Therapy for Newly Diagnosed Patients With B-Cell Precursor Acute Lymphoblastic Leukemia and Lymphoma

St. Jude Children's Research Hospital

Status and phase

Enrolling

Phase 2

Conditions

Lymphoblastic Lymphoma

Acute Lymphoblastic Leukemia

Treatments

Drug: Cytarabine

Drug: Dasatinib

Drug: Cyclophosphamide

Procedure: IT MHA

Drug: Vincristine

Drug: 6-Mercaptopurine

Drug: Methotrexate

Drug: Blinatumomab

Drug: Dexamethasone

Drug: Inotuzumab

Drug: Daunorubicin

Drug: Thioguanine

Drug: Calaspargase

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT06533748

SJALL23H

NCI-2024-06013 (Registry Identifier)

Details and patient eligibility

About

This is a Phase II clinical trial testing the use of two antigen-directed therapies, inotuzumab and blinatumomab, as part of induction therapy for children and young adults with newly diagnosed B-cell precursor acute lymphoblastic leukemia and lymphoma.

Primary Objective

To assess if the flow-cytometry assessed MRD-negative remission rate following an immunotherapy-based Induction in NCI-high risk patients without favorable genetic features is higher than the results of similar patients treated on AALL1131.

Secondary Objectives

To compare flow-cytometry assessed MRD-negative rates at the end of Induction for patients treated with this therapy compared to similar patients treated on TOT17.
To compare the rate of significant toxicities in patients treated with this therapy to those treated with standard-risk therapy on TOT17.
To assess the event free and overall survival of patients treated with this therapy.

Full description

This study utilizes a single arm phase II design. Treatment will consist of 3 main phases: Induction, early post induction [including Consolidation, Blinatumomab 1, High-Dose Methotrexate, Reinduction, Interim, Reconsolidation, and Blinatumomab 2], and Maintenance.

Induction:

Induction includes 7 days of therapy on the INITIALL classification protocol (NCT06289673) as well as 5 further weeks of treatment on this trial. Treatment includes 15 days of oral (PO) or intravenous (IV) dexamethasone, 3 weekly doses of vincristine IV, and 2 doses of inotuzumab IV on Days 2 and 8. Patients will then receive blinatumomab IV from Days 9-36. Dasatinib PO will be added beginning on Day 12 for patients with an ABL-class fusion including patients with Ph+ ALL. These patients will also receive dasatinib in all subsequent cycles of therapy. Intrathecal (IT) MHA will be given. Patients will have a week without chemotherapy at the end of Induction, although patients with Induction failure (MRD ≥5% disease) will proceed directly to consolidation.

Early Post Induction:

Consolidation will be given following completion of Remission Induction Therapy. Patients receive cyclophosphamide intravenous (IV), cytarabine IV, inotuzumab IV, and dasatinib PO for patients with ABL-class fusion. Patients will have a week without chemotherapy at the end of Consolidation.
Blinatumomab 1 will be given for four weeks to all patients after recovery from Consolidation.
High-dose Methotrexate will be given IV every two weeks for four cycles. Patients will also receive an intrathecal chemotherapy treatment with each of the 2 week cycles and will take oral mercaptopurine continuously if tolerated.
Reinduction will consist of dexamethasone for 7 days in the first and third week, 3 weekly doses of vincristine IV, 1 dose of daunorubicin IV, 1 dose of calaspargase IV, intrathecal (IT) MHA one dose, and dasatinib PO daily (for patients with ABL-class fusion).
Interim includes mercaptopurine po daily for 6 weeks, dexamethasone for 1 week (5 days), daunorubicin and vincristine IV on day 1 of weeks 2 and 5, calaspargase IV on day 1 of weeks 1 and 4, IT MHA on day 1 of week 4 and dasatinib po daily for 6 weeks (for patients with ABL-class fusion). Patients will have a week without chemotherapy at the end of Interim Therapy. Patients with Down syndrome will not receive daunorubicin during this phase.
Reconsolidation will repeat therapy given in Consolidation but replace the investigational inotuzumab with traditional mercaptopurine.
Blinatumomab 2 will be given for four weeks to patients with elevated end of induction MRD and patients with Down syndrome after Reconsolidation.

