This study has been transitioned to CTIS with ID 2022-501457-37-00 check the CTIS register for the current data. Primary Objective:- Achieving an event-free survival, which is not inferior to the ML-DS 2006 trial (87±3%)Secondary Objective(s):-…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Event-free survival (EFS), defined as time from diagnosis to the first event or
last follow-up. Events are death from any cause, failure to achieve remission,
relapse, and secondary malignancy. Failure to achieve remission is considered
as an event on day 0.
Secondary outcome
- Overall survival (OS), as defined as the time of diagnosis to death from any
cause or last follow-up.
- Disease-free survival (DFS)
- Early Response Rate (CR, CRp, CRi) after induction
- Treatment-related mortality (TRM)
- Minimal residual disease (FACS and NGS)
- Adverse events (according to NCI CTCAE v4.0)
- Duration of myelosuppression (neutrophils < 0.5 Gpt/L).
Background summary
Children with Down syndrome and myeloid leukemia (ML-DS) have a superior
outcome compared to non-DS patients but suffer from higher constitutional
susceptibility to cytotoxic drugs. We previously analyzed the outcome of 170
pediatric patients with ML-DS enrolled in the prospective, multi-center,
open-label, non-randomized ML-DS 2006 trial. In comparison to the historical
control arm treatment intensity was reduced. The 5-year overall survival,
event-free survival and cumulative incidence of relapse/non-response did not
significantly differ between the ML-DS 2006 trial and the historical control
arm.
Poor early treatment response was identified as independent prognostic factor
predicting a worse EFS. Despite a tolerable toxicity with fewer severe adverse
events than children with non-DS AML five patients died due to therapy
resulting in a therapy-related mortality (TRM) of 2.9%. Severe adverse events
mainly occurred after/during induction and course 4 (high-dose cytarabine).
With regard to the low cumulative incidence or relapse / non-responders of 6±2%
these data imply that therapy should be further reduced or modified in children
with ML-DS and good early response to lower the TRM without impairing the
excellent outcome.
In the ML-DS 2018 trial we will introduce MRD-based risk stratification (after
induction) to reduce the dose of cytarabine in course 4 from 3 g/m²/12h to 1
g/m²/12h in good responders. Additionally, we will substitute idarubicin,
cytarabine and/or etoposide (course 1 and 2) by CPX-351, a liposomal
formulation of cytarabine:daunorubicin encapsulated at a 5:1 molar ratio in
order to achieve a favorable efficiency/toxicity profile, in all children with
ML-DS.
Study objective
This study has been transitioned to CTIS with ID 2022-501457-37-00 check the CTIS register for the current data.
Primary Objective:
- Achieving an event-free survival, which is not inferior to the ML-DS 2006
trial (87±3%)
Secondary Objective(s):
- Reduction of toxicity: severe adverse events (CTCAE v4.0 grade III or higher)
- Evaluation of response
- Identification of prognostic factors (e.g. trisomy 8) concerning the risk of
relapse, toxicity and poor outcome
- To evaluate the role of different methods in the determination of minimal
residual disease measurement
Study design
ML-DS 2018 is a prospective, non-randomized, open-label,
historically-controlled, international and multicenter phase III trial for
children with ML-DS. The single-arm non-inferiority trial will be compared
against the historical control (ML-DS 2006 trial) with event-free survival as
the primary endpoint.
We will investigate, whether substituting course 1 and 2 of standard ML-DS
therapy (defined as ML-DS 2006 protocol) with CPX-351 and reduction of
treatment intensity in course 4 for patients with a good response (<0.1% blasts
in the bone marrow after course 1) does not result in inferior event-free
survival.
Safety-run-in: To confirm that substituting course 1 and 2 of standard ML-DS
therapy (defined as ML-DS 2006 protocol) with CPX-351 does not cause severe
toxicity, we will assess TRM after 10 patients. If TRM occurs in three or more
patients we will refrain from further accrual of patients.
Intervention
1. Introduction of a MRD-based risk stratification (after induction) to reduce
the dose of cytarabine in course 4 from 3 g/m²/12h to 1 g/m²/12h in good
responders.
2. Substitution of idarubicin, cytarabine and/or etoposide (course 1 and 2) by
CPX-351, a liposomal formulation of cytarabine:daunorubicin encapsulated at a
5:1 molar ratio in order to achieve a favorable efficiency/toxicity profile, in
all children with ML-DS.
Study burden and risks
The burden of this treatment is comparable with the burden of the standard
treatment for children with Down Syndrome and Myeloid leukemia. We even aim to
reduce the burden and toxicity for the patients. The duration of
hospitalization won*t be prolonged. Most important risk are standard in a
pediatric oncology treatment. All blood, bone marrow and liquor samples are
according to standard of care.
A potential risk is the use of an agent (CPX-351) that has not yet been tested
and established for this specific indication. A second risk is a potential
higher relapse risk due to reduction of therapy intensity. The risk is low and
justified by the benefit. (see also protocol section 1.2.2)
Chausseestrasse 128/129
Berlin 10115
DE
Chausseestrasse 128/129
Berlin 10115
DE
Listed location countries
Age
Inclusion criteria
-Myeloid Leukemia (ML) or Myelodysplastic Syndrome (MDS), according to WHO
-Trisomy 21: Down syndrome or mosaic
-Age: > 6 months and <= 4 years of age with/without GATA1 mutation OR > 4 years
of age < 6 years of age with GATA1 mutation
- Morphology/Immunophenotyping: FAB M0, M6 or M7
- Lansky performance score at least equal to 50; or Karnofsky performance
status at least equal to 50, whichever is applicable
- Understand and voluntarily provide written permission of parental/legal
representative(s) to the ICF prior to conducting any study related
assessments/procedures, also concerning data and tumor material transfer
according to ICH/GCP and national/local regulations
- Able to adhere to the study visit schedule and other protocol requirements
- Acceptance that vaccination with live vaccines is not possible while
participating in the trial
Exclusion criteria
- Children with Transient Abnormal Myelopoiesis (TAM), according to WHO.
- Cytogenetics: AML with recurrent genetic abnormalities (WHO 2016).
- Previous allogeneic bone marrow, stem cell or organ transplantation.
- Evidence of invasive fungal infection or other severe systemic infection
requiring treatment doses of systemic/parenteral therapy including known active
viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and
C.
- Symptomatic cardiac disorders (CTCAE 4.0 Grade 3 or 4).
- Diagnosed Wilsons Disease
- Major surgery within 21 days of the first dose.
- Any anti-cancer therapy (e.g., intensive chemotherapy, biologics or
radiotherapy) for more than 14 days or within 4 weeks before start of therapy,
except low-dose cytarabine for the treatment of TAM.
- Concomitant treatment with any other anticancer therapy except those
specified in protocol during the study therapy.
- Treated by any investigational agent in a clinical study within previous 4
weeks.
- History of hypersensitivity to the investigational medicinal product or to
any drug with similar chemical structure or to any excipient present in the
pharmaceutical form of the investigational medicinal product.
- Former Enrolment to this study.
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
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-501457-37-00 |
| EudraCT | EUCTR2018-002988-25-NL |
| CCMO | NL74566.041.20 |
| Other | NL9136 |