Testing the Addition of Daratumumab to Chemotherapy for Treating Patients With Newly-Diagnosed T-Cell Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LL)

Not Applicable

Not yet recruiting

• Conditions: Stage II T Lymphoblastic Leukemia/Lymphoma; Stage III T Lymphoblastic Leukemia/Lymphoma; Stage IV T Lymphoblastic Leukemia/Lymphoma; T Acute Lymphoblastic Leukemia; T Lymphoblastic Lymphoma
• Interventions: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Calaspargase Pegol; Procedure: Bone Scan; Drug: Cyclophosphamide; Drug: Bortezomib; Drug: Cytarabine; Drug: Daunorubicin Hydrochloride; Biological: Daratumumab; Procedure: Computed Tomography; Drug: Dexamethasone; Drug: Doxorubicin Hydrochloride; Procedure: Echocardiography Test; Procedure: Lumbar Puncture; Procedure: Magnetic Resonance Imaging; Drug: Mercaptopurine Oral Suspension; Drug: Methotrexate; Drug: Methylprednisolone; Drug: Nelarabine; Drug: Pegaspargase; Drug: Prednisolone; Drug: Prednisone; Other: Questionnaire Administration; Procedure: Positron Emission Tomography; Radiation: Radiation Therapy; Drug: Therapeutic Hydrocortisone; Drug: Thioguanine; Procedure: Ultrasound Imaging; Drug: Vincristine Sulfate

• Registration Number: NCT07072585
• Lead Sponsor: Children's Oncology Group

Brief Summary

This phase II/III trial tests the addition of daratumumab to chemotherapy for treating patients with newly-diagnosed T-ALL and T-LL. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs 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 chemotherapy with daratumumab may kill more cancer cells.

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the event-free survival (EFS) from the end of induction (EOI) in patients with newly diagnosed T-ALL who are randomized to either receive a modified augmented Berlin-Frankfurt-Münster (aBFM) chemotherapy backbone or a modified aBFM backbone with the addition of daratumumab.

II. To compare the EFS from the EOI in patients with newly diagnosed T-LL who are randomized to a modified aBFM chemotherapy backbone with bortezomib or to a modified aBFM backbone with bortezomib and the addition of daratumumab.

SECONDARY OBJECTIVES:

I. To compare health-related quality of life (HRQoL) and therapy-related toxicity and tolerability between patients with T-ALL or T-LL randomized to a modified aBFM backbone or to a modified aBFM backbone with the addition of daratumumab.

II. To compare overall survival (OS) from date of randomization in patients with newly diagnosed T-ALL who are randomized to either receive a modified aBFM chemotherapy backbone or a modified aBFM backbone with the addition of daratumumab.

III. To compare OS from date of randomization in patients with newly diagnosed T-LL who are randomized to a modified aBFM chemotherapy backbone with bortezomib or to a modified aBFM backbone with bortezomib and the addition of daratumumab.

EXPLORATORY OBJECTIVES:

I. In patients with newly diagnosed T-LL, to determine if minimal residual disease (MRD) testing at EOI can predict EFS and/or OS.

II. In T-ALL patients, to describe changes in the immunophenotype (specifically CD38 surface expression on T-ALL/T-LL blasts) and for the development of anti-daratumumab antibodies over the course of treatment and correlate changes with clinical outcomes and demographic variables.

III. To explore the associations between family-reported social determinants of health and both clinical outcomes (including incidence of treatment-related toxicities, EFS, OS), and leukemia/lymphoma and host biology.

IV. To describe outcome differences (EFS and OS) in patients with T-LL who differ in degrees of positron emission tomography (PET)-imaging avid disease at the EOI.

V. To explore potential imaging findings and biomarkers of significant/severe nelarabine-induced central nervous system toxicities by central review of magnetic resonance imaging (MRI) and to investigate possible clinical features in patients experiencing such toxicities.

VI. To bank peripheral blood specimens for future correlative studies in patients with T-LL.

VII. To compare EFS and OS from the EOI in patients with newly diagnosed T-ALL who are MRD positive (≥ 0.01%) at the EOI to those who are MRD negative at the EOI.

OUTLINE: This is a phase II study, followed by a phase III study. Patients are assigned to 1 of 2 groups.