Maintenance therapy follows Reconsolidation or Blinatumomab 2 (for those patients receiving this therapy) and includes 8 pulses of dexamethasone and vincristine given every 4 weeks, weekly methotrexate, daily mercaptopurine, intrathecal therapy, and dasatinib (for patients with ABL-class fusions). Maintenance therapy lasts a total of 80 weeks.

Duration of therapy is approximately 2¼ years. Follow-up is recommended until the patient is in remission for 10 years and is at least 18 years old.

Enrollment

128 estimated patients

Sex

All

Ages

1 to 18 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Enrollment on INITIALL.
Age 1-18.99 years at the time of enrollment on INITIALL.
B-Acute lymphoblastic leukemia or lymphoblastic lymphoma.
No prior chemotherapy excluding therapy given on or allowed by INITIALL.
NCI high-risk (age 10 years or greater or presenting WBC count ≥50,000 cells/microL) or NCI standard-risk and a HR clinical feature as listed below:
- CNS3 disease (≥5 WBC/microL CSF with blasts present)
- Testicular involvement of leukemia
- Steroid pretreatment defined as >24 hours of therapy in the 14 days prior to enrollment on INITIALL if a preceding WBC to define NCI risk is unavailable
For lymphoblastic lymphoma, Stage 3-4 disease OR Stage 1-2 disease in patient ages ≥10 years OR HR clinical feature as defined above.
Adequate liver function defined as:
- Direct bilirubin ≤ 1.5x the upper limit of normal for age and alanine transaminase (ALT) ≤ 5x the upper limit of normal for age.
- Patients with ALT or aspartate transferase (AST) 2.5-5x the upper limit of normal for age are ineligible unless the increase is attributable to hemolysis.
Adequate renal function defined as:
- 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 and female)
  - Age: 2 to <6 years; maximum serum creatinine (mg/dL): 0.8 (male and female)
  - Age: 6 to <10 years; maximum serum creatinine (mg/dL): 1.0 (male and female)
  - Age: 10 to <13 years; maximum serum creatinine (mg/dL): 1.2 (male and 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)
Eligibility for inclusion post-induction requires meeting the first 4 Inclusion criteria above AND:
- Treatment on SJALL23H for Induction OR
- Lymphoblastic lymphoma, initially treated on an SJALL protocol OR standard (non-protocol) therapy, without a complete response at the end of induction OR
- NCI-SR ALL at diagnosis and treated with an SJALL protocol OR standard (non-protocol) therapy who have
  - Slow response to therapy (≥0.1% MRD at end of induction for patients with hyperdiploid ALL or ≥0.01% MRD at end of induction for others with ALL) OR
  - HR genetics as defined in the protocol.

Exclusion criteria

Presence of ETV6::RUNX1 fusion unless also having a HR clinical feature OR slow response to induction therapy.
History or presence of clinically relevant central nervous system (CNS) pathology or event such as epilepsy, childhood or adult non-febrile seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. History of simple febrile seizure during childhood and presence of CNS leukemia at diagnosis are not exclusions to participation.
Active uncontrolled infection.
Current active autoimmune disease or history of autoimmune disease with the potential for CNS involvement.
History of venoocclusive disease/ sinusoidal obstructive syndrome.
Unstable cardiac disease including QTc >500msec.
Inability or unwillingness to give informed consent/ assent as applicable.
Pregnant or lactating.
For patients of reproductive potential, unwillingness to use effective contraception for the duration of protocol therapy.

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

128 participants in 1 patient group

SJALL23H Treated Patients

Experimental group

Description:

All eligible patients receive intervention according to the Detailed Description section with the following: Induction: Dexamethasone, Vincristine, Inotuzumab, Blinatumomab, Dasatinib, IT MHA. Early Post Induction: Cyclophosphamide, Cytarabine, Inotuzumab, Methotrexate, IT MHA, Dasatinib, Blinatumomab, 6-mercaptopurine, Dexamethasone, Vincristine, Daunorubicin, Calaspargase. Maintenance: Dexamethasone, Vincristine, Methotrexate, 6-mercaptopurine, Thioguanine, Dasatinib, IT MHA.

Treatment: