Primary Objective:• To evaluate event-free survival (EFS) after blinatumomab when compared to standard ofcare (SOC) chemotherapySecondary Objective(s):• To evaluate the effect of blinatumomab on overall survival (OS) when compared to SOCchemotherapy…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
• EFS
Secondary outcome
Secondary Endpoints:
• OS
• MRD response, defined as MRD level < 10-4 at the end of treatment with
investigational
product(s)
• Incidence of adverse events (both serious and non-serious), treatment-related
adverse
events, adverse events of interest, clinically significant changes in
laboratory values
• Survival status at 100 days following alloHSCT
• Incidence of anti-blinatumomab antibody formation (blinatumomab arm only)
• population pharmacokinetic (PK) analysis
Background summary
Blinatumomab is a bispecific, single-chain antibody construct designed to link
CD19 expressing B cells, and T cells together, causing T cell activation and a
cytotoxic T cell response against the CD19 expressing cells. In vitro data
indicate that CD19+ lymphoma and leukemia cell lines are extremely sensitive to
blinatumomab-mediated cytotoxicity.
Study objective
Primary Objective:
• To evaluate event-free survival (EFS) after blinatumomab when compared to
standard of
care (SOC) chemotherapy
Secondary Objective(s):
• To evaluate the effect of blinatumomab on overall survival (OS) when compared
to SOC
chemotherapy
• To evaluate reduction in minimal residual disease (MRD) after blinatumomab
when
compared to SOC chemotherapy
• To evaluate the safety of blinatumomab when compared to SOC chemotherapy
• To evaluate the safety of allogeneic hematopoietic stem cell transplantation
(alloHSCT)
after blinatumomab when compared to alloHSCT after SOC chemotherapy
Study design
After induction therapy and 2 cycles of high-risk consolidation 1 and 2 (HC1
and HC2) chemotherapy, subjects will be randomized in a 1:1 ratio to receive a
third consolidation course consisting of either blinatumomab (Arm 1A) or
standard high-risk consolidation 3 (HC3) chemotherapy (Arm 2A). Most subjects
who are in or achieve cytomorphological CR2 (M1 marrow) after completing
consolidation therapy will undergo alloHSCT. Following alloHSCT, subjects will
be followed for disease and survival status for a maximum of 36 months.
Intervention
Amgen Investigational Product Dosage and Administration:
Blinatumomab is administered as a continuous intravenous infusion (CIVI). One
cycle of blinatumomab treatment includes 4 weeks of CIVI of blinatumomab.
AlloHSCT can be conducted any time after completion of the blinatumomab
infusion. If in case of adaptation 3 cycles are
administered, one cycle is defined by a 4- week CIVI of blinatumomab and a
2-week treatment-free interval. Subjects randomized to the blinatumomab arm
will be dosed at 15 µg/m2/day.
Non-Amgen Investigational Product Dosage and Administration:
HC3 is the standard intensive consolidation chemotherapy course based on
modifications to the ALL (Associazone Italiana Ematologica Oncologia
Pediatrica-Berlin-Franklin-Munster) AIEOP-BFM HR2 course. HC3 will be
considered non-Amgen investigational product.
HC1 is the standard intensive consolidation chemotherapy course based on
modifications to the ALL AIEOP-BFM HR1 course.
HC2 is the standard intensive consolidation chemotherapy course based on
modifications to the ALL AIEOP-BFM HR3 course. In case of study design
adaptation, HC1 and HC2 will also be considered non-Amgen investigational
product.
Study burden and risks
Survival for first relapse of B-precursor acute lymphoblastic leukemia (B-ALL)
is suboptimal. Blinatumomab is a promising novel agent for the treatment of
B-lineagelymphoid malignancies. In a Phase 2 trial of adult B-ALL, patients
with MRD persistence or relapse after induction and consolidation therapy
received blinatumomab as a 4-week CIVI at a dose of 15 µg/m2/day. Of 21 treated
patients, 16 patients became MRD
negative as assessed by quantitative PCR for either rearrangements of
immunoglobulin or T cell receptor genes, or specific genetic aberrations. Among
the 16 responders, 12 patients had been molecularly refractory to previous
chemotherapy. Probability for relapse-free survival was 78% at a median
follow-up of 405 days (Topp et al, 2011; Topp et al, 2012a; Topp et al, 2012b).
Blinatumomab was similarly effective and
well tolerated in an anecdotal report of a small series of pediatric cases
(Handgretinger et al, 2011; Schlegel et al, 2014).
Blinatumomab is presently being evaluated in children with R/R ALL in an
Amgen-sponsored Phase 1/2 study (MT103-205) being conducted in collaboration
with the Children*s Oncology Group (COG) and the I-BFM European childhood
leukemia cooperative group with promising early results. As of September 2013,
34 patients have been treated in the Phase 1 portion. Across all dose levels,
11 (32%) patients had CR
(Gore et al, 2013; Stackelberg et al, 2013). The Phase 2 portion of the study
is being conducted at 13 COG and 14 European institutions and closed accrual in
May 2014. The level of single agent activity seen with blinatumomab has not
been seen in recent Phase 2 ALL studies outside the use of tyrosine kinase
inhibitors (TKI) in patients with Ph+ ALL, thus supporting a Phase 3 randomized
clinical trial with EFS endpoints. This
study uses an approach to test whether incorporating blinatumomab into
treatment of high-risk first relapse B-ALL will reduce rates of second relapse
and improve EFS. Additionally, success in relapsed B-ALL will provide
additional rationale to test blinatumomab in newly diagnosed B-ALL patients in
order to reduce rates of first relapse.