GROUP I T-ALL:

INDUCTION: Patients receive cytarabine intrathecally (IT) once at the time of lumbar puncture, or day 1, daunorubicin intravenously (IV) over 1 - 15 minutes on days 1, 8, 15 and 22, dexamethasone orally (PO) or IV twice a day (BID) on days 1 - 28, vincristine IV on days 1, 8, 15 and 22, pegaspargase IV over 1 - 2 hours or intramuscularly (IM) once on day 4 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 4, and methotrexate IT on days 8 and 29 (patients with central nervous system \[CNS\]1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 8, 15, 22 and 29 (patients with CNS3). Induction treatment continues over 35 days in the absence of disease progression or unacceptable toxicity.

EOI: Patients are randomized to 1 of 2 arms.

ARM A:

CONSOLIDATION: Patients receive nelarabine IV over 60 minutes QD on days 1 - 5 and 36 - 40, cyclophosphamide IV over 30 - 60 minutes on days 8 and 43, cytarabine IV over 1 - 30 minutes or subcutaneously (SC) QD on days 8 - 11, 15 - 18, 43 - 46 and 50 - 53, mercaptopurine PO QD on days 8 - 21 and 43 - 56, methotrexate IT on days 15, 22, 50 and 57 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 15, 22, 50 and 57 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM on days 22 and 57 or calaspargase pegol-mknl IV over 1 - 2 hours on days 22 and 57, and vincristine IV on days 22, 29, 57 and 64. Patients with persistent testicular disease undergo radiation therapy QD for 12 fractions within the first two weeks of consolidation. Consolidation treatment continues over 77 days in the absence of disease progression or unacceptable toxicity. Patients with MRD \< 1% following consolidation proceed to interim maintenance.

INTERIM MAINTENANCE: Patients receive methotrexate IT on days 1 and 31 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 1 and 31 (patients with CNS3), methotrexate IV over 2 - 15 minutes on days 1, 11, 21, 31 and 41, pegaspargase IV over 1 - 2 hours or IM on days 2 and 22 or calaspargase pegol-mknl IV over 1 - 2 hours on days 2 and 23, and vincristine IV on days 1, 11, 21, 31 and 41. Interim maintenance treatment continues over 56 days in the absence of disease progression or unacceptable toxicity. Patients with MRD \< 0.1% following interim maintenance proceed to delayed intensification.

DELAYED INTENSIFICATION:

PART 1: Patients receive dexamethasone PO or IV BID on days 1 - 7 and 15 - 21, doxorubicin IV over 3 - 15 minutes on days 1, 8 and 15, methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM once on day 4 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 4, and vincristine IV on days 1, 8 and 15. Delayed intensification part 1 treatment continues over 28 days in the absence of disease progression or unacceptable toxicity.

PART 2: Patients receive nelarabine IV over 60 minutes QD on days 29 - 33, cyclophosphamide IV over 30 - 60 minutes once on day 36, cytarabine IV over 1 - 30 minutes or SC QD on days 36 - 39 and 43 - 46, thioguanine PO QD on days 36 - 49, methotrexate IT on days 36 and 43 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 36 and 43 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM once on day 50 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 50, and vincristine IV on days 50 and 57. Delayed intensification part 2 treatment continues over 35 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE:

CYCLES 1 - 3: Patients receive methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), mercaptopurine PO QD on days 1 - 28 and 36 - 84, prednisone PO or IV BID on days 1 - 5 and 57 - 61 or prednisolone PO or IV BID on days 1 - 5 and 57 - 61 or methylprednisolone IV BID on days 1 - 5 and 57 - 61, vincristine IV on days 1 and 57, methotrexate PO on days 8, 15, 22, 36, 43, 50, 57, 64, 71 and 78, and nelarabine IV over 60 minutes QD on days 29 - 33. Cycles repeat every 84 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES 4 +: Patients receive methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), prednisone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61 or prednisolone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61, mercaptopurine PO QD on days 1 - 84, vincristine IV on days 1, 29 and 57, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Cycles repeat every 84 days until 2 years from the start of interim maintenance in the absence of disease progression or unacceptable toxicity.

