Clinical trial NCT02961881: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Hodgkin's Lymphoma
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2016-11-11
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Dose Limiting-Toxicities (DLTs) After SC Administration
timeFrame: Day 1 to Day 7 of Week 4
measure: Number of Participants With DLTs CTCAE Grade ≥ 3 After SC Administration
timeFrame: Day 1 to Day 7 of Week 4
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) After SC Administration
timeFrame: Day 1 to end of study (approximately 17 weeks)
Secondary outcomes:
measure: Steady State Serum Concentration (Css) of Blinatumomab After cIV Administration
timeFrame: Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
measure: Systemic Clearance (CL) of Blinatumomab After cIV Administration
timeFrame: Once at any timepoint during Day 2 of Weeks 1, 2, 3, 5 and 6
measure: Maximum Observed Concentration (Cmax) of Blinatumomab After SC Administration
timeFrame: 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)
measure: Time at Which Cmax (Tmax) Occurred of Blinatumomab After SC Administration
timeFrame: 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)
measure: Area Under the Concentration-time Curve (AUC) of Blinatumomab After SC Administration for a Dosing Interval t (AUCt)
timeFrame: 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)
measure: Minimum Observed Concentration (Cmin) of Blinatumomab After SC Administration
timeFrame: 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)
measure: Apparent Clearance (CL/F) of Blinatumomab After SC Administration
timeFrame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
measure: Volume of Distribution Based on Terminal Phase (Vz/F) of Blinatumomab After SC Administration
timeFrame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
measure: Terminal Half-life (t1/2,z) of Blinatumomab After SC Administration
timeFrame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
measure: Accumulation Ratio of Blinatumomab After SC Administration
timeFrame: 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)
measure: Bioavailability (F) of SC Blinatumomab
timeFrame: Week 4 Day 5 (pre-dose and 1, 2, 4, 6, 8, 12, 24 and 48 hours post-dose)
measure: Maximum Tolerated Dose (MTD) of SC Blinatumomab
timeFrame: Day 1 to Day 7 of Week 4
measure: Number of Participants With Anti-blinatumomab Antibody Formation After SC Administration
timeFrame: Predose at the re-start of cIV infusion (Week 5 Day 1)
measure: Overall Response Rate (ORR) After SC Administration
timeFrame: Day 1 to end of study (approximately 17 weeks)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: East Melbourne
country: Australia
facility: Epworth Healthcare
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincents Hospital Melbourne
state: Victoria
city: CrÃ©teil Cedex
country: France
facility: Hopital Henri Mondor
city: Paris Cedex 10
country: France
facility: Hopital Saint Louis
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus
city: Frankfurt am Main
country: Germany
facility: UniversitÃ¤tsklinikum Frankfurt/Main
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Bergamo
country: Italy
facility: Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria di Bologna Policlinico S Orsola Malpighi
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Rozzano MI
country: Italy
facility: IRCCS Istituto Clinico Humanitas
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: