Adding Dasatinib or Venetoclax to Standard Chemotherapy for the Treatment in Children with T-Cell Acute Lymphoblastic Leukemia or T-Cell Lymphoma or Mixed Phenotype Acute Leukemia, the SJALL23T Trial

Status: active

This phase II trial tests how well adding dasatinib or venetoclax to standard chemotherapy improves treatment responses in children with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy) or mixed phenotype acute leukemia (MPAL). Dasatinib is in a class of medications called tyrosine kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as dexamethasone, vincristine, calaspargase pegol, daunorubicin, bortezomib, methotrexate, hydrocortisone, cytarabine, cyclophosphamide, mercaptopurine, and nelarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving dasatinib or venetoclax with standard chemotherapy may kill more cancer cells in children with T-ALL, T-LLy or MPAL.

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
Direct bilirubin ≤ 1.5x the upper limit of normal for age
Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age
Calculated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2 using the Bedside Schwartz equation OR creatinine below or equal to the maximum defined below: * Age: 1 to < 2 years - Maximum serum creatinine (mg/dL): 0.6 (Male), 0.6 (Female) * Age: 2 to < 6 years - Maximum serum creatinine (mg/dL): 0.8 (Male), 0.8 (Female) * Age: 6 to < 10 years - Maximum serum creatinine (mg/dL): 1 (Male), 1 (Female) * Age: 10 to < 13 years - Maximum serum creatinine (mg/dL): 1.2 (Male), 1.2 (Female) * Age: 13 to < 16 years - - Maximum serum creatinine (mg/dL): 1.5 (Male), 1.4 (Female) * Age: ≥ 16 years - Maximum serum creatinine (mg/dL): 1.7 (Male), 1.4 (Female)
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 TLLy 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
Consumption of grapefruit, grapefruit products, Seville oranges, or starfruit within 3 days of the start of protocol therapy

Additional locations may be listed on ClinicalTrials.gov for NCT06390319.

State:

United States

California

San Diego

Rady Children's Hospital - San Diego

Status: Active

Contact: Victor Wong

Phone: 858-966-5811

Email: vnwong@rchsd.org

Oklahoma

Tulsa

Natalie Warren Bryant Cancer Center at Saint Francis

Status: Active

Contact: Ashraf Abdelmonem Mohamed

Phone: 972-566-6647

Email: ammohamed@saintfrancis.com

Tennessee

Memphis

Saint Jude Children's Research Hospital

Status: Active

Contact: Seth Evan Karol

Phone: 901-595-1716

Email: Seth.Karol@stjude.org

PRIMARY OBJECTIVES:

I. To evaluate if the end of induction minimal residual disease (MRD)-negative rate is higher in patients with T-ALL treated with dasatinib compared to similar patients treated with 4-drug induction on AALL1231.

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

SECONDARY OBJECTIVES:

I. To assess the event free and overall survival of patients treated with this therapy.

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

EXPLORATORY OBJECTIVES:

I. To describe response patterns in patients with T-acute lymphoblastic lymphoma (T-LLy) treated with this therapy.

II. To describe response patterns in patients with mixed phenotype acute leukemia/lymphoma (MPAL) treated with this therapy.

III. To describe the kinetics of high-throughput sequencing (HTS)- based MRD response during therapy to that of MRD assessed by flow cytometry using bulk tumor, single cell and cell free genomic approaches.

IV. To assess the impact of germline and somatic variants on treatment response and toxicity.

V. To compare network-based Bayesian inference of drivers (NETBID) and pharmacotyping predicted dasatinib and venetoclax sensitivity to response to treatment.

VI. To assess the impact of this therapy on neurocognitive and quality of life outcomes.

OUTLINE:

INDUCTION: All patients receive dexamethasone orally (PO) once daily (QD) on day 1 then twice daily (BID) on days 2-28, vincristine intravenously (IV) on days 1 or 2, 8, 15 and 22, daunorubicin IV on days 2 or 3, 8 and 15, calaspargase pegol IV on day 3 or 4. Patients with T-ALL, non ETP or non-near-ETP also receive dasatinib PO QD on days 4-28. Patients with ETP, near-ETP and MPAL also receive venetoclax PO QD on days 4-17. Patients with T-LLy also receive bortezomib IV on days 5, 8, 11, and 15. Patients will also receive methotrexate, hydrocortisone, and cytarabine (MHA) intrathecally (IT) on days 4, 8, 11, 15, 22, and 29.

CONSOLIDATION: All patients receive cyclophosphamide IV on days 1 and 22, cytarabine IV on days 1-4, 8-11, 22-25 and 29-32, MHA IT on days 1 and 29, and 6- mercaptopurine PO QD on days 1-14 and 22-35. Patients with T-ALL also receive nelarabine IV on days 15-19.

HIGH-DOSE METHOTREXATE: Patients receive methotrexate IV over 24 hours on days 1, 15, 29 and 43, 6-mercaptopurine PO QD on days 1-56 and MHA IT on days 1, 15, 29 and 43.

INTENSIFICATION THERAPY (T-ALL and MPAL PATIENTS ONLY): Patients receive nelarabine IV on days 1-5, cyclophosphamide IV and cytarabine IV on day 8.

INTERIM THERAPY I: Patients receive dexamethasone PO BID on days 1-5, vincristine IV on day 1, daunorubicin IV on day 1, calaspargase pegol IV on day 1 of weeks 1 and 4 and MHA IT on day 1 of week 1. Patients also receive 6-mercaptopurine PO QD on days 1-7 of weeks 1-6.

RE-INDUCTION THERAPY I: All patients receive dexamethasone PO BID on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, calaspargase pegol IV on day 1, daunorubicin IV on day 1, MHA IT on day 1. Patients with T-ALL, non ETP or non-near-ETP also receive dasatinib PO QD on days 1-21. Patients with ETP, near-ETP, and MPAL also receive venetoclax PO QD on days 1-7. Patients with T-LLy also receive bortezomib IV on days 1, 4, 15, and 18.

INTERIM THERAPY II: Patients receive calaspargase pegol IV on day 1 of weeks 1 and 4, 6-mercaptopurine PO QD on days 1-7 of weeks 1-6, vincristine IV on day 1 of weeks 2 and 5, daunorubicin IV on day 1 of weeks 2 and 5, and MHA IT on day 1 of week 2.

RE-INDUCTION THERAPY II: All patients receive dexamethasone PO BID on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, calaspargase pegol IV on day 1, daunorubicin IV on day 1, MHA IT on day 1. Patients with T-ALL, non ETP or non-near-ETP also receive dasatinib PO QD on days 1-21. Patients with ETP, near-ETP, and MPAL also receive venetoclax PO QD on days 1-7. Patients with T-LLy also receive bortezomib IV on days 1, 4, 15, and 18.

EARLY MAINTENANCE THERAPY: Patients receive 6-mercaptopurine PO on days 1-7 and methotrexate PO, IV or intramuscularly (IM) on day 1 of weeks 1, 2, 5, 7, 10, 12, 15, 17-19, 21-23, 25-27, and 29-31. Patients receive cyclophosphamide IV and cytarabine IV on day 1 of weeks 4, 9, and 14. Patients receive dexamethasone PO BID on days 1-5, vincristine IV on day 1 and MHA IT on day 1 of weeks 6, 11, 16, 20, 24, 28, and 32. Patients with T-ALL also receive nelarabine IV on days 1-5 of weeks 3, 8, and 13.

LATE MAINTENANCE THERAPY: Patients receive 6-mercaptopurine PO on days 1-7 and methotrexate IV, PO or IM on day 1 of weeks 33-78 and MHA IT on day 1 of weeks 40, 48, 56, 64, and 72.

Additionally, patients undergo blood sample collection, bone marrow biopsy and aspiration, lumbar puncture, echocardiography on study. Patients with T-LLy may also undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)/ CT or PET/MRI on study.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year then yearly until patient is in remission for 10 years and is at least 18 years old.

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Adding Dasatinib or Venetoclax to Standard Chemotherapy for the Treatment in Children with T-Cell Acute Lymphoblastic Leukemia or T-Cell Lymphoma or Mixed Phenotype Acute Leukemia, the SJALL23T Trial

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