ARM B:

CONSOLIDATION: Patients receive daratumumab IV on days 8, 15, 22, 29, 43, 50, 57 and 64, nelarabine IV over 60 minutes QD on days 1 - 5 and 36 - 41, cyclophosphamide IV over 30 - 60 minutes on days 8 and 43, cytarabine IV over 1 - 30 minutes or SC QD on days 8 - 11, 15 - 18, 43 - 46 and 50 - 53, mercaptopurine PO QD on days 8 - 21 and 43 - 56, methotrexate IT on days 15, 22, 50 and 57 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 15, 22, 50 and 57 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM on days 23 and 58 or calaspargase pegol-mknl IV over 1 - 2 hours on days 23 and 58, and vincristine IV on days 22, 29, 57 and 64. Patients with persistent testicular disease undergo radiation therapy QD for 12 fractions within the first two weeks of consolidation. Consolidation treatment continues over 77 days in the absence of disease progression or unacceptable toxicity. Patients with MRD \< 1% following consolidation proceed to interim maintenance.

INTERIM MAINTENANCE: Patients receive daratumumab IV on days 1, 21 and 41, methotrexate IT on days 1 and 31 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 1 and 31 (patients with CNS3), methotrexate IV over 2 - 15 minutes on days 1, 11, 21, 31 and 41, pegaspargase IV over 1 - 2 hours or IM on days 2 and 22 or calaspargase pegol-mknl IV over 1 - 2 hours on days 2 and 23, and vincristine IV on days 1, 11, 21, 31 and 41. Interim maintenance treatment continues over 56 days in the absence of disease progression or unacceptable toxicity. Patients with MRD \< 0.1% following interim maintenance proceed to delayed intensification.

DELAYED INTENSIFICATION:

PART 1: Patients receive daratumumab IV on days 1 and 15, dexamethasone PO or IV BID on days 1 - 7 and 15 - 21, doxorubicin IV over 3 - 15 minutes on days 1, 8 and 15, methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), vincristine IV on days 1, 8 and 15, and pegaspargase IV over 1 - 2 hours or IM once on day 4 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 4. Delayed intensification part 1 treatment continues over 28 days in the absence of disease progression or unacceptable toxicity.

PART 2: Patients receive nelarabine IV over 60 minutes QD on days 29 - 33, daratumumab IV on days 36 and 50, cyclophosphamide IV over 30 - 60 minutes once on day 36, cytarabine IV over 1 - 30 minutes or SC QD on days 36 - 39 and 43 - 46, thioguanine PO QD on days 36 - 49, methotrexate IT on days 36 and 43 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 36 and 43 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM once on day 51 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 51, and vincristine IV on days 50 and 57. Delayed intensification part 2 treatment continues over 35 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE:

CYCLES 1 - 3: Patients receive methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), mercaptopurine PO QD on days 1 - 28 and 36 - 84, prednisone PO or IV BID on days 1 - 5 and 57 - 61 or prednisolone PO or IV BID on days 1 - 5 and 57 - 61 or methylprednisolone IV BID on days 1 - 5 and 57 - 61, vincristine IV on days 1 and 57, methotrexate PO on days 8, 15, 22, 36, 43, 50, 57, 64, 71 and 78, and nelarabine IV over 60 minutes QD on days 29 - 33. Cycles repeat every 84 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

CYCLES 4 +: Patients receive methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), prednisone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61 or prednisolone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61, mercaptopurine PO QD on days 1 - 84, vincristine IV on days 1, 29 and 57, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Cycles repeat every 84 days until 2 years from the start of interim maintenance in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo echocardiography (ECHO) during screening and bone marrow biopsy and aspiration as well as lumbar puncture throughout the study. Patients may undergo MRI, ultrasound and biopsy on study as well as may undergo blood sample collection throughout the study.

GROUP II T-LL:

INDUCTION: Patients receive bortezomib IV over 3 - 5 seconds or SC on days 1, 4, 8 and 11, cytarabine IT once at the time of lumbar puncture, or day 1, daunorubicin IV over 1 - 15 minutes on days 1, 8, 15 and 22, prednisone PO or IV BID on days 1 - 28 or prednisolone PO or IV BID on days 1 - 28 or methylprednisolone IV BID on days 1 - 28, methotrexate IT on days 8 and 29 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 8, 15, 22 and 29 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM once on day 4 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 4, and vincristine IV on days 1, 8, 15 and 22. Induction treatment continues over 35 days in the absence of disease progression or unacceptable toxicity.

