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)

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

• Health-related quality of life (HRQoL) [Срок оценки: Baseline (at time of randomization) to day 64 of consolidation]
• Incidence of therapy-related toxicity and tolerability [Срок оценки: Assessed up to 3 cycles post randomization (each cycle is approximately 2-3 months)]
• Overall survival (OS) in patients with newly diagnosed T-ALL [Срок оценки: From date of randomization (randomization conducted at the EOI) to date of death (death due to any cause), assessed up to 4 years]
• Overall survival (OS) in patients with newly diagnosed T-LL [Срок оценки: From date of randomization (randomization conducted at the EOI) to date of death (death due to any cause), assessed up to 4 years]