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

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 Overview

• Status: Completed
• Conditions: Non-Hodgkin's Lymphoma
• Intervention / Treatment: Drug: blinatumomab

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Epworth Healthcare
    • Fitzroy, Victoria, Australia, 3065
      • St Vincents Hospital Melbourne
• France
  • Créteil Cedex, France, 94010
    • Hôpital Henri Mondor
  • Paris Cedex 10, France, 75475
    • Hôpital Saint louis
• Germany
  • Dresden, Germany, 01307
    • Universitaetsklinikum Carl Gustav Carus
  • Frankfurt am Main, Germany, 60590
    • Universitätsklinikum Frankfurt/Main
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Italy
  • Bergamo, Italy, 24127
    • Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Universitaria di Bologna Policlinico S Orsola Malpighi
  • Brescia, Italy, 25123
    • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
  • Milano, Italy, 20132
    • IRCCS Ospedale San Raffaele
  • Rozzano MI, Italy, 20089
    • Irccs Istituto Clinico Humanitas
• United Kingdom
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: blinatumomab	Drug: blinatumomab; Blinatumomab used as both continuous IV infusion and subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	Day 1 to end of study (approximately 17 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
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)
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)	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.	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		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).	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.	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.	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).	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.	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.	Day 1 to Day 7 of Week 4
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	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.	Day 1 to end of study (approximately 17 weeks)

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2017
• Primary Completion (Actual): September 2, 2021
• Study Completion (Actual): September 2, 2021

Study Registration Dates

• First Submitted: September 6, 2016
• First Submitted That Met QC Criteria: November 9, 2016
• First Posted (Estimated): November 11, 2016

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Antineoplastic Agents; Blinatumomab
• Other Study ID Numbers: 20140286; 2016-002034-76 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No