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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02961881
Registration number
NCT02961881
Ethics application status
Date submitted
6/09/2016
Date registered
11/11/2016
Date last updated
2/02/2024
Titles & IDs
Public title
A Phase 1b Open-Label Study Investigating the Safety and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the Treatment of Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma
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Scientific title
A Phase 1b Open-Label Study Investigating the Safety and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the Treatment of Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma
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Secondary ID [1]
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2016-002034-76
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Secondary ID [2]
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20140286
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin's Lymphoma
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Condition category
Condition code
Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - blinatumomab
Experimental: blinatumomab -
Treatment: Drugs: blinatumomab
Blinatumomab used as both continuous IV infusion and subcutaneous injection
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration
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Assessment method [1]
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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.
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Timepoint [1]
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Day 1 to Day 7 of Week 4
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Primary outcome [2]
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Number of Participants With DLTs CTCAE Grade = 3 After SC Administration
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Assessment method [2]
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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.
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Timepoint [2]
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Day 1 to Day 7 of Week 4
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Primary outcome [3]
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Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration
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Assessment method [3]
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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.
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Timepoint [3]
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Day 1 to end of study (approximately 17 weeks)
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Secondary outcome [1]
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Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration
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Assessment method [1]
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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).
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Timepoint [1]
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Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
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Secondary outcome [2]
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Systemic Clearance (CL) of Blinatumomab After cIV Administration
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Assessment method [2]
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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.
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Timepoint [2]
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Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
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Secondary outcome [3]
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Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration
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Assessment method [3]
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Timepoint [3]
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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)
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Secondary outcome [4]
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Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration
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Assessment method [4]
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Timepoint [4]
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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)
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Secondary outcome [5]
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Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt)
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Assessment method [5]
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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.
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Timepoint [5]
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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)
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Secondary outcome [6]
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Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration
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Assessment method [6]
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Timepoint [6]
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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)
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Secondary outcome [7]
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Apparent Clearance (CL/F) of Blinatumomab After SC Administration
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Assessment method [7]
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Calculated as CL/F = Dose sc / AUCt-ss (at steady state).
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Timepoint [7]
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Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
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Secondary outcome [8]
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Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration
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Assessment method [8]
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Calculated as Vz/F=CL/F / ?z, where ?z was the first-order rate constant estimated via linear regression of the terminal log-linear decay phase as determined from the noncompartmental analysis.
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Timepoint [8]
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Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
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Secondary outcome [9]
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Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration
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Assessment method [9]
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Calculated as t1/2,z = ln(2) / ?z.
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Timepoint [9]
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Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
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Secondary outcome [10]
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Accumulation Ratio of Blinatumomab After SC Administration
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Assessment method [10]
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Calculated as the ratio of AUCt (last SC dose; Week 4 Day 5) / AUC (first SC dose; Week 4 Day 1).
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Timepoint [10]
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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)
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Secondary outcome [11]
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Bioavailability (F) of SC Blinatumomab
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Assessment method [11]
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Calculated as F = (CL * AUCt-ss) / Dose sc.
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Timepoint [11]
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Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
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Secondary outcome [12]
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Maximum Tolerated Dose (MTD) of SC Blinatumomab
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Assessment method [12]
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The MTD was defined as the highest dose level at which </= 1 of 6 participants experienced a DLT.
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Timepoint [12]
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Day 1 to Day 7 of Week 4
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Secondary outcome [13]
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Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration
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Assessment method [13]
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Timepoint [13]
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Predose at the re-start of cIV infusion (Week 5 Day 1)
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Secondary outcome [14]
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Overall Response Rate (ORR) After SC Administration
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Assessment method [14]
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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.
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Timepoint [14]
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Day 1 to end of study (approximately 17 weeks)
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Eligibility
Key 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)
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
18/09/2017
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
2/09/2021
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Sample size
Target
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Accrual to date
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Final
35
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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Concord Repatriation General Hospital - Concord
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Recruitment hospital [2]
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Epworth Healthcare - East Melbourne
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Recruitment hospital [3]
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St Vincents Hospital Melbourne - Fitzroy
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Recruitment postcode(s) [1]
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2139 - Concord
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Recruitment postcode(s) [2]
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3002 - East Melbourne
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Recruitment postcode(s) [3]
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3065 - Fitzroy
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Illinois
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Country [3]
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United States of America
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State/province [3]
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New Jersey
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Country [4]
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France
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State/province [4]
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Créteil Cedex
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Country [5]
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France
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State/province [5]
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Paris Cedex 10
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Country [6]
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Germany
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State/province [6]
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Dresden
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Country [7]
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Germany
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State/province [7]
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Frankfurt am Main
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Country [8]
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Germany
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State/province [8]
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Ulm
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Country [9]
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Italy
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State/province [9]
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Bergamo
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Country [10]
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Italy
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State/province [10]
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Bologna
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Country [11]
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Italy
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State/province [11]
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Brescia
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Country [12]
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Italy
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State/province [12]
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Milano
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Country [13]
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Italy
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State/province [13]
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Rozzano MI
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Country [14]
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United Kingdom
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State/province [14]
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Leicester
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Amgen
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02961881
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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MD
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Address
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Amgen
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02961881
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