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

NCT05740449 | Withdrawn Phase 1 DMC

• 1 other identifier: 2022-501865-29-00
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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 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

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

Keywords

Acute lymphoblastic leukemia; Lymphoblastic lymphoma; Epigentic approach; decitabine; navitoclax; venetoclax; Relapse; Refractory; Children; Adolescents; Young adults

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• Overall survival (OS)

  7 years

• Event-free survival (EFS)

  7 years

• Cumulative incidence of relapse (CIR)

  7 years

• Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy.

  7 years

• Cumulative overall response rate (ORR)

  7 years

Study Arms (1)

sub-study A - Epigenetic approach

EXPERIMENTAL

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; Drug: Venetoclax; Drug: Navitoclax; Drug: intrathecal chemotherapy

Interventions

Decitabine DRUG

intravenous

sub-study A - Epigenetic approach

Venetoclax DRUG

oral

sub-study A - Epigenetic approach

Navitoclax DRUG

oral

sub-study A - Epigenetic approach

intrathecal chemotherapy DRUG

IT: Methotrexate +/- prednisone/hydrocortisone/cytarabine according to the degree of central nervous involvement

sub-study A - Epigenetic approach

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).
• 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.

You may not qualify if:

• 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.
• 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.
• 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.
• Patients who have previously received decitabine can not participate.
• Patients who have previously received venetoclax or navitoclax separately can be eligible for this sub-study.
• 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
• 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).
• 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.
• 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.

Sponsors & Collaborators

• Princess Maxima Center for Pediatric Oncology: lead
• Innovative Therapies For Children with Cancer Consortium: collaborator
• IBFM: collaborator
• Fight Kids Cancer: collaborator

Study Sites (1)

Princess Máxima Center for Pediatric Oncology

Utrecht, 3584CS, Netherlands

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia; Recurrence; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Decitabine; venetoclax; navitoclax

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Michel Zwaan, Prof. Dr.

  Princess Maxima Center for Pediatric Oncology

  STUDY CHAIR

• Andrej Lissat, MD, PhD

  Charité

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2023
• First Posted: February 23, 2023
• Study Start: October 1, 2023
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029
• Last Updated: June 21, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• 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.
• 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.

Locations

NL (1)