EOI: Patients are randomized to 1 of 2 arms.

ARM C:

CONSOLIDATION: Patients receive cyclophosphamide IV over 30 - 60 minutes on days 1 and 29, cytarabine IV over 1 - 30 minutes or SC QD on days 1 - 4, 8 - 11, 29 - 32 and 36 - 39, mercaptopurine PO QD on days 1 - 14 and 29 - 42, methotrexate IT on days 1, 8, 15 and 22 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 1, 8, 15 and 22 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM on days 15 and 43 or calaspargase pegol-mknl IV over 1 - 2 hours on days 15 and 43, and vincristine IV on days 15, 22, 43 and 50. Patients with persistent testicular disease undergo radiation therapy QD for 12 fractions within the first two weeks of consolidation. Consolidation treatment continues over 63 days in the absence of disease progression or unacceptable toxicity. Patients with a complete response (CR) following consolidation proceed to interim maintenance.

INTERIM MAINTENANCE: Patients receive methotrexate IT on days 1 and 31 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 1 and 31 (patients with CNS3), methotrexate IV over 2 - 15 minutes on days 1, 11, 21, 31 and 41, pegaspargase IV over 1 - 2 hours or IM on days 2 and 22 or calaspargase pegol-mknl IV over 1 - 2 hours on days 2 and 23, and vincristine IV on days 1, 11, 21, 31 and 41. Interim maintenance treatment continues over 56 days in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION:

PART 1: Patients receive bortezomib IV over 3 - 5 seconds or SC on days 1, 4, 15 and 18, dexamethasone PO or IV BID on days 1 - 7 and 15 - 21, doxorubicin IV over 3 - 15 minutes on days 1, 8 and 15, methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), vincristine IV on days 1, 8 and 15, and pegaspargase IV over 1 - 2 hours or IM once on day 4 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 4. Delayed intensification part 1 treatment continues over 28 days in the absence of disease progression or unacceptable toxicity.

PART 2: Patients receive cyclophosphamide IV over 30 - 60 minutes once on day 29, cytarabine IV over 1 - 30 minutes or SC QD on days 29 - 32 and 36 - 39, thioguanine PO QD on days 29 - 42, methotrexate IT on days 29 and 36 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 29 and 36 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM once on day 43 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 43, and vincristine IV on days 43 and 50. Delayed intensification part 2 treatment continues over 28 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), mercaptopurine PO QD on days 1 - 84, prednisone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61 or prednisolone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61 or methylprednisolone IV BID on days 1 - 5, 29 - 33 and 57 - 61, vincristine IV on days 1, 29 and 57, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Cycles repeat every 84 days for 2 years from the start of interim maintenance in the absence of disease progression or unacceptable toxicity.

ARM D:

CONSOLIDATION: Patients receive daratumumab IV on days 1, 8, 15, 22, 29, 36, 43 and 50, cyclophosphamide IV over 30 - 60 minutes on days 1 and 29, cytarabine IV over 1 - 30 minutes or SC QD on days 1 - 4, 8 - 11, 29 - 32 and 36 - 39, mercaptopurine PO QD on days 1 - 14 and 29 - 42, methotrexate IT on days 1, 8, 15 and 22 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 1, 8, 15 and 22 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM on days 16 and 44 or calaspargase pegol-mknl IV over 1 - 2 hours on days 16 and 44, and vincristine IV on days 15, 22, 43 and 50. Patients with persistent testicular disease undergo radiation therapy QD for 12 fractions within the first two weeks of consolidation. Consolidation treatment continues over 63 days in the absence of disease progression or unacceptable toxicity. Patients with a CR following consolidation proceed to interim maintenance.

INTERIM MAINTENANCE: Patients receive daratumumab IV on days 1, 21 and 41, methotrexate IT on days 1 and 31 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT on days 1 and 31 (patients with CNS3), methotrexate IV over 2 - 15 minutes on days 1, 11, 21, 31 and 41, pegaspargase IV over 1 - 2 hours or IM on days 2 and 22 or calaspargase pegol-mknl IV over 1 - 2 hours on days 2 and 23, and vincristine IV on days 1, 11, 21, 31 and 41. Interim maintenance treatment continues over 56 days in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION:

PART 1: Patients receive daratumumab IV on days 1 and 15, bortezomib IV over 3 - 5 seconds or SC on days 1, 4, 15 and 18, dexamethasone PO or IV BID on days 1 - 7 and 15 - 21, doxorubicin IV over 3 - 15 minutes on days 1, 8 and 15, methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), vincristine IV on days 1, 8 and 15, and pegaspargase IV over 1 - 2 hours or IM once on day 4 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 4. Delayed intensification part 1 treatment continues over 28 days in the absence of disease progression or unacceptable toxicity.

