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

ConditionsAcute Lymphoblastic Leukemia, in RelapseLymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) RecurrentLymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) RecurrentLymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) RefractoryLymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Refractory
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age1-21
SponsorPrincess Maxima Center for Pediatric Oncology

About this trial

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 C is a phase I/II trial evaluating the safety and efficacy of ruxolitinib and venetoclax in combination with dexamethasone, cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the IL7R/JAK-STAT pathway.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

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 molecular profiling at first diagnosis lacking molecular diagnostics at relapse or refractory disease may be allowed to be included after discussion with the sponsor.

Disqualifiers

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.

Trial design

Design model

Single group

Treatments tested in this trial

  • Ruxolitinib

    Drug

    oral

  • Venetoclax

    Drug

    oral

  • Dexamethasone

    Drug

    oral/intravenous

  • Cyclophosphamide

    Drug

    intravenous

  • Cytarabine

    Drug

    intravenous

  • intrathecal chemotherapy

    Drug

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

Treatment groups

26 Participants
are divided into 1 treatment group
Group A: Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabineExperimental treatment 6 interventions

Trial outcomes

Primary outcomes

1

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

Time frame
3 years
2

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.

Time frame
6 years

Secondary outcomes

1

Overall survival (OS)

Defined as time from C1D1 until death of any cause.

Time frame
7 years
2

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).

Time frame
7 years
3

Cumulative incidence of relapse (CIR)

Estimate of the risk, that a patient will develop a relapse over a specified period of time.

Time frame
7 years
4

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

The rate of those proceeding to subsequent allogenic HSCT

Time frame
7 years

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Princess Maxima Center for Pediatric Oncology

Lead sponsor

Innovative Therapies For Children with Cancer Consortium

Collaborator

IBFM

Collaborator

Fight Kids Cancer

Collaborator

Source ClinicalTrials.gov
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