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HEM-iSMART-B: Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies (HEM-iSMART B)

Primary Purpose

Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent, Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent

Status
Not yet recruiting
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Dasatinib
Venetoclax
Dexamethasone
Cyclophosphamide
Cytarabine
intrathecal chemotherapy
Sponsored by
Princess Maxima Center for Pediatric Oncology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring Acute lymphoblastic leukemia, Relape, Biomarker driven clinical trial, Dasatinib, Refractory, Chemotherapy, Children, Adolescents, Young adults, Lymphoblastic lymphoma

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 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 Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50% (Appendix I). 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. 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). 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. 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) 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: Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1. 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. Breast feeding. 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. Patients whose tumor present known mutationts confering resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations). 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. 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. Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion. Subjects unwilling or unable to comply with the study procedures. 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). 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. 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. 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). 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. Received immunosuppression post allogenic HSCT within one moth of study entry. History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis. Evidence of clinically active tuberculosis (clinical diagnosis per local practice). Wash-out periods of prior medication: 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. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed. 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. 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) 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. 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.

Sites / Locations

  • Princess Máxima Center for Pediatric Oncology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine

Arm Description

Sub-study B Each cycle lasts 28 days. Cycle 1: All patients in cycle 1 will receive 28 days of of dasatinib (days 1-14), 28 days of venetoclax (days 1-28), one block of five days of dexamethasone (days 1-5), one dose of cyclophosphamide (day 3) and two blocks of four consecutive days of cytarabine (days 5 to 8 and days 12 to 15). A 1-day venetoclax ramp-up is proposed in this study. Cycle 2 and subsequent cycles: Dasatinib and ventoclax one a day (day 1-28); one block of five days of dexamethasone (days 1-5), one dose of cyclophosphamide (day 1) and two blocks of four consecutive days of cytarabine (days 3 to 6 and days 10 to 13). Patients in dose level -1, receive a lower dose of venetoclax. Patients in dose level 2 receive a higher dose of venetoclax. All patients receive age adapted intrathecal chemotherapy.

Outcomes

Primary Outcome Measures

Phase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D).
Defined as the highest dose level tested at which 0/6 or 1/6 patients experiences dose limiting toxicities (DLT) during course 1 with at least 2 patients experiencing DLT at the next higher dose.
Phase II: Best Overall Response Rate (ORR).
For patients with leukemia: CR and MRD response after 1 cycle of treatment. This includes determination of CR, CRp, CRi and minimal residual disease (MRD) negativity rate in patients suffering from overt morphological relapse of T-ALL at time of enrolment (morphological disease (M2/M3)), and the MRD negativity rate in those that entered with high-MRD levels but in morphological CR. These results will together be presented as a composite endpoint Overall Response rate (ORR). MRD negativity will be defined as ≤1x10-4 as generated by multi-parameter flow cytometry. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria. In case of bone-marrow involvement MRD will be taken into account. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria.

Secondary Outcome Measures

Overall survival (OS)
Defined as time from C1D1 until death of any cause.
Event-free survival (EFS)
Defined as time from C1D1 to the first event (subsequent relapse after CR (including molecular reappearance), death of any cause, failure to achieve remission (CR, CRp or CRi), or secondary malignancy).
Cumulative incidence of relapse (CIR)
Estimate of the risk, that a patient will develop a relapse over a specified period of time.
Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy.
The rate of those proceeding to subsequent allogenic HSC
Cumulative overall response rate (ORR)
Defined as the CR, CRp, CRi and MRD negativity rates after more than 1 cycle of treatment.
Rate of dose limiting toxicities (DLTs)
Number of participants with dose limiting toxicities (DLTs)
Peak Plasma Concentration (Cmax)
Estimation of venetoclax and dasatinib Cmax

Full Information

First Posted
February 20, 2023
Last Updated
April 7, 2023
Sponsor
Princess Maxima Center for Pediatric Oncology
Collaborators
Innovative Therapies For Children with Cancer Consortium, IBFM, Fight Kids Cancer
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1. Study Identification

