The goal of this research study is to evaluate a chemotherapy regiment for the treatment of newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs). The names of the study drugs involved in this study are: * blinatumomab (a type of immunotherapy drug) * cyclophosphamide (a type of chemotherapy drug) * cytarabine (a type of antineoplastic agent) * dexamethasone (a type of synthetic glucocorticoid) * doxorubicin (a type of antineoplastic agent) * etoposide (a type of antineoplastic agent) * mercaptopurine (a type of antineoplastic agent) * methotrexate (a type of chemotherapy drug) * pegaspargase (a type of antineoplastic agent) * vincristine (a type of antineoplastic agent)
This Phase 2, single-arm research study is to evaluate a chemotherapy regiment the treatment of newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs). The U.S. Food and Drug Administration (FDA) has approved all of the drugs of treatment being studied but the investigators of this research study want to understand more about the safety and effectiveness of the chemotherapy regimen in adolescents and young adults with newly diagnosed Philadelphia chromosome-negative ALL. The research study procedures include screening for eligibility, in-clinic visits, blood tests, urine tests, saliva tests, X-rays, electrocardiograms (ECGs), echocardiograms (ECHOs), Dual-Energy X-ray Absorptiometry (DEXA) scans, bone marrow aspirations/biopsies. Participation in this study is expected to last about 10 years, 2 years of treatment followed by 8 years of follow up. It is expected that about 67 people will take part in this research study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
67
A bispecific T-cell engager (BiTE) antibody, single-use vial via intravenous infusion, per standard of care
A modified enzyme L-asparaginase, single-use vial via intravenous infusion, per standard of care
An alkylating agent, single-use vial via intravenous infusion, per standard of care
An antineoplastic antimetabolite, multi-dose vial via intrathecal injection (through the spinal space), per standard of care
A synthetic glucocorticoid, tablets or single-use vials via orally or intravenous infusion (through the vein), per standard of care
An anthracycline antibiotic, single-use or multi-dose vials via intravenous infusion, per standard of care
A derivative of podophyllotoxin, multi-dose vial via intravenous infusion, per standard of care
A purine antagonist, tablet via orally, per standard of care
A folate analogue, multi-dose and single-use vials via intrathecal injection, per standard of care
A vinca alkaloid, single-use vials via intravenous injection, per standard of care
Dana Farber Cancer Institute
Boston, Massachusetts, United States
RECRUITINGTreatment Completion Rate Through Time Point 3 (TP3)
Treatment completion rate through TP3 is defined as the proportion of Adolescents and Young Adults (AYAs) participants who receive all protocol-specified therapy through TP3, without early discontinuation.
Time frame: Timeframe for TP3 depends on disease immunophenotype. Participants with CD19-positive B-ALL, TP3 occurs at the end of Blinatumomab Cycle 2 on Day 28 (130 days from study start). For participants with T-cell ALL or those who do not receive blinatum
Rate of Treatment-Related Mortality (TRM)
Rate of TRM is defined as the proportion of participants who die due to treatment-related causes.
Time frame: Up to 115 weeks
Rate of Treatment Discontinuation due to Toxicity or Disease
Rate of treatment discontinuation during Induction, Consolidation, and Continuation phases, defined as the proportion of participants who stop protocol-specified therapy due to regimen-related toxicity and/or treatment failure.
Time frame: Up to 115 weeks
Rate of Asparaginase Non-Completion
Rate of asparaginase non-completion is defined as the proportion of participants who did not complete all planned doses of asparaginase per protocol.
Time frame: This endpoint is assessed during Consolidation II, which occurs approximately from Day 270 to Day 480 of study treatment.
Reason of Asparaginase Non-Completion
This outcome summarizes the reasons participants discontinue asparaginase treatment earlier than planned.
Time frame: Up to 115 weeks
Grade 3 Infections Toxicity Rate
Grade 3 infection toxicity rate is defined as the proportion of participants who experience grade 3 bacterial or fungal infections that are assessed as possibly, probably, or definitely related to the study treatment during the induction, consolidation, and continuation phases. Toxicity grades are determined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
Time frame: Adverse events will be followed for 30 days after completion of protocol treatment, with the overall treatment period up to 115 weeks.
Grade 3 Asparaginase-associated Toxicities Rate
Grade 3 asparaginase-associated toxicity rate is defined as the proportion of participants who experience grade 3 asparaginase-associated toxicities (including thromboembolic events, pancreatitis, hypertriglyceridemia, hyperbilirubinemia, hypersensitivity, and hyperglycemia) that are assessed as possibly, probably, or definitely related to the study treatment during the induction, consolidation, or continuation phases. Toxicity grades are determined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
Time frame: Adverse events will be followed for 30 days after completion of protocol treatment, with the overall treatment period up to 115 weeks.
