blinatumomab administered subcutaneously * To determine the incidence of anti-blinatumomab antibody formation following SC administration * To evaluate efficacy response following treatment with SC blinatumomab administration Exploratory Objective: * To determine the pharmacodynamics (PD) time profiles for B-and T-lymphocytes as well as cytokine profiles during SC administration * To evaluate efficacy response following treatment with SC blinatumomab administration using Lugano criteria if positron emission tomography-computed tomography (PET/CT) is used for evaluation
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
35
Blinatumomab used as both continuous IV infusion and subcutaneous injection
City of Hope National Medical Center
Duarte, California, United States
Rush University Medical Center
Chicago, Illinois, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
Concord Repatriation General Hospital
Concord, New South Wales, Australia
Epworth Healthcare
East Melbourne, Victoria, Australia
St Vincents Hospital Melbourne
Fitzroy, Victoria, Australia
Hopital Henri Mondor
Créteil Cedex, France
Hopital Saint Louis
Paris, France
Universitaetsklinikum Carl Gustav Carus
Dresden, Germany
Universitätsklinikum Frankfurt/Main
Frankfurt am Main, Germany
...and 7 more locations
Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration
The occurrence of any of the following toxicities during the DLT evaluation period was considered a DLT, if judged by the investigator to be related to the administration of blinatumomab: * Death * Any toxicity, regardless of grade, that lead to a participant's removal from the study by the investigator and/or sponsor * Persistent Common Terminology Criteria for Adverse Events (CTCAE) grade \>/= 2 non-hematologic adverse events (AEs) that were deemed intolerable by the participant or the treating physician and that did not respond to appropriate medical management within 5 days and lead to treatment discontinuation * Recurrent grade 2 seizures * All grade 3 and 4 AEs and laboratory abnormalities, which occurred during the SC administration portion of the treatment period with exceptions noted in protocol section 6.2.1.2.3.
Time frame: Day 1 to Day 7 of Week 4
Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration
All toxicities were graded using the CTCAE version 4.0: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal.
Time frame: Day 1 to Day 7 of Week 4
Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration
An AE was defined as any untoward medical occurrence in a clinical study participant. The AE did not necessarily have a causal relationship with study treatment. The definition of AEs included worsening of a pre-existing medical condition. TEAEs included AEs starting on or after first dose of investigational product and up to the end of study date. All AEs were graded using the CTCAE version 4.0: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal.
Time frame: Day 1 to end of study (approximately 17 weeks)
Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration
Summarized as the observed concentrations collected after 5 half-lives after the start of the IV infusion of each dose (i.e., 9, 28 and 112 μg/day).
Time frame: Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
Systemic Clearance (CL) of Blinatumomab After cIV Administration
Calculated as CL=R0/Css; where R0 is the infusion rate (μg/hr) and Css is the average Css. Both R0 and Css were dose-normalized to 112 μg/day for this calculation.
Time frame: Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration
Time frame: Week 4 Day 1 (pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose) and Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration
Time frame: Week 4 Day 1 (pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose) and Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt)
Estimated using the linear trapezoidal method; where t is a dosing interval. AUC over the dosing interval, t where t is 12 hours for Cohorts 1 and 2, 24 hours for Cohorts 3 and 4, and 48 hours for Cohort 5.
Time frame: Week 4 Day 1 (pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose) and Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration
Time frame: Week 4 Day 1 (pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose) and Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Apparent Clearance (CL/F) of Blinatumomab After SC Administration
Calculated as CL/F = Dose sc / AUCt-ss (at steady state).
Time frame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration
Calculated as Vz/F=CL/F / λz, where λz was the first-order rate constant estimated via linear regression of the terminal log-linear decay phase as determined from the noncompartmental analysis.
Time frame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration
Calculated as t1/2,z = ln(2) / λz.
Time frame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Accumulation Ratio of Blinatumomab After SC Administration
Calculated as the ratio of AUCt (last SC dose; Week 4 Day 5) / AUC (first SC dose; Week 4 Day 1).
Time frame: Week 4 Day 1 (pre-dose and 1, 2, 4, 6, 8 and 12 hours post-dose) and Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Bioavailability (F) of SC Blinatumomab
Calculated as F = (CL \* AUCt-ss) / Dose sc.
Time frame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Maximum Tolerated Dose (MTD) of SC Blinatumomab
The MTD was defined as the highest dose level at which \</= 1 of 6 participants experienced a DLT.
Time frame: Day 1 to Day 7 of Week 4
Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration
Time frame: Predose at the re-start of cIV infusion (Week 5 Day 1)
Overall Response Rate (ORR) After SC Administration
Percentage of participants achieving ORR (complete response \[CR\] + partial response \[PR\]) was determined by best overall response using Cheson criteria: * CR: disappearance of all evidence of disease. * PR: regression of measurable disease and no new sites. The 95% confidence interval (CI) was calculated using Clopper-Pearson exact CI. Participants were considered as non-responders if there was no response assessment available.
Time frame: Day 1 to end of study (approximately 17 weeks)
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