Primary :• To evaluate the safety and tolerability of blinatumomab incombination with AMG 404 in adults with R/R B-ALL• To estimate the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of AMG 404 when combined with cIV…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
bloedkanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Dose-limiting toxicities (DLT)
• Treatment-emergent adverse events (TEAEs), serious TEAEs, treatment-related
TEAEs and adverse events of interest (EOI).
Secondary outcome
• CR/CRh* within the first 2 cycles and across all cycles,
• CR within the first 2 cycles and across all cycles
• Duration of CR
• Duration of CR/CRh
• Blinatumomab PK parameters
• AMG 404 PK parameters
• Anti-blinatumomab Antibodies
• Anti-AMG 404 antibodies
Background summary
Acute lymphoblastic leukemia is a malignant disease of lymphatic progenitor
cells in the BM or sites of lymphatic system. Immature lymphoblasts proliferate
in the BM and may infiltrate other organs. As a consequence, the normal
hematopoiesis in the BM is suppressed. Acute lymphoblastic leukemia is a rare
malignant disease with an overall incidence of 1.1/100 000 per year. Acute
lymphoblastic leukemia has a bimodal distribution with an early peak at 4 to 5
years of age (incidence of 4.5/100 000 per year) followed by a second gradual
increase at 50 years (incidence of 2/100 000 per year). It represents 80% of
acute childhood leukemia and 20% of acute leukemia cases in adults (Howlader et
al, 2012; Jabbour et al, 2005; Larson, 2005; Pui and Evans, 1998).
Study objective
Primary :
• To evaluate the safety and tolerability of blinatumomab incombination with
AMG 404 in adults with R/R B-ALL
• To estimate the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose
(RP2D) of AMG 404 when combined with cIV blinatumomab
Secondary:
• To evaluate the efficacy of blinatumomab and AMG 404 combination therapy in
the treatmentof R/R B-ALL
• To characterize PK following blinatumomab and AMG 404 combination therapy
• To evaluate the immunogenicity oblinatumomab and AMG 404 following
blinatumomab and AMG 404 combination therapy
Study design
This is a multicenter, non-randomized, open-label, Phase 1b trial of
blinatumomab in combination with AMG 404 in adults with relapsed or refractory
B-precursor acute lymphoblastic leukemia (R/R B-ALL), evaluating safety,
tolerability, pharmacokinetics (PK), and efficacy of blinatumomab and AMG 404
combination therapy. The study will consist of up to a 3-week screening and
prephase period, a treatment period, a safety follow-up (SFU) visit 30 (± 7)
days after last dose of blinatumomab, and an end of study (EOS) visit 120 ±7
days after the last administration of AMG 404.
Subjects in this study will receive at least 2 and up to 5 cycles of
combination therapy with blinatumomab and AMG 404 in combination (Blin + 404).
Cohort 1
Each cycle will be 42 days and includes a 14-day blinatumomab treatment-free
interval between Days 29 and 42. Blinatumomab cIV will be given on Day 1 to Day
28. In Cycle 1, blinatumomab will be administered at 9 µg/day on Day 1 to Day
7, then at 28 µg/day on Day 8 to Day 28 for subjects >=45 kg
and 5 µg/m2/day, not to exceed 9 µg/day, on Day 1 to Day 7, then 15 µg/m2/day
on Day 8 to Day 28 for subjects < 45 kg, not to exceed 28 µg/day.
In Cycle 2 to Cycle 5, blinatumomab will be administered at a dose of 28 µg/day
for subjects >=45 kg and 15µg/m2/day for subjects < 45 kg, not to exceed 28 µg/
day on Day 1 to Day 28. AMG 404 will be administered intravenously (IV) over
approximately 30 minutes starting on Day 11 of Cycle 1 and dosed every 4 weeks
(Q4W) thereafter.
For cohort 1c, 2a and 2b, please refer to section 4.1 of the protocol.
The planned doses of AMG 404 in Cohorts 1 and 2a will be 240 and 480 mg,
respectively. Other cohorts may be considered to evaluate different dosing
schedules of AMG 404 in relation to the blinatumomab infusion (refer to Figure
4-2 of the protocol).
The study will consist of 2 stages, dose exploration and dose expansion.
In the dose exploration stage, subjects will be enrolled in groups of 3 to 6.
