Primary objective:To evaluate the anti-leukemic activity of isatuximab in combination with standard chemotherapies in pediatric participants of ages 28 days to less than 18 years with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) or Acute…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Complete Response (CR) rate in Acute myeloid leukemia (AML) cohort
Complete Response (CR) rate in B-cell Acute lymphoblastic leukemia (B-ALL)
cohort
Complete Response (CR) rate in T-cell Acute lymphoblastic leukemia (T-ALL)
cohort
Secondary outcome
Safety and tolerability assessments: Adverse events
Assessment of infusion reactions (IR's)
Pharmacokinetics of isatuximab: Cmax, Ctrough and AUC
Minimal residual disease in participants achieving CR or CRi.
Overall response rate
Overall survival
Event free survival
Duration of response
Change in CD38 receptor density and occupancy
Background summary
More than 80% of children affected by acute leukemia are successfully treated;
however, relapse remains a remarkable clinical concern, with 50% to 60% of
relapsing patients facing a fatal outcome. Management of relapsed patients
includes standardized intensive risk-adapted regimens based on conventional
drugs and hematopoietic stem cells transplantation for patients with
unfavorable features. Biological targeted drugs, in particular the mAbs, could
be novel potential agents to be integrated in salvage acute leukemia therapy to
further improve patients* outcomes.
Therefore, there is a need to find new systemic treatment for cancer and new
approaches are now being tested: compounds targeting specific
protein/components of the tumor cells, which do not exist on normal cells or
are over-expressed in cancer cells. An effective biologic agent could represent
a valuable treatment option for these patients. From previous nonclinical
studies it has been shown that patients with acute leukemia express CD38.
Isatuximab (SAR650984) is an immunoglobulin G1 class naked monoclonal antibody
(mAb) binding electively the human CD38 membrane protein, which is expressed in
a number of hematological malignancies from B lymphocyte, T-lymphocyte, and
myeloid origin.
Isatuximab is being developed for the treatment of a number of hematological
malignancies expressing the CD38 antigen. When given in combination with other
anti-cancer agents, the overall safety profile of the combinations appears
consistent with the safety profile of each drug individually.
Isatuximab demonstrated in vivo antitumor activity as a single agent and in
combination with reference treatments on several CD38-positive tumor models. In
addition, Isatuximab demonstrated antitumor activity against primary patient
cells ex vivo supporting its clinical evaluation in CD38+ multiple myeloma
(MM), non-Hodgkin*s lymphoma, and leukemia patients including ALL of both B-
and T-cell origin and AML.
Study objective
Primary objective:
To evaluate the anti-leukemic activity of isatuximab in combination with
standard chemotherapies in pediatric participants of ages 28 days to less than
18 years with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) or Acute
Myeloid Leukemia (AML).
Secondary objective:
- Safety and tolerability assessments
- Assessment of infusion reactions (IRs)
- Pharmacokinetics (PK) of isatuximab
- Minimal residual disease
- Overall response rate
- Overall survival
- Event free survival
- Duration of Response
- Relationship between clinical effects and CD38 receptor density and occupancy
Study design
A phase 2, single arm, open label study.
Intervention
For All patients the IntReALL-schema will be used as SoC; isatuximab will be
added to that schedule.
Treatment induction
isatuximab: day 1, day 8, day 15, day 22 and day 29
dexamethasone: day -3 until and including day -1, day 1, day 8, day 15 until
and including day 19, day 22, and day 29 until and including day 33
cyclofosfamide: day 1 (if WBC counts is higher than 20 x 109/L)
mitoxantrone: day 8 and day 9
vincristine: day 10, day 17, day 24 and day 31
pegaspargase: day 10 and day 24 (if intolerant for pegaspargase then
l-asparaginase (erwinase) is allowed)
IT chemo - methotrexate: day 8 and day 15
Treatment consolidation:
isatuximab: day 43 and day 57
dexamethasone: day 43 until and including day 47, and day 57
vincristine: day 38
pegaspargase: day 44 (if intolerant for pegaspargase then l-asparaginase
(erwinase) is allowed)
cyclophosphamide: day 50 until and including day 54
etoposide: day 50 until and including day 54
IT chemo - methotrexate: day 43
For AML patients the FLA-dauno schema will be used as SoC; isatuximab will be
added to that schedule.
Treatment per cycle:
isatuximab: day 1, day 8 and day 15
dexamethasone: day -3 until and including day -1, day 1, day 8 and day 15
cytarabine or hydroxyurea: day 1 (if WBC counts is higher than 20 x 109/L)
fludarabine: day 8 until and including day 12
cytarabine: day 8 until and including day 12
anthracycline - daunorubicin (non liposomal) (combined with dexrazoxane): day
8, day 10 and day 12
IT chemo - methotrexate: day 7
Study burden and risks
The risks are related to the blood samples and the biopts taken, and also the
possible side effects of the study drug and the SoC chemotherapy.
The burden for the patient are the frequent visits to the hospital.
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Listed location countries
Age
Inclusion criteria
- Participant must be 28 days to less than 18 years of age, at the time of
signing the informed consent.
- Participants must have a confirmed diagnosis of relapsed ALL of T or B cell
origin including LBL, or relapsed AML (excluding M3 type: acute promyelocytic
leukemia) including participants with history of myelodysplasia (MDS).
- Participants must be previously treated for their disease and have relapsed
or are refractory to most recent treatment. Participants in first or second
relapse will be eligible regardless of the remission duration.
- Participants with no more than 1 prior salvage therapy.
- WBC counts below 20 x 109/L on Day 1 before isatuximab administration.
Exclusion criteria
- Any serious active disease or co-morbid condition which, in the opinion of
the Investigator, may
interfere with the safety of the study treatment or the compliance with the
study protocol.
- Participants must have been off prior treatment with
immunotherapy/investigational agents and
chemotherapy for >2 weeks and must have recovered from acute toxicity before
the first study
treatment administration. Exceptions are participants who need to receive
cytoreductive chemotherapy in orde to decrease tumor burden. Treatment may
start earlier if necessitated by the patient's medical condition (eg, rapidly
progressive disease) following discussion with the Sponsor.
- Prior stem cell transplant within 3 months and/or evidence of active systemic
Graft versus Host
Disease (GVHD) and/or immunosuppressive therapy for GVHD within 1 week before
the first study
treatment administration.
- Participants with LBL with bone marrow blasts <5%.
- Participants with Burkitt-type ALL.
- Acute leukemia with testicular or central nerve system involvement alone.
- Participants who have developed therapy related acute leukemia.
- Live vaccine(s) within 30 days prior to the first IMP administration or plans
to receive such vaccines during the study until 90 days after the last IMP
administration.
- Participants with white blood cell count > 50 x 109/L at the time of the
screening visit.
- Participants who have been exposed to anti-CD38 therapies within 6 months
prior to Day-1.
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 | EUCTR2018-002697-45-NL |
| ClinicalTrials.gov | NCT03860844 |
| CCMO | NL68342.041.19 |