Combination Chemotherapy in Treating Patients with Acute Lymphoblastic Leukemia or Lymphoma

Status: Active

Description

This randomized phase II / III trial studies the side effects of combination chemotherapy and how well it works in treating patients with acute lymphoblastic leukemia or lymphoma. Drugs used in combination chemotherapy 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.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis of B- or T-ALL or LLy by immunophenotyping: * LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by morphology and flow cytometry; if any of these show >= 25% blasts, patient will be considered to have leukemia
  • No prior therapy, or limited prior therapy, including systemic glucocorticoids for one week or less, one dose of vincristine, emergency radiation therapy (e.g., to the mediastinum, head and neck, orbit, etc.) and one dose of intrathecal chemotherapy
  • Written, informed consent and assent following Institutional Review Board, National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office for Human Research Protections (OHRP) guidelines

Exclusion Criteria

  • Participants who are pregnant or lactating; males or females of reproductive potential must agree to use effective contraception for the duration of study participation
  • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent

Locations & Contacts

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Hiroto Inaba
Phone: 901-595-3144
Email: Hiroto.Inaba@stjude.org

Texas

Fort Worth
Cook Children's Medical Center
Status: Active
Contact: Kenneth Matthew Heym
Phone: 682-885-4007
Email: kenneth.heym@cookchildrens.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To improve the event-free survival of provisional standard- or high-risk patients with genetically or immunologically targetable lesions or minimal residual disease (MRD) >= 5% at day 15 or >= 1% at the end of remission induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T cells/blinatumomab for refractory B acute lymphoblastic leukemia (B-ALL), and the proteasome inhibitor bortezomib for those lacking targetable lesions.

II. To improve overall treatment outcome of T acute lymphoblastic leukemia (T-ALL) by optimizing pegaspargase and cyclophosphamide treatment, by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD >= 0.01% at the end of induction.

III. To examine in a randomized study design whether the administration of two doses of rituximab to children with B-ALL during early remission induction therapy decreases allergic reactions to pegaspargase.

IV. To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in patients with the CEP72 CC or CT genotype.

SECONDARY OBJECTIVES:

I. To estimate the event-free survival and overall survival of children with acute lymphoblastic leukemia (ALL) and to assess the non-inferiority of total therapy study XVII (TOTXVII) compared to the historical control given by total therapy study XVI (TOTXVI).

II. To estimate the event-free survival and overall survival of children with acute lymphoblastic lymphoma (LLy) when ALL diagnostic and treatment approaches are used.

III. To examine in a randomized study design whether the administration of two doses of rituximab to children with B-ALL during early remission induction therapy can lower the minimal residual disease levels in the middle and at the end of Remission Induction.

IV. To determine the tolerability of combination therapy with ruxolitinib and early intensification therapy in patients with activation of JAK-STAT signaling and day 15 MRD >= 5% or day 42 MRD >= 1% and all patients with early T cell precursor leukemia.

V. To use data from clinical genomic sequencing of diagnosis, germline and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance.

VI. To evaluate and implement sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid.

VII. To assess clonal diversity and evolution of pre-leukemic and leukemic populations using sensitive deoxyribonucleic acid (DNA) variant detection and single-cell genomic analyses in a non-clinical, research setting.

VIII. To identify germline or somatic genomic variants associated with drug resistance of ALL cells to conventional and newer targeted anti-leukemic agents in a non-clinical, research setting.

IX. To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis.

X. To conduct serial neurocognitive monitoring of patients and to compare the benefits of a computer-based cognitive intervention administered during therapy with that administered at the end of therapy on performance measures and parent ratings of neurocognitive outcomes.

XI. To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover.

EXPLORATORY OBJECTIVES:

I. To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy).

II. To perform a detailed assessment of thiopurine metabolism and to correlate with 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome.

III. To establish xenografts of representative subtypes of ALL, including high-risk, poorly responsive, refractory and relapsed cases, and to correlate diagnosis, interim and relapse genomic features.

