Adding Dasatinib Or Venetoclax To Improve Responses In Children With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (ALL) Or Lymphoma (T-LLY) Or Mixed Phenotype Acute Leukemia (MPAL)

April 25, 2024 updated by: St. Jude Children's Research Hospital

SJALL23T: Adding Dasatinib Or Venetoclax To Improve Responses In Children With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (ALL) Or Lymphoma (T-LLY) Or Mixed Phenotype Acute Leukemia (MPAL)

This is a clinical trial testing whether the addition of one of two chemotherapy agents, dasatinib or venetoclax, can improve outcomes for children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma or mixed phenotype acute leukemia.

Primary Objective

  • To evaluate if the end of induction MRD-negative rate is higher in patients with T-ALL treated with dasatinib compared to similar patients treated with 4-drug induction on AALL1231.
  • To evaluate if the end of induction MRD-negative rate is higher in patients with ETP or near-ETP ALL treated with venetoclax compared to similar patients treated with 4-drug induction on AALL1231.

Secondary Objectives

  • To assess the event free and overall survival of patients treated with this therapy.
  • To compare grade 4 toxicities, event-free survival (EFS) and overall survival (OS) of patients treated with this therapy in induction and reinduction to toxicities of similar patients treated on TOT17.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Patients will be identified in the first 3 days of therapy during their treatment on INITIALL.

Treatment will consist of 3 main phases: Induction, Early Post Induction [including Consolidation, High-Dose Methotrexate, Intensification, Interim 1, Reinduction 1, Interim 2, and Reinduction 2], and Maintenance.

Induction:

  • Remission Induction includes 3 days of therapy on the INITIALL classification protocol as well as the remainder of a total of 4 weeks of induction treatment on this trial. Treatment includes a total of 28 days of dexamethasone, 4 weekly doses of vincristine, 3 doses of daunorubicin, 1 dose of Calaspargase pegol, 6 doses of Intrathecal triple therapy (IT MHA), and one of 3 additional drugs. Patients with T-ALL without near-ETP or ETP phenotype (hereafter referred to simply as T-ALL) will receive 25 days of dasatinib. Patients with ETP or near-ETP ALL as well as those with MPAL will receive 14 days of venetoclax. Patients with T-LLy will receive bortezomib. Patients will have a week without chemotherapy at the end of Induction, although patients with Induction failure (MRD ≥5% disease) will proceed directly to consolidation.

Early Post Induction:

  • Consolidation will be given following completion of Remission Induction Therapy. Patients will receive 2 cycles of BFM-1b therapy (a single dose of cyclophosphamide at the start of week 1, 4 daily doses of cytarabine in two consecutive weeks, and 2 weeks of mercaptopurine) separated by a week of nelarabine. Patients will have a week without chemotherapy at the end of Consolidation.
  • High-dose Methotrexate will be given for 4 cycles to all patients. Patients will also receive an intrathecal chemotherapy treatment with each of the 2-week cycles and will take oral mercaptopurine continuously if tolerated.
  • Intensification will be given to patients with T-ALL or ETP/ near-ETP. This therapy includes a week of nelarabine, one week of combination cyclophosphamide and cytarabine, and 1 week of rest without chemotherapy.
  • Interim Therapy 1 includes 6 weeks of oral mercaptopurine, 2 weeks (5 days of each week) of dexamethasone, and two doses (weeks 1 and 4) of daunorubicin, vincristine, and calaspargase pegol.
  • Reinduction Therapy 1 will consist of 3 weekly doses of vincristine, 1 dose of daunorubicin and calaspargase pegol at the start of the first week, and dexamethasone for 7 days in the first and third weeks. Patients will also receive the same additional agent received during induction based on immunophenotype.
  • Interim Therapy 2 includes 6 weeks of oral mercaptopurine, two doses (weeks 1 and 4) of daunorubicin, vincristine, and calaspargase pegol.
  • Reinduction Therapy 2 will consist of 3 weekly doses of vincristine, 1 dose of daunorubicin and calaspargase pegol at the start of the first week, and dexamethasone for 7 days in the first and third weeks. Patients will also receive the same additional agent received during induction based on immunophenotype.

Maintenance therapy:

  • Early Maintenance Therapy follows Reinduction 2 and lasts 31 weeks. Patients will receive mercaptopurine and methotrexate interrupted by 1 week of nelarabine (week 3), 5 cyclophosphamide/ cytarabine pulses, and every 4-week dexamethasone/ vincristine pulses. For the first 32 weeks, patients will also receive every 4-week pulses including 5 days of dexamethasone and 1 dose of vincristine. Patients will receive low-dose methotrexate in all weeks when they do not receive dexamethasone or vincristine. All patients will receive every 4-week intrathecal chemotherapy beginning 4 weeks after the week of nelarabine.
  • Late Maintenance Therapy follows early maintenance and includes daily mercaptopurine, weekly methotrexate, and every 8-week intrathecal chemotherapy. It lasts a total of 44 weeks.

