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

Non-Hodgkin's Lymphoma Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02961881
• Other study ID #: 20140286
• Secondary ID: 2016-002034-76
• Status: Completed
• Phase: Phase 1
• Start date: September 18, 2017
• Est. completion date: September 2, 2021

Study information

• Verified date: May 2023
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: September 2, 2021
• Est. primary completion date: September 2, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin
• Non-Hodgkin's Lymphoma

Intervention

Drug:
• blinatumomab
Blinatumomab used as both continuous IV infusion and subcutaneous injection

Locations

Country	Name	City	State
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Epworth Healthcare	East Melbourne	Victoria
Australia	St Vincents Hospital Melbourne	Fitzroy	Victoria
France	Hopital Henri Mondor	Créteil Cedex
France	Hopital Saint Louis	Paris Cedex 10
Germany	Universitaetsklinikum Carl Gustav Carus	Dresden
Germany	Universitätsklinikum Frankfurt/Main	Frankfurt am Main
Germany	Universitatsklinikum Ulm	Ulm
Italy	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII	Bergamo
Italy	Azienda Ospedaliera Universitaria di Bologna Policlinico S Orsola Malpighi	Bologna
Italy	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia	Brescia
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	IRCCS Istituto Clinico Humanitas	Rozzano MI
United Kingdom	Leicester Royal Infirmary	Leicester
United States	Rush University Medical Center	Chicago	Illinois
United States	City of Hope National Medical Center	Duarte	California
United States	Hackensack University Medical Center	Hackensack	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Day 1 to Day 7 of Week 4
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.	Day 1 to Day 7 of Week 4
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.	Day 1 to end of study (approximately 17 weeks)
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).	Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
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.	Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
Secondary	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)
Secondary	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)
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.	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)
Secondary	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)
Secondary	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)
Secondary	Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration	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.	Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
Secondary	Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration	Calculated as t1/2,z = ln(2) / ?z.	Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
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).	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)
Secondary	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)
Secondary	Maximum Tolerated Dose (MTD) of SC Blinatumomab	The MTD was defined as the highest dose level at which	Day 1 to Day 7 of Week 4
Secondary	Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration		Predose at the re-start of cIV infusion (Week 5 Day 1)
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.	Day 1 to end of study (approximately 17 weeks)

External Links

•   AmgenTrials clinical trials website