IV. To prospectively determine the risk and epidemiology of breakthrough infection or febrile neutropenia and adverse effects of antibiotics administered as prophylaxis or treatment.

OUTLINE:

TRIPLE INTRATHECAL CHEMOTHERAPY (ITT): Patients receive methotrexate intrathecally (IT), therapeutic hydrocortisone IT, and cytarabine IT on days 1 and 15. Patients may receive additional ITT on days 8 and 22, on days 4, 8, 11, and 22, or day 43.

REMISSION INDUCTION: Patients receive prednisone or prednisolone orally (PO) on days 1-28, vincristine sulfate IV on days 1, 8, 15, and 22, daunorubicin hydrochloride intravenously (IV) on days 2 and 8, rituximab IV on days 6 and 24, pegaspargase IV or intramuscularly (IM) on days 7 and 25, cyclophosphamide IV on day 22, cytarabine IV on days 22-25 and 29-32, mercaptopurine PO on days 22-35, dasatinib PO daily starting day 15 until the end of therapy, and bortezomib IV or subcutaneously (SC) on days 29 and 32. Patients with T lymphoblastic leukemia/lymphoma also receive daunorubicin hydrochloride IV on day 15.

EARLY INTENSIFICATION THERAPY: Patients receive vincristine sulfate IV on days 43 and 50, dexamethasone PO daily on days 43-46, pegaspargase IV or IM on day 46, cyclophosphamide IV on day 50, cytarabine IV on days 50-53, mercaptopurine PO on day 50-56, ITT on day 43, dasatinib PO daily starting on day 43 until the end of therapy, ruxolitinib PO twice daily (BID) starting on days 45-48 and days 52-56, and bortezomib IV or SC on days 50 and 53.

CONSOLIDATION: Patients receive high-dose methotrexate on days 1, 15, 29, and 43, mercaptopurine PO on days 1-56, pegaspargase IV or IM on days 3, 17, 31, and 45, ITT on days 1, 15, 29, and 43, and dasatinib PO daily and ruxolitinib PO BID until end of therapy.

IMMUNOTHERAPY: Patients with standard-risk B-ALL/LLy with positive MRD at the end of induction receive blinatumomab IV on days 1-28 and ITT on day 29, prior to initiation of continuation therapy. Patients with high-risk B-ALL/LLy receive CAR T-cell therapy.

REINTENSIFICATION I: Patients with non-early T cell precursor (ETP) ALL and LLy receive dexamethasone PO or IV BID on days 1-6, cytarabine IV every 12 hours on days 1-2, etoposide IV over 1 hour every 12 hours on days 3-5, ITT on day 5, and pegaspargase IV or IM on day 6. Patients with high-risk ETP ALL receive vorinostat PO on days 1-3, idarubicin IV over 1 hour on days 4-6, cytarabine IV over 2 hours every 12 hours on days 4-6, and ITT on day 1 or earlier.

REINTENSIFICATION II: Patients receive clofarabine IV over 2 hours, etoposide IV over 2 hours, cyclophosphamide IV over 30-60 minutes, and dexamethasone IV or PO BID on days 1-5. Patients also receive ITT on day 1 or earlier.

CONTINUATION: Prior to initiation of continuation therapy, T-ALL patients with leukemia cells in cebrospinal fluid or positive MRD at the end of remission induction receive nelarabine IV on days 1-5 of week 1, cyclophosphamide IV on day 1 of week 2, cytarabine on day 1 of week 2. T-ALL patients receive nelarabine IV continuation weeks 22, 27, 32, 37, and 42.