As experience with blinatumomab remains relatively limited, this study will
include close early stopping rules for medically important adverse events, such
as relevant neurologic events, in subjects receiving blinatumomab. In addition,
the potential for adverse effects from long term depletion of CD19+ normal
lymphocytes with decrease in immune globulins following blinatumomab treatment
is unknown and so monitoring for immuneglobulin recovery and for potential
adverse effects related to delayed recovery are included.
Neurologic events have been described with blinatumomab mainly in adult
patients but still will be closely monitored on this study. One potential
concern regards the safety of combining blinatumomab with intrathecal
chemotherapy. In the current Phase 1/2 pediatric study cited above, intrathecal
MTX or intrathecal triples are included prior to Cycle 1, at Day 15 of Cycle 1
and at Day 29 of each cycle. No unusual or
increased CNS side effects have been seen in this setting (Gore et al, 2013;
Stackelberg et al, 2013).
CRS has also been described. This is more prevalent in patients with higher
leukemia burden. Pre-medication with dexamethasone immediately before treatment
start, in order to mitigate first dose effects, is mandated in the protocol. An
anti-IL6 monoclonal
antibody (i.e. tocilizumab) was shown to be effective in one patient in
reverting overt and life-threatening CRS (Teachey et al, 2013). Other common
transient adverse events associated with cytokine release are pyrexia,
headache, and elevation in liver enzymes,
which have not led to treatment discontinuation. Thus the potential benefit
reported to date for blinatumomab outweighs the potential risk.
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
* Subjects with Philadelphia (Ph-) chromosome negative high-risk (HR) first
relapse B-precursor ALL (as defined by I-BFM SG/IntReALL criteria), * Subjects
with M1 or M2 marrow at the time of randomization , * Age > 28 days and <18
years at the time of informed consent/assent, * Subject*s legally acceptable
representative has provided informed consent when the subject is legally too
young to provide informed consent and the subject has provided written assent
based on local regulations and/or guidelines prior to any study-specific
activities/procedures being initiated
* Availability of the following material from relapse diagnosis for central
analysis of MRD by PCR: clone-specific primers and reference DNA, as well as
primer sequences and analyzed sequences of clonal rearrangements (cases with
isolated extramedullary relapse or cases with technical and/or logistic hurdles
to obtain and process bone marrow material are exempt from providing this
material. In these cases, central MRD analysis only by Flow is permitted).)
Exclusion criteria
* Clinically relevant CNS pathology requiring treatment (eg, unstable
epilepsy) Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects
with CNS relapse at the time of relapse are eligible if CNS is successfully
treated prior to enrollment., * Abnormal renal or hepatic function prior to
start of treatment (day 1) as defined below:
a. Serum creatinine levels above upper limit of normal, based on the normal
ranges for age and gender of the local laboratories
b. Total bilirubin > 3.0 mg/dL prior to start of treatment (unless related to
Gilbert*s or Meulengracht disease)
* Peripheral neutrophils < 500/µl prior to start of treatment,
* Peripheral platelets < 50,000/µl prior to start of treatment,
* Currently receiving treatment in another investigational device or drug
study, or less than 4 weeks since ending treatment on another investigational
device or drug study(s). Other investigational procedures while participating
in this study are excluded. Procedures required by IntReALL HR guidelines are
allowed.,
* Chemotherapy related toxicities that have not resolved to <= grade 2 ,
* Symptoms and/or clinical signs and/or radiological and/or sonographic signs
that indicate an acute or uncontrolled chronic infection, any other concurrent
disease or medical condition that could be exacerbated by the treatment or
would seriously complicate compliance with the protocol,
* documented infection with HIV,
* Known hypersensitivity to immunoglobulins or any of the products or
components to be administered during dosing (excluding asparaginase),
* Post-menarchal subject who is pregnant or breastfeeding, or is planning to
become pregnant or breastfeed while receiving protocol-required therapy and for
at least 48 hours after the last dose of blinatumomab, or 12 months after the
last dose of chemotherapy
* Post-menarchal female subject who is not willing to practice true abstinence
or use a highly effective form of contraception while receiving
protocol-required therapy and for at least 48 hours after the last dose of
blinatumomab, or 12 months after the last dose of chemotherapy
* Sexually mature male subject who is not willing to practice true abstinence
or use a condom while receiving protocol-required therapy and for at least 48
hours thereafter ,
* Sexually mature male subject who is not willing to abstain from sperm
donation while receiving protocol-required therapy and for at least 48 hours
thereafter
Refer to section 4.2 of the protocol.
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 | EUCTR2014-002476-92-NL |
| ClinicalTrials.gov | NCT02393859 |
| CCMO | NL52375.078.15 |