Non-Hodgkin's Lymphoma
Conditions
Brief summary
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
Interventions
DRUGblinatumomab
Blinatumomab used as both continuous IV infusion and subcutaneous injection
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject or subject's legally acceptable representative has provided informed consent. * Age greater than or equal to 18 years old at the time of informed consent * Subjects must have a histologically determined B cell NHL subtype as defined in the bullets below. In addition, they must have disease that is primary refractory after initial therapy or have relapsed disease. * Follicular Lymphoma I, II, IIIA * Marginal zone lymphoma (extranodal, nodal or splenic). Subjects with gastric mucosa- * associated lymphoid tissue must have progressed after Helicobacter pylori therapy and * radiation. Subjects with splenic marginal zone lymphoma must have prior splenectomy. * Lymphoplasmocytic lymphoma * Mantle cell lymphoma (\[MCL\] with the exception of aggressive MCL, defined as Ki67 \> 30%, * or blastoid histology) * Small lymphocytic lymphoma • Subjects without standard therapy alternatives, or contraindicated for standard therapy by investigator, or subjects unwilling to receive standard therapy. Disease status must be 1 of the following: * Primary refractory (at least 1 prior line of therapy) * Relapsed within 1 year of first response * Responded to initial therapy for ≥ 1 year and relapsed after 2 or more lines of therapy, including an anti-CD20 monoclonal antibody * Measurable disease that has not been previously irradiated on positron emission tomography- computed tomography (PET-CT), or computed tomography (CT), of at least 1.5 cm within the last 21 days before the start of IP treatment. * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 * Life expectancy greater than or equal to 3 months as determined by treating physician. * Subjects must have adequate organ and marrow at screening as defined below: * peripheral neutrophils \>500/µL prior to start of treatment * hemoglobin ≥8 g/dL * Platelets greater than or equal to 50,000 mcL * aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) \< 5 × upper limit of normal (ULN * Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) * Creatinine clearance greater than or equal to 50 mL/min (Cockcroft-Gault)
Exclusion criteria
* Currently receiving treatment in another investigational device or drug study, or less than 30 days between ending treatment on another investigational device or drug study(ies) and start of IP treatment. Other investigational procedures while participating in this study are excluded. * Known hypersensitivity to immunoglobulins or any other component of the study drug * Subject likely to not be available to complete all protocol required study visits or procedures to the best of the subject and investigator's knowledge * 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 or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation procedures or completion. * Subjects who have had treatments with anti-cancer agents including rituximab or obinutuzumab and/or other monoclonal antibody or radioimmunotherapy within 6 weeks before the starting IP treatment. * Autologous stem cell transplantation within 12 weeks before the starting IP treatment or past history of allogeneic stem cell transplantation. * Subjects who have received anti-CD 19 targeted therapies, chimeric antigen receptor T-cell or other cellular therapies for the treatment of their lymphoma . * Subjects with suspected or known brain metastases should be excluded from this clinical study because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus. * History of or current relevant central nervous system pathology such as epilepsy, recurrent seizures, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome or psychosis. * History of malignancy other than their lymphoma with the exception of: * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician. * 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. * Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. * Uncontrolled intercurrent illness including, but not limited to, ongoing or uncontrolled systemic fungal bacteria, viral, or other infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * A female who is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 48 hours (Period 1) or 96 hours (Period 2), respectively, after the last dose of blinatumomab (Female subjects of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test). * A female of childbearing potential unwilling to use highly effective method of contraception during treatment and for an additional 48 hours (Period 1) or 96 hours (Period 2), respectively, after the last dose of blinatumomab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration | Day 1 to Day 7 of Week 4 | 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. |
| Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration | Day 1 to Day 7 of Week 4 | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Day 1 to end of study (approximately 17 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | 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) | 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) | 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. |
| Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | 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 | Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose) | Calculated as CL/F = Dose sc / AUCt-ss (at steady state). |
| Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration | Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose) | 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. |
| Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration | Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6 | 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). |
| Accumulation Ratio of Blinatumomab After SC Administration | 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) | Calculated as the ratio of AUCt (last SC dose; Week 4 Day 5) / AUC (first SC dose; Week 4 Day 1). |
| Bioavailability (F) of SC Blinatumomab | Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose) | Calculated as F = (CL \* AUCt-ss) / Dose sc. |
| Maximum Tolerated Dose (MTD) of SC Blinatumomab | Day 1 to Day 7 of Week 4 | The MTD was defined as the highest dose level at which \</= 1 of 6 participants experienced a DLT. |
| Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration | Predose at the re-start of cIV infusion (Week 5 Day 1) | — |
| Overall Response Rate (ORR) After SC Administration | Day 1 to end of study (approximately 17 weeks) | 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. |
| Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration | Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose) | Calculated as t1/2,z = ln(2) / λz. |
| Systemic Clearance (CL) of Blinatumomab After cIV Administration | Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6 | 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. |
| Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | 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) | — |
Countries
Australia, France, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Of the 39 participants screened, 35 participants were enrolled at 10 centers in the United States, Europe and Australia between 18 September 2017 and 02 September 2021.
Pre-assignment details
The participants underwent an initial continuous intravenous (cIV) blinatumomab run-in period (Weeks 1 to 3). The participants received subcutaneous (SC) administration at Week 4 followed by a treatment free period of 2 to 3 days. After the SC administration period, participants received cIV treatment to complete 6 weeks of therapy (Weeks 5 to 6).
Participants by arm
| Arm | Count |
|---|---|
| Blinatumomab Cohort 1 The participants underwent an initial cIV blinatumomab run-in period (Weeks 1 to 3) in which doses increased each week as follows: Week 1: 9 μq/day; Week 2: 28 μq/day; and Week 3: 112 μq/day. The run-in period was followed by a 12-hour treatment free period. The participants then received 112 μq SC administrations q12h for 5 days at Week 4 followed by a treatment free period of 2 to 3 days. After the SC administration period, the participants received 112 μq/day cIV blinatumomab during Weeks 5 and 6. | 7 |
| Blinatumomab Cohort 2 The participants underwent an initial cIV blinatumomab run-in period (Weeks 1 to 3) in which doses increased each week as follows: Week 1: 9 μq/day; Week 2: 28 μq/day; and Week 3: 112 μq/day. The run-in period was followed by a 12-hour treatment free period. The participants then received 225 μq SC administrations q12h for 5 days at Week 4 followed by a treatment free period of 2 to 3 days. After the SC administration period, the participants received 112 μq/day cIV blinatumomab during Weeks 5 and 6. | 8 |
| Blinatumomab Cohort 3 Blinatumomab Cohort 3 The participants underwent an initial cIV blinatumomab run-in period (Weeks 1 to 3) in which doses increased each week as follows: Week 1: 9 μq/day; Week 2: 28 μq/day; and Week 3: 112 μq/day. The run-in period was followed by a 12-hour treatment free period. The participants then received 450 μq SC administrations q24h for 5 days at Week 4 followed by a treatment free period of 2 to 3 days. After the SC administration period, the participants received 112 μq/day cIV blinatumomab during Weeks 5 and 6. | 8 |
| Blinatumomab Cohort 4 The participants underwent an initial cIV blinatumomab run-in period (Weeks 1 to 3) in which doses increased each week as follows: Week 1: 9 μq/day; Week 2: 28 μq/day; and Week 3: 112 μq/day. The run-in period was followed by a 12-hour treatment free period. The participants then received 675 μq SC administrations q24h for 5 days at Week 4 followed by a treatment free period of 2 to 3 days. After the SC administration period, the participants received 112 μq/day cIV blinatumomab during Weeks 5 and 6. | 6 |
| Blinatumomab Cohort 5 The participants underwent an initial cIV blinatumomab run-in period (Weeks 1 to 3) in which doses increased each week as follows: Week 1: 9 μq/day; Week 2: 28 μq/day; and Week 3: 112 μq/day. The run-in period was followed by a 12-hour treatment free period. The participants then received 675 μq SC administrations q48h for 5 days at Week 4 followed by a treatment free period of 2 to 3 days. After the SC administration period, the participants received 112 μq/day cIV blinatumomab during Weeks 5 and 6. | 6 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 2 | 0 | 1 |
| Overall Study | Disease progression | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Participant request | 0 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Blinatumomab Cohort 1 | Blinatumomab Cohort 2 | Blinatumomab Cohort 3 | Blinatumomab Cohort 4 | Blinatumomab Cohort 5 | Total |
|---|---|---|---|---|---|---|
| Age, Customized 18 - 64 years | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 5 Participants | 21 Participants |
| Age, Customized 65 - 74 years | 2 Participants | 2 Participants | 5 Participants | 3 Participants | 1 Participants | 13 Participants |
| Age, Customized 75 - 84 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized ≥ 85 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 7 Participants | 8 Participants | 6 Participants | 6 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black (or African American) | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 7 Participants | 8 Participants | 6 Participants | 6 Participants | 31 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 5 Participants | 3 Participants | 1 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 3 Participants | 5 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 35 | 0 / 34 | 0 / 33 | 0 / 6 | 0 / 7 | 0 / 7 | 0 / 6 | 0 / 5 | 1 / 28 | 0 / 31 | 2 / 35 | 2 / 35 |
| other Total, other adverse events | 23 / 35 | 22 / 34 | 23 / 33 | 2 / 6 | 6 / 7 | 6 / 7 | 6 / 6 | 4 / 5 | 19 / 28 | 24 / 31 | 34 / 35 | 35 / 35 |
| serious Total, serious adverse events | 5 / 35 | 5 / 34 | 8 / 33 | 0 / 6 | 1 / 7 | 1 / 7 | 0 / 6 | 0 / 5 | 10 / 28 | 2 / 31 | 18 / 35 | 19 / 35 |
Outcome results
Primary
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