Patients with standard/high-risk ALL and LLy receive dexamethasone PO BID on days 1-5 of weeks 1, 4, 14, 25, 29, 33, 37, 41, 45, and 49, doxorubicin IV on day 1 of weeks 1, 4, 11, and 14, mercaptopurine PO on days 1-7 of weeks 1-6, 10-16, 21-23, 26-27, 30-31, 34-35, 38-39, 42-43, and 46-47, pegaspargase IV or IM on day 1 of weeks 1, 3, 5, 11, 13, and 15, methotrexate IV or IM on days 1 of weeks 21-23, 26-27, 30-31, 34-35, 38-39, 42-43, and 46-47, cyclophosphamide IV on day 1 of weeks 24, 28, 32, 36, 40, 44, and 48, cytarabine IV on days 1 of weeks 24, 28, 32, 36, 40, 44, and 48, and vincristine sulfate IV on day 1 of weeks 1, 4, 11, and 14.

Patients with low risk ALL and LLy receive dexamethasone PO BID on days 1-5 of weeks 1, 4, 14, 25, 29, 33, 37, 41, 45, and 49, mercaptopurine PO on days 1-7 of weeks 1-6, 10-16, 20, 21-49, and 50-57, methotrexate IV or IM on day 1 of weeks 2, 3, 5, 6, 10-13, 15, 16, 20-24, 26-28, 30-32, 34-36, 38-40, 42-44, 46-48, and vincristine sulfate IV on day 1 of weeks 1, 4, 14, 25, 29, 33, 37, 41, 45, and 49. Patients may also receive ITT at weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45, and 49.

Patients are then randomized into 1 of 2 arms.

ARM I: Patients with standard/high-risk ALL and LLy receive mercaptopurine PO on days 1-7 and methotrexate IV or IM on day 1 of weeks 50-51, 53-55, and 57-120, and cyclophosphamide IV on day 1 and cytarabine IV on day1 of weeks 52 and 56. Patients with low-risk ALL and LLy receive mercaptopurine PO on days 1-7 and methotrexate IV or IM on day 1 of weeks 50-51, 53-55, and 57-120.

ARM II: Patients with standard/high-risk ALL and LLy receive mercaptopurine PO on days 1-7 of weeks 50-51, 54-55, and 58-120, and methotrexate IV or IM on day 1 of weeks 50-51, 54-55, 58-60, 62-64, 66-68, 70-72, 74-76, 78-80, 82-84, 86-88, 90-92, 94-96, 98-100, and 102-120, cyclophosphamide IV on day 1 of weeks 52 and 56, cytarabine IV on day 1 of weeks 52 and 56, dexamethasone PO BID on days 1-5 and vincristine sulfate IV on day 1 on weeks 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, and 101. Patients with low-risk ALL and LLy receive mercaptopurine PO on days 1-7 of weeks 50-120, methotrexate IV or IM on day 1 of weeks 50-52, 54-56, 58-60, 62-64, 66-68, 70-72, 74-76, 78-80, 82-84, 86-88, 90-92, 94-96, 98-100, dexamethasone PO BID on days 1-5 and vincristine sulfate IV on day 1 on weeks 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, and 101.

REINDUCTION I (weeks 7-9 of Continuation): Patients receive dexamethasone PO BID on days 1-8 and 15-21, pegaspargase IV or IM on days 1 and 15, and vincristine sulfate IV on days 1, 8, and 15. Patients with standard/high-risk ALL and LLy also receive doxorubicin IV on day 1.

REINDUCTION II (weeks 17-19 of Continuation): Patients receive dexamethasone PO BID on days 1-8 and 15-21, pegaspargase IV or IM on days 1 and 15, and vincristine sulfate IV on days 1, 8, and 15. Patients with standard/high-risk ALL and LLy also receive high-dose cytarabine IV over 3 hours every 12 hours on days 15 and 16.

Treatment continues in the absence of disease progression or unexpected toxicity.

Trial Phase & Type

Trial Phase

Phase II/III

Trial Type

Treatment

Lead Organization

Lead Organization
St. Jude Children's Research Hospital

Principal Investigator
Hiroto Inaba

Trial IDs

Primary ID TOT17
Secondary IDs NCI-2017-00582
Clinicaltrials.gov ID NCT03117751