Duration of therapy is approximately 2¼ years. It is recommended that patients be followed every 4 months for 1 year, every 6 months for 1 year and then yearly until the patient is in remission for 10 years and is at least 18 years old.

Study Type

Interventional

Enrollment (Estimated)

145

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • St. Jude Children'S Research Hospital
        • Contact:
        • Principal Investigator:
          • Seth E. Karol, MD, MSCI

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Enrollment on INITIALL.
  • Age 1-18.99 years at the time of enrollment on INITIALL.
  • T-Acute lymphoblastic leukemia or lymphoblastic lymphoma or mixed phenotype acute leukemia/ lymphoma
  • No prior chemotherapy excluding therapy given on or allowed by INITIALL.
  • Patient has completed no more than 3 days of chemotherapy on INITIALL.

Exclusion Criteria:

  • Inability or unwillingness to give informed consent/ assent as applicable.
  • Patients with > Grade 2 neuropathy at the time of enrollment (participant with T-LLy only).
  • Documented malabsorption syndrome or any other condition that precludes receipt of oral medications.
  • Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
  • Pregnant or lactating.
  • For patients of reproductive potential, unwillingness to use highly effective contraception for the duration of protocol therapy and for 90 days afterwards.
  • Receipt of a strong or moderate CYP3A4 inducer such as rifampin, carbamazepine, phenytoin, and St. John's wort within 7 days of the start of protocol treatment.
  • For patients with ETP ALL, near-ETP ALL, and MPAL: consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days of the start of protocol therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Patients with T-ALL (except ETP or near-ETP)

All eligible patients receive intervention according to the Detailed Description section with the following:

Induction: Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Dasatinib, IT MHA

Early Post Induction: Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, IT MHA, Methotrexate, Dasatinib, Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol

Maintenance: Mercaptopurine, Methotrexate, Nelarabine, Cyclophosphamide, Cytarabine, Dexamethasone, Vincristine, Dasatinib, IT MHA, Thioguanine
Drug: Dasatinib
Given PO
Other Names:
  • Sprycel®
Drug: Nelarabine
Given IV
Other Names:
  • Arranon
  • Atriance
Drug: Dexamethasone
Given orally (PO) or intravenously (IV).
Other Names:
  • Decadron
  • Hexadrol®
Drug: Cyclophosphamide
Given IV.
Other Names:
  • Cytoxan®
Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
Drug: Vincristine
Given IV.
Other Names:
  • Oncovin
  • Vincristine Sulfate
Drug: Cytarabine
Given IV or IT.
Other Names:
  • Ara-C
  • Cytosine arabinoside
Drug: Calaspargase pegol
Given IV.
Other Names:
  • ASPARLAS
Drug: Intrathecal triple therapy (methotrexate + hydrocortisone + cytarabine)
Given Intrathecal (IT), Age adjusted.
Other Names:
  • IT MHA
Drug: Methotrexate
Given IT, IV, PO or intramuscular (IM).
Other Names:
  • Trexall®
Drug: Thioguanine
Given PO (participants intolerant to mercaptopurine).
Other Names:
  • 6-thioguanine
  • Tabloid®
Experimental: Patients with ETP or near-ETP ALL or MPAL

All eligible patients receive intervention according to the Detailed Description section with the following:

Induction: Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Venetoclax, IT MHA

Early Post Induction: Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, IT MHA, Methotrexate, Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Venetoclax

Maintenance: Mercaptopurine, Methotrexate, Nelarabine, Cyclophosphamide, Cytarabine, Dexamethasone, Vincristine, IT MHA, Thioguanine
Drug: Nelarabine
Given IV
Other Names:
  • Arranon
  • Atriance
Drug: Dexamethasone
Given orally (PO) or intravenously (IV).
Other Names:
  • Decadron
  • Hexadrol®
Drug: Cyclophosphamide
Given IV.
Other Names:
  • Cytoxan®
Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
Drug: Vincristine
Given IV.
Other Names:
  • Oncovin
  • Vincristine Sulfate
Drug: Cytarabine
Given IV or IT.
Other Names:
  • Ara-C
  • Cytosine arabinoside
Drug: Calaspargase pegol
Given IV.
Other Names:
  • ASPARLAS
Drug: Intrathecal triple therapy (methotrexate + hydrocortisone + cytarabine)
Given Intrathecal (IT), Age adjusted.
Other Names:
  • IT MHA
Drug: Methotrexate
Given IT, IV, PO or intramuscular (IM).
Other Names:
  • Trexall®
Drug: Thioguanine
Given PO (participants intolerant to mercaptopurine).
Other Names:
  • 6-thioguanine
  • Tabloid®
Drug: Venetoclax
Given PO (ETP, near-ETP, and MPAL only).
Other Names:
  • Venclexta®
Experimental: Patients with T-LLy

