• Primary- To determine the maximum tolerated dose (MTD) of blinatumomab in combination with pembrolizumab in adult subjects with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL).• Secondary-To evaluate the safety, efficacy, and…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Kanker in de bloedcellen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of dose limiting toxicities (DLTs)
Secondary outcome
• Objective response (OR) (including CR and PR) by the Lugano Classification
(Cheson et al, 2014) and Revised Response Criteria (Cheson et al, 2007)during
the first 12 weeks since starting blinatumomab and during the treatment period
• Complete response (CR) by the Lugano Classification (Cheson et al, 2014) and
Revised Response Criteria (Cheson et al, 2007) during the first 12 weeks since
starting blinatumomab and during the treatment period
• Duration of response (DOR) for subjects with OR (ie, CR and partial remission
(PR) by the Lugano Classification (Cheson et al, 2014) during the first 12
weeks since starting blinatumomab)
• Progression free survival (PFS)
• Overall survival (OS)
• Blinatumomab PK parameters
• Pembrolizumab PK parameters
Background summary
The annual incidence of Non-Hodgkin Lymphoma (NHL) in Europe and the USA is
estimated to be 15 to 20 cases/100,000 (Fisher and Fisher, 2004). Diffuse Large
B-Cell Lymphoma is the most common lymphoid malignancy in adults, accounting
for 31% of all NHL in Western countries and 37% of all B-cell tumors worldwide
(NHL classification project, Blood 1997; Swerdlow et al, WHO classification
2016). The peak incidence of DLBCL is in the seventh decade (Martelli et al,
2013), with incidences increasing from 0.3/100.000/y (35-39 years) to
26.6/100,000/y (80-84 years; Morgan et al, 1997).
Blinatumomab (BLINCYTO®, AMG 103, formerly also known as MT103 or bscCD19xCD3)
is a member of a novel class of bispecific antibody constructs called BiTE®, or
bispecific T-cell engagers (Dreier et al, 2002; Schlereth et al, 2006).
Blinatumomab is a BiTE® antibody construct with dual binding specificities. T
cells are bound by its anti-CD3 moiety, whereas B lymphoblasts and other B
cells are bound by the anti-CD19 moiety. This unique feature of blinatumomab
allows it to transiently connect malignant cells with T cells, thereby inducing
T cell mediated killing of the bound malignant cell.
Blinatumomab specifically targets cells that express CD19, a marker solely
expressed by B cells, including B-precursor acute lymphoblastic leukemia (ALL)
cells, with an affinity of 1.6 x 10-9 M. Blinatumomab recruits and activates T
cells via a lower affinity interaction with CD3 (8.7 x 10-8 M). These activated
T cells then induce a half-maximal target cell lysis ranging in vitro between
10 to 100 pg/mL showing blinatumomab to be an extremely potent molecule (Dreier
et al, 2002).
As of July 2017, blinatumomab (BLINCYTO) is indicated for the treatment of
relapsed or refractory B-cell precursor ALL in the United States. It is
indicated in multiple countries outside of the United States for Philadelphia
chromosome-negative relapsed or refractory B-cell precursor ALL (eg, European
Union [EU], Mexico, Canada, Norway, Iceland, Australia, and South Korea).
Additionally, confirmation of clinical benefit is a condition of approval in
multiple countries (eg, European Medicines Agency [EMA]).
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal
antibody (mAb) with high specificity of binding to the programmed cell death 1
(PD-1) receptor, thus inhibiting its interaction with programmed cell death
ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on
preclinical in vitro data, pembrolizumab has high affinity and potent receptor
blocking activity for PD-1.
Pembrolizumab has an acceptable preclinical safety profile and is in clinical
development as an intravenous (IV) immunotherapy for advance malignancies.
KeytrudaTM (pembrolizumab) is indicated for the treatment of patients across a
number of indications.