PART 2: Patients receive daratumumab IV QD on days 29 and 43, cyclophosphamide IV over 30 - 60 minutes once on day 29, cytarabine IV over 1 - 30 minutes or SC QD on days 29 - 32 and 36 - 39, thioguanine PO QD on days 29 - 42, methotrexate IT QD on days 29 and 36 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT QD on days 29 and 36 (patients with CNS3), pegaspargase IV over 1 - 2 hours or IM once on day 44 or calaspargase pegol-mknl IV over 1 - 2 hours once on day 44, and vincristine IV QD on days 43 and 50. Delayed intensification part 2 treatment continues over 28 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive methotrexate IT once on day 1 (patients with CNS1 or CNS2) or methotrexate IT, hydrocortisone IT and cytarabine IT once on day 1 (patients with CNS3), mercaptopurine PO QD on days 1 - 84, prednisone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61 or prednisolone PO or IV BID on days 1 - 5, 29 - 33 and 57 - 61 or methylprednisolone IV BID on days 1 - 5, 29 - 33 and 57 - 61, vincristine IV on days 1, 29 and 57, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78. Cycles repeat every 84 days for 2 years from the start of interim maintenance in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo ECHO during screening and lumbar puncture as well as computed tomography (CT) or MRI, PET or PET-CT or bone scan throughout the study. Patients may undergo ultrasound and biopsy on study as well as may undergo blood sample collection and bone marrow biopsy and aspiration throughout the study.

After completion of study treatment, patients are followed up for 10 years.

Study Timeline

• Study First Submitted: 2025-05-07
• Status Verified: 2025-06
• Study First Submitted QC: 2025-07-09
• Last Update Submitted: 2025-07-09
• Study First Posted: 2025-07-18
• Last Update Posted: 2025-07-18
• Study Start: 2025-09-30
• Primary Completion: 2035-09-01
• Study Completion: 2035-09-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1708

Inclusion Criteria

• All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrolled on AALL2331.

• Patients must be > 365 days and < 21 years of age at the time of diagnosis.

• * Newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-lineage lymphoblastic lymphoma (T-LL) stages II-IV.

  • Note: A diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (CD19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a, and are present either in peripheral blood or > 25% in the bone marrow. If surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including TdT, CD34 or CD99 will be assessed for expression. Cases with uncertain expression will receive additional review within the appropriate Children's Oncology Group (COG) reference laboratory.
  • For T-LL patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to T-ALL. For tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-LL defined by the submitting institution will be accepted.

Exclusion Criteria

• Diagnosis of Down syndrome (trisomy 21).

• Patients with known Charcot-Marie-Tooth disease.

• * Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of T-ALL, T-LL or for any cancer diagnosis prior to the initiation of protocol therapy on AALL2331 with the exception of:

  • Steroid pretreatment: Prednisone or methylprednisolone for ≤ 120 hours (5 days) in the 7 days prior to initiating induction chemotherapy or for ≤ 336 hours (14 days) in the 28 days prior to initiation of protocol therapy does not affect eligibility.
  • Intrathecal cytarabine; or
  • Pretreatment with hydroxyurea; or
  • 600 cGy of chest irradiation, if medically necessary.
  • Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone used during sedation to prevent or treat airway edema. Patients who receive a single dose of dexamethasone to prevent or treat airway edema in the 28 days preceding diagnosis are eligible for this study.

• * Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.

  • Lactating females who plan to breastfeed their infants.

• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

• Known severe persistent asthma anytime in the previous two years or uncontrolled asthma of any classification.

• Peripheral neurotoxicity: Pre-existing ≥ grade 2 sensory or motor peripheral neurotoxicity.