All eligible patients receive intervention according to the Detailed Description section with the following:

Induction: Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Bortezomib, IT MHA

Early Post Induction: Cyclophosphamide, Cytarabine, Mercaptopurine, IT MHA, Methotrexate, Dexamethasone, Vincristine, Daunorubicin, Calaspargase pegol, Bortezomib

Maintenance: Mercaptopurine, Methotrexate, Cyclophosphamide, Cytarabine, Dexamethasone, Vincristine, IT MHA, Thioguanine
Drug: Dexamethasone
Given orally (PO) or intravenously (IV).
Other Names:
  • Decadron
  • Hexadrol®
Drug: Cyclophosphamide
Given IV.
Other Names:
  • Cytoxan®
Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
Drug: Vincristine
Given IV.
Other Names:
  • Oncovin
  • Vincristine Sulfate
Drug: Cytarabine
Given IV or IT.
Other Names:
  • Ara-C
  • Cytosine arabinoside
Drug: Calaspargase pegol
Given IV.
Other Names:
  • ASPARLAS
Drug: Intrathecal triple therapy (methotrexate + hydrocortisone + cytarabine)
Given Intrathecal (IT), Age adjusted.
Other Names:
  • IT MHA
Drug: Methotrexate
Given IT, IV, PO or intramuscular (IM).
Other Names:
  • Trexall®
Drug: Thioguanine
Given PO (participants intolerant to mercaptopurine).
Other Names:
  • 6-thioguanine
  • Tabloid®
Drug: Bortezomib
Given IV (T-LLy only).
Other Names:
  • Velcade®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Minimal residual disease (MRD)-negativity rate in patients with T cell acute lymphoblastic leukemia
Time Frame: Up to end of induction day 29 or death
Comparison of the probability of achieving negative MRD (<0.01%) and M1 bone marrow status at the end of induction between this protocol and COG AALL1231 will be performed. Statistical analysis of the primary objective will be conducted according to a group sequential design with 1 interim analysis, by a slightly modified version of the procedure for binary endpoint.
Up to end of induction day 29 or death
MRD-negativity rate in patients with ETP or near ETP ALL
Time Frame: Up to end of induction day 29 or death
The proportion of patients with ETP or near-ETP treated with venetoclax based induction will be compared to the rate of such unsuccessful induction in patients treated on AALL1231 with a standard 4-drug induction. The probability of achieving negative MRD will be tested using a one-sided exact binomial proportion test.
Up to end of induction day 29 or death

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event-free survival (EFS)
Time Frame: Up to 10 years
Kaplan-Meier estimates for EFS will be calculated along with standard error.
Up to 10 years
Overall survival (OS)
Time Frame: Up to 10 years
Kaplan-Meier estimates for OS will be calculated along with standard error.
Up to 10 years
Incidence of grade 4 toxicities
Time Frame: Up to 30 days after last dose of study treatment
Adverse events will be graded using Common Terminology Criteria for Adverse Events version 5 and compared using Fisher's or exact Chi-square test.
Up to 30 days after last dose of study treatment
EFS compared to Total 17 (TOT17-NCT03117751)
Time Frame: Up to 10 years
Comparisons of EFS to the corresponding TOT17 will be performed by the log-rank test.
Up to 10 years
OS compared to TOT17
Time Frame: Up to 10 years
Comparisons of OS to the corresponding TOT17 will be performed by the log-rank test.
Up to 10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Jude Children's Research Hospital

Collaborators

AbbVie

Investigators

  • Principal Investigator: Seth E. Karol, MD, MSCI, St. Jude Children'S Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2024

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

December 1, 2033

Study Registration Dates

First Submitted

April 25, 2024

First Submitted That Met QC Criteria

April 25, 2024

First Posted (Actual)

April 30, 2024

Study Record Updates

Last Update Posted (Actual)

April 30, 2024

Last Update Submitted That Met QC Criteria

April 25, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SJALL23T
  • NCI-2024-03015 (Registry Identifier: NCI Clinical Trial Registration Program)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

IPD Sharing Time Frame

Data will be made available at the time of article publication.

IPD Sharing Access Criteria

Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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