Trial Title:
HEM-iSMART-B: Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
NCT ID:
NCT05751044
Condition:
Acute Lymphoblastic Leukemia
Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent
Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent
Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Refractory
Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Refractory
Conditions: Official terms:
Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, Non-Hodgkin
Hematologic Neoplasms
Recurrence
Cytarabine
Dexamethasone
Cyclophosphamide
Venetoclax
Dasatinib
Conditions: Keywords:
Acute lymphoblastic leukemia
Relape
Biomarker driven clinical trial
Dasatinib
Refractory
Chemotherapy
Children
Adolescents
Young adults
Lymphoblastic lymphoma
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Dasatinib
Description:
Oral
Arm group label:
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
oral
Arm group label:
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Intervention type:
Drug
Intervention name:
Dexamethasone
Description:
oral/intervenous
Arm group label:
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
intravenous
Arm group label:
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Intervention type:
Drug
Intervention name:
Cytarabine
Description:
intravenous
Arm group label:
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Intervention type:
Drug
Intervention name:
intrathecal chemotherapy
Description:
IT: Methotrexate +/- prednisone/hydrocortisone/cytarabine according to the degree of
central nervous involvement
Arm group label:
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Summary:
HEM-iSMART is a master protocol which investigates multiple investigational medicinal
products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R)
ALL and LBL. Sub-protocol B is a phase I/II trial evaluating the safety and efficacy of
dasatinib + venetocolax in combination with dexamethasone + Cyclophosphamide and
cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations
in the MAPK/SRC pathway.
Detailed description:
HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that
introducing targeted therapy using a biomarker driven approach for treatment
stratification may improve the outcome of children with R/R acute lymphoblastic leukemia
(ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that
allows for the investigation of multiple IMPs and generate pivotal safety and efficacy
evidence within the sub-protocols to establish and define the benefits and risks of new
treatments for children with R/R leukemia.
Sub-protocol B within HEM-iSMART, is a phase I/II, multicenter, international, open-label
clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and
efficacy of dasatinib + venetoclax in combination with dexamethasone, cyclophosphamide
and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with
actionable alterations in the MAPK/SRC pathway will be eligible for sub-protocol B
including but not limited to NUP214-ABL1 fusion or other ABL1 fusion, activating the
kinase domain, or ABL1 amplification, or PDGFRβ-fusion with various fusion partners
including but not limited to: AGGF1, DOCK2, SATB1, ETV6 and/or Patients showing a very
deep ex-vivo dasatinib IC50 below 10 nM (only data generated in the Zurich Leukemia
Research Laboratory Assay will be considered).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Children between 1 year (≥ 12 months) and 18 years of age at the time of first
diagnosis and less than 21 years at the time of inclusion
2. Performance status: Karnofsky performance status (for patients >12 years of age) or
Lansky Play score (for patients ≤12 years of age) ≥ 50% (Appendix I).
3. Written informed consent from parents/legal representative, patient, and
age-appropriate assent before any study specific screening procedures are conducted,
according to local, regional or national guidelines.
4. For all oral medications patients must be able to comfortably swallow capsules
(except for those for which an oral solution is available or dissolving of tablets
is allowed based on investigator brochure (IB); nasogastric or gastrostomy feeding
tube administration is allowed only if indicated).
5. Patients must have had advanced molecular profiling and flow-cytometric analysis of
their recurrent or refractory disease at a time-point before the first inclusion
into this trial (see section 9.1 for detailed description of the molecular
diagnostics required). Drug response profiling and methylation is highly recommended
but not mandatory. Patients with advanced molecular profiling at diagnosis may be
allowed to be included after discussion with the sponsor.
6. Patients whose tumor present the following alterations: NUP214-ABL1 fusion or other
ABL1 fusion, activating the kinase domain, or ABL1 amplification, or PDGFRβ-fusion
with various fusion partners including but not limited to: AGGF1, DOCK2, SATB1, ETV6
and/or Patients showing a very deep ex-vivo dasatinib IC50 below 10 nM (Only data
generated in centralized laboratory, where a robust DRP platform has been
established with a reference cohort in place, will be considered)
7. Adequate organ function:
- RENAL AND HEPATIC FUNCTION (Assessed within 48 hours prior to C1D1) :
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age or calculated
creatinine clearance as per the Schwartz formula or radioisotope
glomerular filtration rate ≥ 60 mL/min/1.73 m2.
- Direct bilirubin ≤ 2 x ULN (≤ 3.0 × ULN for patients with Gilbert's
syndrome).
- Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
≤ 5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic
transaminase/SGOT ≤ 5 x ULN. Note: Patients with hepatic disfunction
related to the underling disease can be eligible even if they do not
fulfill the aforementioned values for hepatic transaminases. In these
cases, patients need to be discussed with the sponsor to confirm the
eligibility.
- CARDIAC FUNCTION:
- Shortening fraction (SF) >29% (>35% for children < 3 years) and/or left
ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by
echocardiography or MUGA.
- Absence of QTcF prolongation (QTc prolongation is defined as >450 msec on
baseline ECG, using the Friedericia correction), or other clinically
significant ventricular or atrial arrhythmia.
Exclusion Criteria:
1. Pregnancy or positive pregnancy test (urine or serum) in females of childbearing
potential. Pregnancy test must be performed within 7 days prior to C1D1.