• Seizure disorder: Patients must not have an uncontrolled seizure disorder. Patients with a seizure history or a controlled seizure disorder are eligible. A controlled seizure disorder is defined as having stable or decreasing symptoms over the past 3 months without anti-epileptic medications or is on a stable or decreasing dose of anti-epileptic medication.

• * Patients who are previously known to be seropositive for HIV except for HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of enrollment on this trial.

  • Patients with evidence of chronic hepatitis B (HBV) infection, except for patients who have an HBV viral load that is undetectable on suppressive therapy.
  • Patients with a history of hepatitis C virus (HCV) infection, except for those patients who have been treated and cured, or patients who are currently on HCV treatment who have an undetectable HCV viral load.

• Patients with significant hepatic dysfunction defined as those with an alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) > 10x upper limit of normal (ULN) or direct bilirubin > 2x ULN unless the patient has known Gilbert's syndrome or has hepatic involvement from leukemic or lymphomatous infiltration.

• All patients and/or their parents or legal guardians must sign a written informed consent.

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I, Arm A (T-ALL, no daratumumab)	Biopsy Procedure	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Biospecimen Collection	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Bone Marrow Aspiration	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Bone Marrow Biopsy	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Calaspargase Pegol	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Cyclophosphamide	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Cytarabine	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Daunorubicin Hydrochloride	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Dexamethasone	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Doxorubicin Hydrochloride	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Echocardiography Test	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Lumbar Puncture	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Magnetic Resonance Imaging	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Mercaptopurine Oral Suspension	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Methotrexate	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Methylprednisolone	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Nelarabine	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Pegaspargase	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Prednisolone	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Prednisone	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Questionnaire Administration	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Radiation Therapy	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Therapeutic Hydrocortisone	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Thioguanine	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Ultrasound Imaging	See Detailed Description
Group I, Arm A (T-ALL, no daratumumab)	Vincristine Sulfate	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Biopsy Procedure	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Biospecimen Collection	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Bone Marrow Aspiration	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Bone Marrow Biopsy	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Calaspargase Pegol	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Cyclophosphamide	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Cytarabine	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Daratumumab	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Daunorubicin Hydrochloride	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Dexamethasone	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Doxorubicin Hydrochloride	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Echocardiography Test	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Lumbar Puncture	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Magnetic Resonance Imaging	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Mercaptopurine Oral Suspension	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Methotrexate	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Methylprednisolone	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Nelarabine	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Pegaspargase	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Prednisolone	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Prednisone	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Questionnaire Administration	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Radiation Therapy	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Therapeutic Hydrocortisone	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Thioguanine	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Ultrasound Imaging	See Detailed Description
Group I, Arm B (T-ALL, daratumumab)	Vincristine Sulfate	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Biopsy Procedure	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Biospecimen Collection	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Bone Marrow Aspiration	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Bone Marrow Biopsy	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Bone Scan	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Bortezomib	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Calaspargase Pegol	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Computed Tomography	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Cyclophosphamide	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Cytarabine	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Daunorubicin Hydrochloride	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Dexamethasone	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Doxorubicin Hydrochloride	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Echocardiography Test	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Lumbar Puncture	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Magnetic Resonance Imaging	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Mercaptopurine Oral Suspension	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Methotrexate	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Methylprednisolone	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Pegaspargase	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Positron Emission Tomography	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Prednisolone	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Prednisone	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Questionnaire Administration	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Thioguanine	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Radiation Therapy	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Therapeutic Hydrocortisone	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Ultrasound Imaging	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Biospecimen Collection	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Bone Marrow Aspiration	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Bone Marrow Biopsy	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Bone Scan	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Bortezomib	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Calaspargase Pegol	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Computed Tomography	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Cyclophosphamide	See Detailed Description
Group II, Arm C (T-LL, no daratumumab)	Vincristine Sulfate	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Biopsy Procedure	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Cytarabine	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Daratumumab	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Daunorubicin Hydrochloride	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Dexamethasone	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Doxorubicin Hydrochloride	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Echocardiography Test	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Lumbar Puncture	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Magnetic Resonance Imaging	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Mercaptopurine Oral Suspension	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Methotrexate	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Methylprednisolone	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Pegaspargase	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Positron Emission Tomography	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Prednisolone	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Prednisone	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Questionnaire Administration	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Radiation Therapy	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Therapeutic Hydrocortisone	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Thioguanine	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Ultrasound Imaging	See Detailed Description
Group II, Arm D (T-LL, daratumumab)	Vincristine Sulfate	See Detailed Description