Grade 3 Orthopedic Toxicity Rate
Grade 3 orthopedic toxicity rate is defined as the proportion of participants who experience grade 3 osteopenia or osteoporosis that are assessed as possibly, probably, or definitely related to the study treatment at the end of treatment, or osteonecrosis (ON) or fractures during or after treatment. Toxicity grades are assigned according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
Time frame: Adverse events will be followed for 30 days after completion of protocol treatment, with the overall treatment period up to 115 weeks. Ostenonecrosis and fractures will be followed up to 10 years.
Complete remission Rate (CRR)
CRR is defined as proportion of participants who achieve CR. Complete response (CR) is defined as an interpretable bone marrow with less than 5% malignant lymphoblasts, no lymphoblasts in peripheral blood, an absolute phagocyte count greater than 1000/µL and platelets above 100,000/µL (for participants with M2 marrow at Day 32 who achieve CR at TP2, APC above 500/µL and platelets above 50,000/µL are acceptable), no evidence of extramedullary leukemia or blasts in spinal fluid, at least a 70% reduction in the anterior mediastinal mass if present at diagnosis as measured by the sum of the products of the two greatest diameters on CT or chest X-ray, and for any other large radiographic masses at diagnosis, a 70% reduction in SPD if restaging imaging is obtained.
Time frame: CR can be documented either at the end of Induction IA (32 days) or Induction IB (74 days).
Measurable Residual Disease (MRD) Negativity Rate at the end of Induction IA (Time Point 1)
The proportion of who achieve measurable residual disease (MRD) negativity at the end of Induction IA (Time Point 1). MRD negativity is assessed by multiparameter flow cytometry (MPFC), next-generation sequencing (NGS), and/or KMT2A::AFF4 RT-PCR.
Time frame: At the end of Induction IA (32 days from study start)
Measurable Residual Disease (MRD) Negativity Rate at the end of Induction IB (Time Point 2)
The proportion of who achieve measurable residual disease (MRD) negativity at the end of Induction IB (Time Point 2). MRD negativity is assessed by multiparameter flow cytometry (MPFC), next-generation sequencing (NGS), and/or KMT2A::AFF4 RT-PCR.
Time frame: At the end of Induction IB (74 days from study start)
Measurable Residual Disease (MRD) Negativity Rate at Time Point 3 (TP3)
The proportion of who achieve measurable residual disease (MRD) negativity at TP3. MRD negativity is assessed by multiparameter flow cytometry (MPFC), next-generation sequencing (NGS), and/or KMT2A::AFF4 RT-PCR.
Time frame: For CD19-positive B-ALL, TP3 is reached at the end of Blinatumomab Cycle 2 on Day 28 (Day 130 from study start). For T-cell ALL or participants not receiving blinatumomab, TP3 occurs on Day 28 of Consolidation IC (Day 102 from study start).
Median Event-Free Survival (EFS)
EFS based on Kaplan-Meier method is defined as the time from registration to induction failure, relapse, second malignancy, or death due to any cause. Relapse is defined as the presence of more than 5% lymphoblasts in bone marrow confirmed by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests; the development of biopsy-proven extramedullary disease (e.g., CSF, testicle, lymph node, skin); or CNS relapse, defined as a CSF sample with more than 5 WBCs per high-power field with lymphoblasts on cytospin, or two consecutive CSF specimens meeting the CNS-2 criteria (\<5 WBC/µL with lymphoblasts) obtained at least three weeks apart. Participants alive without disease relapse are censored at date of last disease evaluation (which can include clinical evaluation and blood counts, does not require a bone marrow examination).
Time frame: Up to 10 years
Median Disease-Free Survival (DFS)
DFS based on Kaplan-Meier method is defined as the time from confirmed complete remission (CR) to the earlier of relapse or death due to any cause. Relapse is defined as the presence of more than 5% lymphoblasts in bone marrow confirmed by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests; the development of biopsy-proven extramedullary disease (e.g., CSF, testicle, lymph node, skin); or CNS relapse, defined as a CSF sample with more than 5 WBCs per high-power field with lymphoblasts on cytospin, or two consecutive CSF specimens meeting the CNS-2 criteria (\<5 WBC/µL with lymphoblasts) obtained at least three weeks apart. Participants who are alive without disease relapse are censored at the date of last disease evaluation.
Time frame: Up to 10 years
Median Overall Survival (OS)
Overall Survival (OS) based on Kaplan-Meier method is defined as the time from registration to death due to any cause or censored at date last known alive.
Time frame: Up to 10 years
Rate of Allogeneic Transplantation
Rate of allogeneic transplantation is defined as the proportion of participants who undergo allogeneic transplantation while in their first complete remission (CR).
Time frame: CR can be documented either at the end of Induction IA (32 days) or Induction IB (74 days).
Reason of Allogeneic Transplantation
This outcome measures the number of participants who undergo allogeneic transplantation in their first complete remission (CR) and the reasons for transplantation.
Time frame: CR can be documented either at the end of Induction IA (32 days) or Induction IB (74 days).
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