HEM-iSMART E: Capivasertib + Venetoclax + Dexamethasone in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

NCT07175415 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: 2025-523132-39-00
• Study Type: interventional
• Target: 42
• Locations: 0 countries
• Sites: N/A

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 E is a phase I/II trial evaluating the safety and efficacy of capivasertib + venetocolax in combination with dexamethasone in children and AYA with R/R ped ALL/LBL whose tumor present with alterations of the PAM pathway, or lacking any mutations.

Conditions

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

Keywords

Acute lymphoblastic leukemia; relapse; biomarker driven clinical trial; refractory; capivasertib; venetoclax; children; adolescents; young adults; lymphoblastic lymphoma

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.

  2 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. For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria.

  4 years

Secondary Outcomes (7)

• Overall survival (OS)

  5 years

• Event-free survival (EFS)

  5 years

• Cumulative incidence of relapse (CIR)

  5 years

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

  5 years

• Cumulative overall response rate (ORR)

  5 years

Study Arms (1)

Capivasertib + Venetoclax + Dexamethasone

EXPERIMENTAL

Sub-study E: Each cycle lasts 28 days. Cycle 1: All patients in cycle 1 will receive 4 blocks of of capivasertib (days D4-7, 11-14, 18-21, 25-28), 28 days of venetoclax (days 1-28), and one block of seven days of dexamethasone (days 1-7). A 1-day venetoclax ramp-up is proposed in this study. Cycle 2 and subsequent cycles: similar to cycle 1. Patients in dose level -1, receive a lower dose of venetoclax. Patients in dose level 2 receive a higher dose of capivasertib. All patients receive age adapted intrathecal chemotherapy.

Drug: Capivasertib; Drug: Venetoclax; Device: Dexamethasone; Drug: Intrathecal chemotherapy

Interventions

Capivasertib DRUG

Oral

Capivasertib + Venetoclax + Dexamethasone

Venetoclax DRUG

Oral

Capivasertib + Venetoclax + Dexamethasone

Dexamethasone DEVICE

oral/intravenous

Capivasertib + Venetoclax + Dexamethasone

Intrathecal chemotherapy DRUG

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

Capivasertib + Venetoclax + Dexamethasone

Eligibility Criteria

• Age: 2 Years - 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 \>16 years of age) or Lansky Play score (for patients ≤16 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 tablets (except for those for which the AAF is available; nasogastric or gastrostomy feeding tube administration is allowed only if indicated).
• In the Phase II portion of the trial, 30% of the eligible patients will have to show alterations in the PI3K/AKT/mTOR pathway as follows: PI3K (including PIK3CA, PIK3CB, PIK3R1), AKT and loss of PTEN.
• Patients with spinal cord compression should be deemed clinically stable prior to enrolment into the trial.
• 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.
• 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.
• Absence of mean resting QTcF prolongation obtained from triplicate ECG performed at screening according to age group: (aged \<12 years of age QTcF \>440msec) (aged ≥12 years QTcF \>450msec), using the Fridericia correction \[QTcF formula\]) 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 of childbearing potential not willing to use highly effective contraceptive method (pearl index \<1) as defined in CTFG HMA 2020 (Appendix II) during trial participation and until 30 days after end of study intervention for females and 16 weeks for males.
• Breast feeding.
• History of another primary malignancy.
• 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 mutations conferring resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations) and capivasertib (e.g. mutations in TSC1, TSC2 and STK11).
• 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 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.
• Previous treatment with capivasertib and venetoclax in combination (Patients who have previously received venetoclax in alternative combinations can be eligible for this sub-protocol. Patients previously treated with capivasertib are not eligible).
• Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. See Section 7, Appendix III for details. In general, strong and moderate inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John's wort). In addition, participants should avoid herbal supplements and ingestion of large amounts of foods and beverages known to potently modulate CYP3A4 enzyme activity during study treatment.
• Drugs known to significantly prolong the QT interval and associated with torsade de points (TdP) within 5 half-lives of the first dose of study treatment. Clinically significant electrolyte abnormalities associated with QTc prolongation and/or any factors, that in the judgement of the investigator may significantly increase the risk of QTc prolongation. History of QTc prolongation, congenital long QT syndrome, medical history significant for arrhythmia which is not resolved.
• 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).

Sponsors & Collaborators

• Princess Maxima Center for Pediatric Oncology: lead
• AstraZeneca: collaborator
• AbbVie: collaborator

MeSH Terms

Conditions

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

Interventions

capivasertib; venetoclax

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

Study Officials

• Andrej Lissat, MD PhD

  Charite University, Berlin, Germany

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anne Elsinghorst Elsinghorst

CONTACT

+31650006270; hem-ismart@prinsesmaximacentrum.nl

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: September 9, 2025
• First Posted: September 16, 2025
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2031
• Study Completion (Estimated): October 1, 2032
• Last Updated: September 16, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share