HEM-iSMART-A: Decitabine / Venetoclax and Navitoclax in Pediatric Patients With Relapsed or Refractory Hematological Malignancies (HEM-iSMART A)

International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol A: Decitabine / Venetoclax and Navitoclax in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

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 A is a phase I/II trial evaluating the safety and efficacy of Decitabine / Venetoclax and Navitoclax in children and AYA with R/R pediatric ALL/LBL

Study Overview

• Status: Withdrawn
• Conditions: Acute Lymphoblastic Leukemia, in Relapse; 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
• Intervention / Treatment: Drug: Decitabine; Drug: Venetoclax; Drug: Navitoclax; Drug: intrathecal chemotherapy

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 A 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 decitabine, venetoclax and navitoclax in children, adolescents and young with R/R ALL and LBL. The epigenetic approach may improve outcome for patients whose tumor lack molecular alterations.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3584CS
    • Princess Máxima Center for Pediatric Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Children between 4 years and 18 years of age at the time of first diagnosis and less than 21 years at the time of inclusion. Children must have a body weight ≥ 20 kg.
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 of this protocol 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. 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; 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. 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.
6. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
7. Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion.
8. Subjects unwilling or unable to comply with the study procedures.
9. Patients who have previously received decitabine can not participate.
10. Patients who have previously received venetoclax or navitoclax separately can be eligible for this sub-study.
11. 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
12. Patients who have received strong and moderate CYP3A4 inhibitors/inducers within 7 days prior to the first dose of study drug (also see Appendix VI of the Master Protocol).
13. Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. See Section 7, Appendix III and or 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.
14. 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).
15. 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.
16. Received immunosuppression post allogenic HSCT within one moth of study entry.

17. 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:

       • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: sub-study A - Epigenetic approach; Decitabine / Venetoclax and Navitoclax. Each cycle lasts 28 days. Cycle 1: Decitabine is given 10 mg/m2 intravenous, once a day on 5 consecutive days (Day 1 - 5), venetoclax 400 mg adult equivalent dose, once a day, Day 1 - Day 28 orally, with a ramp-up dose on day 1 and navitoclax once a day, Day 3 - 28 orally depending on the weight of the patient (dose level 1). Cycle 2: Decitabine is given 10 mg/m2 intravenous, once a day on 5 consecutive days (Day 1 - 5), venetoclax 400 mg adult equivalent dose, once a day, Day 1 - Day 28 orally and navitoclax once a day, Day 1 - 28 orally depending on the weight of the patient (dose level 1). Patients in dose level 2: will receive decitabine 20 mg/m2 intravenous once a day on 5 consecutive days (Day 1 - 5). Patients in dose level -1: will receive venetoclax 200 mg adult equivalent dose, once a day, Day 1 - Day 28 orally. All patients receive age adapted intrathecal chemnotherapy.

Drug: Decitabine; intravenous; Drug: Venetoclax; oral; Drug: Navitoclax; oral; Drug: intrathecal chemotherapy; IT: Methotrexate +/- prednisone/hydrocortisone/cytarabine according to the degree of central nervous involvement

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 years
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.	6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Defined as time from C1D1 until death of any cause.	7 years
Cumulative incidence of relapse (CIR)	Estimate of the risk, that a patient will develop a relapse over a specified period of time.	7 years
Rate of dose limiting toxicities (DLTs)	Number of participants with dose limiting toxicities (DLTs)	7 years
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).	7 years
Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy.	The rate of those proceeding to subsequent allogenic HSCT	7 years
Cumulative overall response rate (ORR)	Defined as the CR, CRp, CRi and MRD negativity rates after more than 1 cycle of treatment	7 years
Peak plasma concentration (Cmax)	Estimation of decitabine, venetoclax and navitoclax Cmax	6 years

Collaborators and Investigators

• Sponsor: Princess Maxima Center for Pediatric Oncology
• Collaborators: Innovative Therapies For Children with Cancer Consortium; IBFM; Fight Kids Cancer
• Investigators: Study Chair: Michel Zwaan, Prof. Dr., Princess Máxima Center for Pediatric Oncology; Principal Investigator: Andrej Lissat, MD, PhD, Charité

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2023
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: February 13, 2023
• First Submitted That Met QC Criteria: February 13, 2023
• First Posted (Actual): February 23, 2023

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: June 19, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Adolescents; Children; Refractory; venetoclax; Lymphoblastic lymphoma; Young adults; Relapse; decitabine; Acute lymphoblastic leukemia; navitoclax; Epigentic approach
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Disease Attributes; Hematologic Diseases; Lymphoma; Hematologic Neoplasms; Leukemia; Recurrence; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Venetoclax; Navitoclax
• Other Study ID Numbers: 2022-501865-29-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No