Unique Protocol Identification Number
NCT05751044
Brief Title
HEM-iSMART-B: Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
Acronym
HEM-iSMART B
Official Title
International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Sub-protocol B Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 1, 2023 (Anticipated)
Primary Completion Date
October 1, 2030 (Anticipated)
Study Completion Date
October 1, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Princess Maxima Center for Pediatric Oncology
Collaborators
Innovative Therapies For Children with Cancer Consortium, IBFM, Fight Kids Cancer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
Acute lymphoblastic leukemia, Relape, Biomarker driven clinical trial, Dasatinib, Refractory, Chemotherapy, Children, Adolescents, Young adults, Lymphoblastic lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
26 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine
Arm Type
Experimental
Arm Description
Sub-study B Each cycle lasts 28 days. Cycle 1: All patients in cycle 1 will receive 28 days of of dasatinib (days 1-14), 28 days of venetoclax (days 1-28), one block of five days of dexamethasone (days 1-5), one dose of cyclophosphamide (day 3) and two blocks of four consecutive days of cytarabine (days 5 to 8 and days 12 to 15). A 1-day venetoclax ramp-up is proposed in this study. Cycle 2 and subsequent cycles: Dasatinib and ventoclax one a day (day 1-28); one block of five days of dexamethasone (days 1-5), one dose of cyclophosphamide (day 1) and two blocks of four consecutive days of cytarabine (days 3 to 6 and days 10 to 13). Patients in dose level -1, receive a lower dose of venetoclax. Patients in dose level 2 receive a higher dose of venetoclax. All patients receive age adapted intrathecal chemotherapy.
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Intervention Description
Oral
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
oral
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
oral/intervenous
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
intravenous
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
intravenous
Intervention Type
Drug
Intervention Name(s)
intrathecal chemotherapy
Intervention Description
IT: Methotrexate +/- prednisone/hydrocortisone/cytarabine according to the degree of central nervous involvement
Primary Outcome Measure Information:
Title
Phase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D).
Description
Defined as the highest dose level tested at which 0/6 or 1/6 patients experiences dose limiting toxicities (DLT) during course 1 with at least 2 patients experiencing DLT at the next higher dose.
Time Frame
3 years
Title
Phase II: Best Overall Response Rate (ORR).
Description
For patients with leukemia: CR and MRD response after 1 cycle of treatment. This includes determination of CR, CRp, CRi and minimal residual disease (MRD) negativity rate in patients suffering from overt morphological relapse of T-ALL at time of enrolment (morphological disease (M2/M3)), and the MRD negativity rate in those that entered with high-MRD levels but in morphological CR. These results will together be presented as a composite endpoint Overall Response rate (ORR). MRD negativity will be defined as ≤1x10-4 as generated by multi-parameter flow cytometry. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria. In case of bone-marrow involvement MRD will be taken into account. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria.
Time Frame
6 years
Secondary Outcome Measure Information:
Title
Overall survival (OS)
Description
Defined as time from C1D1 until death of any cause.
Time Frame
7 years
Title
Event-free survival (EFS)
Description
Defined as time from C1D1 to the first event (subsequent relapse after CR (including molecular reappearance), death of any cause, failure to achieve remission (CR, CRp or CRi), or secondary malignancy).
Time Frame
7 years
Title
Cumulative incidence of relapse (CIR)
Description
Estimate of the risk, that a patient will develop a relapse over a specified period of time.
Time Frame
7 years
Title
Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy.
Description
The rate of those proceeding to subsequent allogenic HSC
Time Frame
7 years
Title
Cumulative overall response rate (ORR)
Description
Defined as the CR, CRp, CRi and MRD negativity rates after more than 1 cycle of treatment.
Time Frame
7 years
Title
Rate of dose limiting toxicities (DLTs)
Description
Number of participants with dose limiting toxicities (DLTs)
Time Frame
7 years
Title
Peak Plasma Concentration (Cmax)
Description
Estimation of venetoclax and dasatinib Cmax
Time Frame
6 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50% (Appendix I). 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. 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). 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. 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) 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: Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1. 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. Breast feeding. 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. Patients whose tumor present known mutationts confering resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations). 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. 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. Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion. Subjects unwilling or unable to comply with the study procedures. 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). 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. 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. 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). 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. Received immunosuppression post allogenic HSCT within one moth of study entry. History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis. Evidence of clinically active tuberculosis (clinical diagnosis per local practice). Wash-out periods of prior medication: 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. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed. 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. 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) 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anne Elsinghorst
Phone
+31650006270
Email
hem-ismart@prinsesmaximacentrum.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michel Zwaan, Prof. Dr.
Organizational Affiliation
Princess Máxima Center
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Andrej Lissat, MD PhD
Organizational Affiliation
Charite University, Berlin, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Princess Máxima Center for Pediatric Oncology
City
Utrecht
ZIP/Postal Code
3584CS
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
All individual participant data will be used to generate a publication.
IPD Sharing Time Frame
CSRs will also be provided at the end of specific sub-protocols or specific phases of a sub-protocol, and when needed for regulatory purposes. Examples for generating 'primary CSRs' may include: After Last Patient Last Visit (LPLV) in a study having ORR as endpoint After the RP2D is determined in a Phase I part of a given sub-protocol After the follow-up of a specific sub-protocol is completed.
IPD Sharing Access Criteria
A summary of the study results will be made public via clinicaltrials.gov as well as to Ethical committees/ Health Authorities and all participating patients by providing them through their treating physicians a patient letter with a summary of the results.

Learn more about this trial

HEM-iSMART-B: Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

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