The Dose Level Review Team (DLRT) will meet after all subjects in a group are
DLT evaluable to determine if additional subjects need to be enrolled into the
cohort, if it is appropriate to dose escalate or de-escalate, or to stop the
study for safety concerns. Maximum of 9 subjects overall may be enrolled at
each dose level during dose exploration.
The planned dose level for blinatumomab are:
Cohort 1 cycle 1: administer 9 µg/day on Day 1 to Day 7 and 28 µg/day on Day 8
to Day 28 for subjects >=45 kg. Administer 5 µg/m2/day, not to exceed 9 µg/day,
on Day 1 to Day 7, then 15 µg/m2/day on Day 8 to Day 28 for subjects < 45 kg,
not to exceed 28 µg/day.
For cycle 1 the dose levels for AMG 404 are:
• Cohort 1: 240 mg Q4W starting on Day 11 of Cycle 1
• Cohort 2a: 480 mg Q4W starting on Day 1 of Cycle 1
• Cohort 2b: 240 mg Q4W starting on Day 1 of Cycle 1
• Cohort 1c: 120 mg Q4W starting on Day 11 of Cycle 1
• Cohort 2: 480 mg Q4W starting on Day 11 of Cycle 1
• Cohort 1b: 120 mg Q4W starting on Day 11 of Cycle 1
Refer to section 6.2.1.1. of the protocol.
Intervention
Blinatumomab will be administered as a continuous IV for 28 days per cycle and
AMG 404 will be administered intravenously (IV) over approximately 30 minutes
starting on Day 1 or 11 of Cycle 1 and dosed every 4 weeks (Q4W) thereafter.
Study burden and risks
Please see section E9 en E9a.
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
• Age >= 18 years at enrollment.
• Subjects with B-precursor ALL, with any of the following:
-Refractory to primary induction or refractory to salvage therapy.
-In untreated first, second or greater relapse or refractory relapse or relapse
after salvage therapy
-Relapse at any time after allogeneic HSCT:
o Relapse is defined as achievement of CR (CR1) during upfront therapy then
relapse during or after continuation therapy.
o Refractory disease is defined as the absence of CR after standard induction
therapy.
o Refractory relapse lack of CR after first salvage therapy
o Second relapse or later relapse defined as relapse after achieving a second
CR (CR2) in first or later salvage.
• Greater than or equal to 5% blasts in the BM.
• Eastern Cooperative Oncology Group performance status (ECOG PS) <= 2.
• Negative pregnancy test in women of childbearing potential.
Refer to section 5.1 of the protocol.
Exclusion criteria
• History or presence of clinically relevant CNS pathology such as epilepsy,
childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries,
dementia, Parkinson*s disease, cerebellar disease, organic brain syndrome or
psychosis.
• Presence of ALL in the CNS (confirmed by presence of blast cells in CSF) or
testes.
• Isolated extramedullary disease.
• Current autoimmune disease or history of autoimmune disease with potential
CNS involvement.
• Allogeneic HSCT within 12 weeks before the start of protocol-specified
therapy.
• Active acute or chronic graft versus host disease requiring systemic
treatment with immunosuppressive medication.
• Cancer chemotherapy (radiotherapy, chemotherapy, antibody therapy, molecular
targeted therapy) within 14 days prior to study Day 1 with the exception of
intrathecal chemotherapy and/or low dose maintenance therapy (eg vinca
alkaloids, mercaptopurine, methotrexate, or hydroxyurea). If subject is
eligible for pre phase then all low dose chemotherapy with the exception of
intrathecal chemotherapy must be discontinued prior to starting pre phase.
Tyrosine kinase inhibitors use in patients with Ph+ ALL is allowed.
• Immunotherapy (eg rituximab, alemtuzumab) within 4 weeks before start of
protocol-specified therapy. Prior treatment (given > 4 weeks prior to protocol
therapy) with any CD19-directed therapy (eg, blinatumomab, CD19-directed
chimeric antigen receptor T-cell therapy, anti-CD19 antibodies will be allowed).
Refer to section 5.2 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 | EUCTR2019-004304-36-NL |
| ClinicalTrials.gov | NCT-nummerisnognietbekend.Hetnummervolgt. |
| CCMO | NL72451.042.20 |