Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma

Summary

The overarching objective of this study is to use novel precision medicine strategies based on inherited and acquired leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy).

Primary Therapeutic Objectives:

* 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 Day 22 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 cell / blinatumomab for refractory B-acute lymphoblastic leukemia (B-ALL) or B-lymphoblastic lymphoma (B-LLy), and the proteasome inhibitor bortezomib for those lacking targetable lesions.
* To improve overall treatment outcome of T acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LLy) by optimizing pegaspargase and cyclophosphamide treatment and 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 and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction.
* 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 standard/high-risk patients with the CEP72 CC or CT genotype.

Secondary Therapeutic Objectives:

* To estimate the event-free survival and overall survival of children with ALL and to assess the non-inferiority of TOTXVII compared to the historical control given by TOTXVI.
* To estimate the event-free survival and overall survival of children with LLy when ALL diagnostic and treatment approaches are used.
* To evaluate the efficacy of blinatumomab in B-ALL patients with end of induction MRD ≥0.01% to \<1% and those (regardless of MRD level or TOTXVII risk category) with the genetic subtypes of BCR-ABL1, ABL-class fusion, JAK-STAT activating mutation, hypodiploid, iAMP21, ETV6-RUNX1-like, MEF2D, TCF3-HLF, or BCL2/MYC or with Down syndrome, by comparing event-free survival to historical control from TOTXVI.
* To determine the tolerability of combination therapy with ruxolitinib and Early Intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD ≥5%, Day 42 MRD ≥1%, or LLy patients without complete response at the End of Induction and all patients with early T cell precursor leukemia.

Biological Objectives:

* To use data from clinical genomic sequencing of diagnosis, germline/remission and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance.
* To evaluate and implement deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid.
* To assess clonal diversity and evolution of pre-leukemic and leukemic populations using DNA variant detection and single-cell genomic analyses in a non-clinical, research setting.
* 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.
* 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.

Supportive Care Objectives

* To conduct serial neurocognitive monitoring of patients to investigate the neurocognitive trajectory, mechanisms, and risk factors.
* To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover.

There are several Exploratory Objectives.

Conditions

• Acute Lymphoblastic Leukemia
• Acute Lymphoblastic Lymphoma

Interventions

DRUG

Prednisone

Given orally (PO).

DRUG

Vincristine

Given intravenously (IV).

DRUG

Daunorubicin

Given IV.

DRUG

Pegaspargase

Given IV or intramuscularly (IM) .

DRUG

Erwinase®

To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).

DRUG

Cyclophosphamide

Given IV.

DRUG

Cytarabine

Given IV or by subcutaneous injection (SQ).

DRUG

Mercaptopurine

Given PO.

DRUG

Dasatinib

Given PO.

DRUG

Methotrexate

Given IV.

DRUG

Blinatumomab

Given IV.

DRUG

Ruxolitinib

Given PO.

DRUG

Bortezomib

Given IV or subcutaneously (SQ).

DRUG

Dexamethasone

Given PO.

DRUG

Doxorubicin

Given IV.

DRUG

Etoposide

Given IV.

DRUG

Clofarabine

Given IV.

DRUG

Vorinostat

Given PO.

DRUG

Idarubicin

Given IV.

DRUG

Nelarabine

Given IV.

DRUG

Thioguanine

Participants with mercaptopurine-related pancreatitis. Given PO.

DRUG

Asparaginase Erwinia chrysanthemi (recombinant)-rywn

To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).

DRUG

Calaspargase Pegol

To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.

Sponsors & Collaborators

• Incyte Corporation

  collaborator INDUSTRY

• Amgen

  collaborator INDUSTRY

• Servier

  collaborator INDUSTRY

• St. Jude Children's Research Hospital

  lead OTHER

Principal Investigators

• Hiroto Inaba, MD, PhD · St. Jude Children's Research Hospital

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Model

PARALLEL

Eligibility

Min Age

1 Year

Max Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-03-29

Primary Completion

2026-09-30

Completion

2028-09-30

FDA Drug

Yes

Countries

• United States
• Australia

Study Locations