2. Sexually active participants not willing to use highly effective contraceptive
method (pearl index <1) as defined in CTFG HMA 2020 (Appendix II) during trial
participation and until 6 months after end of antileukemic therapy.
3. Breast feeding.
4. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, or malabsorption syndrome) in case of oral IMPs.
5. Patients whose tumor present known mutationts confering resistance to venetoclax
(e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys
mutations).
6. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to the
study drugs, or drugs chemically related to study treatment or excipients that
contraindicate their participation, including conventional chemotherapeutics (i.e.
cytarabine and cyclophosphamide when applicable, intrathecal agents) and corticoids.
7. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection
or any other uncontrolled infection.
a. Additional specifications for SARS-CoV-2 (COVID-19): i. Patients with a recent
positive test for SARS-CoV-2 (COVID-19) and no follow-up negative PCR test are not
eligible.
ii. Patients with recent contact to persons with COVID-19 and persons with signs and
symptoms of COVID-19 infection must be tested before enrolling. In case of contact
with a COVID-19 positive person, at least 5 days should be observed between last
contact and COVID testing. A negative PCR test is required to be eligible.
iii. A negative COVID-19 test result is defined as at least 1 negative PCR test at
least 24 hours after resolution of clinical symptoms. Resolution of clinical
symptoms is defined as resolution of fever without use of antipyretics and
improvement in respiratory symptoms (e.g., cough, shortness of breath).
iv. Frequency or timing of COVID-19 testing and interval between testing for the
above viral clearance criteria may be adjusted to the applicable country and
institutional guidelines.
8. Severe concomitant disease that does not allow treatment according to the protocol
at the investigator's discretion.
9. Subjects unwilling or unable to comply with the study procedures.
10. Previous treatment with dasatinib and venetoclax in combination (Patients who have
previously received any of these two drugs separately can be eligible for this
sub-protocol).
11. Current use of a prohibited medication or herbal preparation or requires any of
these medications during the study. See Section 7, Appendix III and IV for details.
In general, CYP3A4 inhibitors/Pgp inhibitors, moderate or strong inducers of CYP3A4
or drugs inducing QTc changes (prolongation of the QT interval or inducing Torsade
de Points) are not permitted. Among others and not exclusively that relates to
antiviral, antifungal, antibiotic, antimalarial, antipsychotic and antidepressive
drugs.
12. Patients who have consumed grapefruit, grapefruit products, Seville oranges
(Including marmalade containing Seville oranges) or starfruit within 72 hours prior
to the first dose of study drug.
13. Unresolved toxicity greater than NCI CTCAE v 5.0 ≥ grade 2 from previous anti-cancer
therapy, including major surgery, except those that in the opinion of the
investigator are not clinically relevant given the known safety/toxicity profile of
the study treatment (e.g., alopecia and/or peripheral neuropathy related to platinum
or vinca alkaloid based chemotherapy) (Common Terminology Criteria for Adverse
Events (CTCAE) (cancer.gov).
14. Active acute graft versus host disease (GvHD) of any grade or chronic GvHD of grade
2 or higher. Patients receiving any agent to treat or prevent GvHD post bone marrow
transplant are not eligible for this trial.
15. Received immunosuppression post allogenic HSCT within one moth of study entry.
16. History of bone disorders such as osteogenesis imperfecta, rickets, renal
osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc.
prior to the underlying diagnosis.
17. Evidence of clinically active tuberculosis (clinical diagnosis per local practice).
18. Wash-out periods of prior medication:
1. CHEMOTHERAPY: At least 7 days must have elapsed since the completion of
cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine, oral
methotrexate and steroids which are permitted up until 48 hours prior to
initiating protocol therapy. Patients may have received intrathecal therapy
(IT) at any time prior to study entry.
2. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first
dose of drug. Palliative radiation in past 21 days is allowed.
3. HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT):
- Autologous HSCT within 2 months prior to the first study drug dose.
- Allogeneic HSCT within 3 months prior to the first study drug dose.
4. IMMUNOTHERAPY: At least 42 days must have elapsed after the completion of any
type of immunotherapy other than monoclonal antibodies (e.g. CAR-T therapy)
5. MONOCLONAL ANTIBODIES AND INVESTIGATIONAL DRUGS: At least 21 days or 5 times
the half-life (whichever is shorter) from prior treatment with monoclonal
antibodies or any investigational drug under investigation must have elapsed
before the first study drug.
6. SURGERY: Major surgery within 21 days of the first dose. Gastrostomy,
ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and
insertion of central venous access devices are not considered major surgery.
Gender:
All
Minimum age:
1 Year
Maximum age:
21 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Princess Máxima Center for Pediatric Oncology
Address:
City:
Utrecht
Zip:
3584CS
Country:
Netherlands
Start date:
October 1, 2024
Completion date:
October 1, 2031
Lead sponsor:
Agency:
Princess Maxima Center for Pediatric Oncology
Agency class:
Other
Collaborator:
Agency:
Innovative Therapies For Children with Cancer Consortium
Agency class:
Other
Collaborator:
Agency:
IBFM
Agency class:
Other
Collaborator:
Agency:
Fight Kids Cancer
Agency class:
Other
Source:
Princess Maxima Center for Pediatric Oncology
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05751044