Primary Outcome Measures

Name	Time	Method
Event-free survival (EFS) in patients with newly diagnosed T-cell lymphoblastic leukemia (T-ALL)	From date of randomization (randomization conducted at the end of induction [EOI]) to date of first event (consolidation failure, interim maintenance failure, relapse, secondary malignant neoplasm [SMN], death from any cause), assessed up to 4 years.	Will compare EFS in patients with newly diagnosed T-ALL who are randomized to either receive a modified augmented Berlin-Frankfurt-Munich (aBFM) chemotherapy backbone or a modified aBFM backbone with the addition of daratumumab. Patients without an EFS event will be censored at the date of last follow-up. The survival time analyses assume a Weibull distribution with a shape parameter of 0.45 (based on historical controls). A phase 2/3 design will be used.
EFS in patients with newly diagnosed T-cell lymphoblastic lymphoma (T-LL)	From date of randomization (randomization conducted at the EOI) to date of first event (consolidation failure, relapse, progressive disease, SMN, death from any cause), assessed up to 4 years.	Will compare EFS in patients with newly diagnosed T-LL who are randomized to a modified aBFM chemotherapy backbone with bortezomib or to a modified aBFM backbone with bortezomib and the addition of daratumumab. Patients without an EFS event will be censored at the date of last follow-up. The survival time analyses assume a Weibull distribution with a shape parameter of 0.45 (based on historical controls).

Secondary Outcome Measures

Name	Time	Method
Health-related quality of life (HRQoL)	Baseline (at time of randomization) to day 64 of consolidation	Will compare HRQoL between patients with T-ALL or T-LL randomized to a modified aBFM backbone or to a modified aBFM backbone with the addition of daratumumab. Will use the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health scale (PGH-7). The PROMIS PGH-7 has a standard deviation of 10 points, with higher scores indicating better HRQoL.
Incidence of therapy-related toxicity and tolerability	Assessed up to 3 cycles post randomization (each cycle is approximately 2-3 months)	Will compare therapy-related toxicity and tolerability between patients with T-ALL or T-LL randomized to a modified aBFM backbone or to a modified aBFM backbone with the addition of daratumumab. Will be assessed for all patients and the rates compared between the randomized arms (T-ALL: arm A versus (vs) arm B and T-LL: arm C vs arm D). Rates by arm will be reviewed by the study committee on a monthly basis and will also be provided in the biannual reports to the Children's Oncology Group Data and Safety Monitoring Committee for review. Any concerns regarding excessive rates of any toxicities will be discussed in the context of any required therapy modifications.
Overall survival (OS) in patients with newly diagnosed T-ALL	From date of randomization (randomization conducted at the EOI) to date of death (death due to any cause), assessed up to 4 years	Will compare OS in patients with newly diagnosed T-ALL who are randomized to either receive a modified aBFM chemotherapy backbone or a modified aBFM backbone with the addition of daratumumab. Patients who are alive will be censored at date of last follow-up. Comparison of OS between the two randomized arms will be conducted at the time of the final analysis for the primary objective (EFS). Analyses will be based on stratified log-rank tests. In addition, descriptive OS rates post randomization will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. In particular, 4-year OS rates in arm A and arm B will be estimated. Estimation of treatment effect will be done using intent-to-treat (ITT) analysis. Hazard ratio (HR) and the confidence interval will be estimated based on Cox regression models as appropriate.
Overall survival (OS) in patients with newly diagnosed T-LL	From date of randomization (randomization conducted at the EOI) to date of death (death due to any cause), assessed up to 4 years	Will compare OS in patients with newly diagnosed T-LL who are randomized to a modified aBFM chemotherapy backbone with bortezomib or to a modified aBFM backbone with bortezomib and the addition of daratumumab. Patients who are alive will be censored at date of last follow-up. Comparison of OS between the two randomized arms will be conducted at the time of the final analysis for the primary objective (EFS). Analyses will be based on log-rank tests. In addition, descriptive OS rates post randomization will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. In particular, 4-year OS rates in arm C and arm D will be estimated. Estimation of treatment effect will be done using ITT analysis. HR and the confidence interval will be estimated based on Cox regression models as appropriate.