Study objective
• Primary
- To determine the maximum tolerated dose (MTD) of blinatumomab in combination
with pembrolizumab in adult subjects with relapsed or refractory (r/r) diffuse
large B-cell lymphoma (DLBCL).
• Secondary
-To evaluate the safety, efficacy, and pharmacokinetics (PK) of blinatumomab in
combination with pembrolizumab in adult subjects with r/r DLBCL.
• Exploratory
- To evaluate blood and tissue biomarkers.
- To evaluate minimal residual disease (MRD) response by next generation
sequencing (NGS).
Study design
This is an open label, multicenter, phase 1b study testing the combination of
blinatumomab with
pembrolizumab in r/r DLBCL.
The study will consist of 2 portions:
• Part 1 (n = 6 - 30) will test the safety of up to 3 different blinatumomab
target dose levels in combination with pembrolizumab in a rolling
6 design. A Dose Level Review Team (DLRT) will review the safety data to
evaluate possible drug effects and DLTs. Subjects who are not on the dose
ultimately selected for part 2 will remain on their initial dose throughout the
study.
• Part 2 (n = 40) will consist of an expansion cohort to assess PK, safety, and
preliminary efficacy data at the chosen target dose. The part 2 dose will be
determined by the totality of the clinical data from part 1 as determined by
the DLRT.
The study design includes:
• A 21-day screening period
• A standard (core) treatment period of blinatumomab (first cycle) of 8 weeks
• A second (consolidation) cycle of blinatumomab of 28 days after a 28-day (± 3
days)
• blinatumomab treatment free period, that can be administered to subjects with
stable
• disease (SD), PR, or CR.
• Pembrolizumab treatment until disease progression or up to 35 cycles in the
absence of
• disease progression:
• *to begin on study day 15 for subjects in cohort Ia
OR
• *to begin on study day 19 for subjects in cohort IIa and IIIa
• A safety follow-up visit after 30 days (+ 7 days) of last dose of each
protocol specified
therapy.
Follow-up for survival and collection of subsequent anticancer therapies will
occur every 12 weeks (± 28 days) following blinatumomab safety follow-up visit
until approximately 24 months from the last dose of pembrolizumab. For complete
details regarding design and escalation rules, please refer to Section 3.
Intervention
Please refer to section study design
Study burden and risks
See E9 and E9a
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
This study seeks to enroll adult subjects with histologically confirmed Diffuse
Large B Cell Lymphoma that is either:
-refractory after at least one regimen of systemic chemotherapy and/or targeted
therapy, and refractory is defined as progressive or stable disease as the best
response to the most recent systemic chemotherapy regimen or disease
progression or relapse within 12 months after autologous stem cell
transplantation; when using PET for assessment, for subjects with refractory
disease and who have received radiotherapy, PET positivity should be
demonstrated no less than 6 weeks after the last dose of radiotherapy (Crump et
al, 2017; Neelapu et al, 2017; Cheson et al, 2007), or
-in first or later relapse if have received at least 2 systemic regimens since
time of diagnosis, or
-relapsed post autologous or allogeneic HSCT with adequate organ function after
proximity to transplantation time exclusions as specified in Exclusion Criteria
208 and 209.
For a full list of eligibility criteria, please refer to Section 4.1 and
Section 4.2
Exclusion criteria
Subjects will be excluded if they have Richter's transformation (DLBCL arising
in the setting of
prior chronic lymphocytic leukemia) or Primary Mediastinal B cell Lymphoma
(PMBCL) or have
history or presence of clinically relevant central nervous system (CNS)
pathology such as
epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson*s
disease, cerebellar disease, organic brain syndrome, or psychosis or has
evidence of active, non-infectious
pneumonitis, or has a history of interstitial lung disease.
For a full list of eligibility criteria, please refer to Section 4.1 and
Section 4.2
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002191-27-NL |
| ClinicalTrials.gov | NCT03340766 |
| CCMO | NL67477.078.18 |