Population: DLT analysis set included DLT-evaluable participants who received all (q48h dosing), \>/= 4/5 (q24h dosing) or \>/= 8/9 (q12h dosing) doses of SC blinatumomab or experienced a DLT during the DLT evaluable period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Blinatumomab SC Cohort 1 | Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 2 | Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration | 1 Participants |
| Blinatumomab SC Cohort 3 | Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration | 1 Participants |
| Blinatumomab SC Cohort 4 | Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 5 | Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration | 0 Participants |
Primary
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
Population: DLT analysis set included DLT-evaluable participants who received all (q48h dosing), \>/= 4/5 (q24h dosing) or \>/= 8/9 (q12h dosing) doses of SC blinatumomab or experienced a DLT during the DLT evaluable period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Blinatumomab SC Cohort 1 | Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 2 | Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration | 1 Participants |
| Blinatumomab SC Cohort 3 | Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration | 1 Participants |
| Blinatumomab SC Cohort 4 | Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 5 | Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration | 0 Participants |
Primary
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)
Population: Safety analysis set included participants that were enrolled and received at least 1 dose of blinatumomab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs | 2 Participants |
| Blinatumomab SC Cohort 1 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs CTCAE Grade ≥ 3 | 1 Participants |
| Blinatumomab SC Cohort 2 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs | 6 Participants |
| Blinatumomab SC Cohort 2 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs CTCAE Grade ≥ 3 | 1 Participants |
| Blinatumomab SC Cohort 3 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs CTCAE Grade ≥ 3 | 2 Participants |
| Blinatumomab SC Cohort 3 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs | 6 Participants |
| Blinatumomab SC Cohort 4 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs | 6 Participants |
| Blinatumomab SC Cohort 4 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs CTCAE Grade ≥ 3 | 1 Participants |
| Blinatumomab SC Cohort 5 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs | 4 Participants |
| Blinatumomab SC Cohort 5 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration | Any TEAEs CTCAE Grade ≥ 3 | 0 Participants |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Accumulation Ratio of Blinatumomab After SC Administration | 3.25 ratio | Geometric Coefficient of Variation 61 |
| Blinatumomab SC Cohort 2 | Accumulation Ratio of Blinatumomab After SC Administration | 4.14 ratio | Geometric Coefficient of Variation 35 |
| Blinatumomab SC Cohort 3 | Accumulation Ratio of Blinatumomab After SC Administration | 2.31 ratio | Geometric Coefficient of Variation 63 |
| Blinatumomab SC Cohort 4 | Accumulation Ratio of Blinatumomab After SC Administration | 1.71 ratio | Geometric Coefficient of Variation 109 |
| Blinatumomab SC Cohort 5 | Accumulation Ratio of Blinatumomab After SC Administration | 1.01 ratio | Geometric Coefficient of Variation 107 |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Apparent Clearance (CL/F) of Blinatumomab After SC Administration | 5.85 L/hr | Geometric Coefficient of Variation 21 |
| Blinatumomab SC Cohort 2 | Apparent Clearance (CL/F) of Blinatumomab After SC Administration | 5.55 L/hr | Geometric Coefficient of Variation 41 |
| Blinatumomab SC Cohort 3 | Apparent Clearance (CL/F) of Blinatumomab After SC Administration | 6.25 L/hr | Geometric Coefficient of Variation 92 |
| Blinatumomab SC Cohort 4 | Apparent Clearance (CL/F) of Blinatumomab After SC Administration | 7.43 L/hr | Geometric Coefficient of Variation 77 |
| Blinatumomab SC Cohort 5 | Apparent Clearance (CL/F) of Blinatumomab After SC Administration | 7.43 L/hr | Geometric Coefficient of Variation 236 |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing. At Week 4 Day 1, AUCt was only reported for SC dosing regimens in Cohorts 1 and 2 as PK sampling was taken only over the 12-hour period following dosing as pre-specified in protocol section 7.1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Blinatumomab SC Cohort 1 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 5 | 19100 hr•pg/mL | Geometric Coefficient of Variation 21 |
| Blinatumomab SC Cohort 1 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 1 | 6080 hr•pg/mL | Geometric Coefficient of Variation 80 |
| Blinatumomab SC Cohort 2 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 5 | 40500 hr•pg/mL | Geometric Coefficient of Variation 41 |
| Blinatumomab SC Cohort 2 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 1 | 9430 hr•pg/mL | Geometric Coefficient of Variation 40 |
| Blinatumomab SC Cohort 3 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 5 | 72000 hr•pg/mL | Geometric Coefficient of Variation 92 |
| Blinatumomab SC Cohort 4 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 5 | 90900 hr•pg/mL | Geometric Coefficient of Variation 77 |
| Blinatumomab SC Cohort 5 | Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt) | Week 4 Day 5 | 90800 hr•pg/mL | Geometric Coefficient of Variation 236 |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Bioavailability (F) of SC Blinatumomab | 32.1 percent bioavailability | Geometric Coefficient of Variation 38 |
| Blinatumomab SC Cohort 2 | Bioavailability (F) of SC Blinatumomab | 22.5 percent bioavailability | Geometric Coefficient of Variation 54 |
| Blinatumomab SC Cohort 3 | Bioavailability (F) of SC Blinatumomab | 33.8 percent bioavailability | Geometric Coefficient of Variation 215 |
| Blinatumomab SC Cohort 4 | Bioavailability (F) of SC Blinatumomab | 24.6 percent bioavailability | Geometric Coefficient of Variation 53 |
| Blinatumomab SC Cohort 5 | Bioavailability (F) of SC Blinatumomab | 30.2 percent bioavailability | Geometric Coefficient of Variation 180 |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing. Descriptive statistics for first SC dose of 675 μg on Week 4 Day 1 were determined using parameter estimates from participants in Cohorts 4 and 5 as pre-specified in SAP section 10.7.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Blinatumomab SC Cohort 1 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 5 | 2070 pg/mL | Geometric Coefficient of Variation 15 |
| Blinatumomab SC Cohort 1 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 1 | 877 pg/mL | Geometric Coefficient of Variation 88 |
| Blinatumomab SC Cohort 2 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 5 | 4340 pg/mL | Geometric Coefficient of Variation 36 |
| Blinatumomab SC Cohort 2 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 1 | 1810 pg/mL | Geometric Coefficient of Variation 93 |
| Blinatumomab SC Cohort 3 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 1 | 2650 pg/mL | Geometric Coefficient of Variation 98 |
| Blinatumomab SC Cohort 3 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 5 | 4290 pg/mL | Geometric Coefficient of Variation 98 |
| Blinatumomab SC Cohort 4 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 1 | 4260 pg/mL | Geometric Coefficient of Variation 103 |
| Blinatumomab SC Cohort 5 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 5 | 5690 pg/mL | Geometric Coefficient of Variation 71 |
| Blinatumomab SC Cohort 5 | Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration | Week 4 Day 5 | 4340 pg/mL | Geometric Coefficient of Variation 304 |
Secondary
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
Population: DLT analysis set included all DLT-evaluable participants who received all doses (q48h), at least 4/5 doses (q24h) or at least 8/9 doses (q12h) of SC blinatumomab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab SC Cohort 1 | Maximum Tolerated Dose (MTD) of SC Blinatumomab | NA μq |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing. At Week 4 Day 1, Cmin was only reported for SC dosing regimens in Cohorts 1 and 2 as PK sampling was taken only over the 12-hour period following dosing as pre-specified in protocol section 7.1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Blinatumomab SC Cohort 1 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 5 | 1290 pg/mL | Geometric Coefficient of Variation 30 |
| Blinatumomab SC Cohort 1 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 1 | 651 pg/mL | Geometric Coefficient of Variation 93 |
| Blinatumomab SC Cohort 2 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 5 | 2550 pg/mL | Geometric Coefficient of Variation 41 |
| Blinatumomab SC Cohort 2 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 1 | 1470 pg/mL | Geometric Coefficient of Variation 101 |
| Blinatumomab SC Cohort 3 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 5 | 1950 pg/mL | Geometric Coefficient of Variation 94 |
| Blinatumomab SC Cohort 4 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 5 | 2130 pg/mL | Geometric Coefficient of Variation 104 |
| Blinatumomab SC Cohort 5 | Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration | Week 4 Day 5 | 147 pg/mL | Geometric Coefficient of Variation 66 |
Secondary
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)
Population: Safety analysis set included participants that were enrolled and received at least 1 dose of blinatumomab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Blinatumomab SC Cohort 1 | Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 2 | Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 3 | Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 4 | Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration | 0 Participants |
| Blinatumomab SC Cohort 5 | Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration | 0 Participants |
Secondary
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)
Population: Full analysis set included participants that were enrolled and received at least 1 dose of blinatumomab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab SC Cohort 1 | Overall Response Rate (ORR) After SC Administration | 66.7 percentage of participants |
| Blinatumomab SC Cohort 2 | Overall Response Rate (ORR) After SC Administration | 71.4 percentage of participants |
| Blinatumomab SC Cohort 3 | Overall Response Rate (ORR) After SC Administration | 71.4 percentage of participants |
| Blinatumomab SC Cohort 4 | Overall Response Rate (ORR) After SC Administration | 83.3 percentage of participants |
| Blinatumomab SC Cohort 5 | Overall Response Rate (ORR) After SC Administration | 40.0 percentage of participants |
Secondary
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
Population: Pharmacokinetic (PK) analyses set included all participants who received any cIV blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing. Css data during cIV dosing was reported per dose level as pre-specified in statistical analysis plan (SAP) section 10.7.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration | 238 pg/mL | Geometric Coefficient of Variation 137 |
| Blinatumomab SC Cohort 2 | Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration | 672 pg/mL | Geometric Coefficient of Variation 94 |
| Blinatumomab SC Cohort 3 | Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration | 2780 pg/mL | Geometric Coefficient of Variation 87 |
| Blinatumomab SC Cohort 4 | Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration | 2700 pg/mL | Geometric Coefficient of Variation 85 |
Secondary
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
Population: PK analyses set included all participants who received any cIV blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing. CL data prior to SC dosing was dose-normalized and reported together as pre-specified in SAP section 10.7.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Systemic Clearance (CL) of Blinatumomab After cIV Administration | 1.67 L/hr | Geometric Coefficient of Variation 111 |
| Blinatumomab SC Cohort 2 | Systemic Clearance (CL) of Blinatumomab After cIV Administration | 1.73 L/hr | Geometric Coefficient of Variation 85 |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration | 9.87 hours | Geometric Coefficient of Variation 12 |
| Blinatumomab SC Cohort 2 | Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration | 10.7 hours | Geometric Coefficient of Variation 22 |
| Blinatumomab SC Cohort 3 | Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration | 7.30 hours | Geometric Coefficient of Variation 21 |
| Blinatumomab SC Cohort 4 | Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration | 11.7 hours | Geometric Coefficient of Variation 30 |
| Blinatumomab SC Cohort 5 | Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration | 9.20 hours | Geometric Coefficient of Variation 83 |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing. Descriptive statistics for first SC dose of 675 μg on Week 4 Day 1 were determined using parameter estimates from participants in Cohorts 4 and 5 as pre-specified in SAP section 10.7.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 1 | 5.0 hours |
| Blinatumomab SC Cohort 1 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 5 | 2.8 hours |
| Blinatumomab SC Cohort 2 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 5 | 4.0 hours |
| Blinatumomab SC Cohort 2 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 1 | 7.9 hours |
| Blinatumomab SC Cohort 3 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 1 | 12 hours |
| Blinatumomab SC Cohort 3 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 5 | 7.6 hours |
| Blinatumomab SC Cohort 4 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 1 | 12 hours |
| Blinatumomab SC Cohort 5 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 5 | 8.0 hours |
| Blinatumomab SC Cohort 5 | Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration | Week 4 Day 5 | 9.5 hours |
Secondary
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)
Population: PK analyses set included all participants who received any SC blinatumomab and had at least one PK sample. These participants were evaluated for PK unless significant protocol deviations affected the data analysis or if key dosing, dosing interruption, or sampling information was missing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab SC Cohort 1 | Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration | 83.4 liters | Geometric Coefficient of Variation 19 |
| Blinatumomab SC Cohort 2 | Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration | 100 liters | Geometric Coefficient of Variation 93 |
| Blinatumomab SC Cohort 3 | Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration | 58.6 liters | Geometric Coefficient of Variation 115 |
| Blinatumomab SC Cohort 4 | Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration | 120 liters | Geometric Coefficient of Variation 97 |
| Blinatumomab SC Cohort 5 | Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration | 133 liters | Geometric Coefficient of Variation 9623 |