Total Therapy XVII for Leukemia

Recruiting at 8 trial locations

Overseen By Hiroto Inaba, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: St. Jude Children's Research Hospital

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

790 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants should have no prior therapy or limited prior therapy, which might imply some restrictions. It's best to discuss your current medications with the trial team for specific guidance.

What data supports the effectiveness of the drug Asparaginase Erwinia chrysanthemi (recombinant)-rywn in treating leukemia?

Research shows that Asparaginase Erwinia chrysanthemi is effective for patients with acute lymphoblastic leukemia (ALL) who develop hypersensitivity to E. coli-derived asparaginases. It maintains adequate asparaginase activity levels, which are crucial for the treatment's success, and has a safety profile consistent with other asparaginases. ^{1 2 3 4 5}

Is Asparaginase Erwinia chrysanthemi (recombinant)-rywn safe for humans?

Asparaginase Erwinia chrysanthemi (recombinant)-rywn has been shown to be generally safe in humans, but it can cause side effects like pancreatitis (inflammation of the pancreas), allergic reactions, and increased liver enzymes. In a study, 51% of patients experienced serious side effects, leading to discontinuation in some cases. ^{1 2 3 4 6}

What makes the drug Asparaginase Erwinia chrysanthemi (recombinant)-rywn unique for treating leukemia?

Asparaginase Erwinia chrysanthemi (recombinant)-rywn is unique because it is used for patients with leukemia who have developed hypersensitivity to E. coli-derived asparaginases. It is a recombinant version that provides an alternative with improved pharmacokinetics, requiring multiple doses to replace a single dose of the standard E. coli-derived asparaginase, making it suitable for those who cannot tolerate the standard treatment. ^{1 2 3 4 7}

Research Team

Hiroto Inaba, MD, PhD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children aged 1-18 with newly diagnosed B-cell or T-cell acute lymphoblastic leukemia (ALL) or lymphoma, who haven't had much treatment before. They must be able to give consent and not be pregnant, breastfeeding, or unwilling to use contraception.

Inclusion Criteria

I am between 1 and 18 years old.

I have been diagnosed with a type of leukemia.

My cancer has less than 25% tumor cells in my bone marrow and blood.

Exclusion Criteria

I cannot or do not want to give my consent to participate.

Participants who are pregnant or lactating. Males or females of reproductive potential must agree to use effective contraception for the duration of study participation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Remission Induction

Initial treatment phase with prednisone, vincristine, daunorubicin, and pegaspargase to induce remission

6 weeks

Weekly visits for drug administration

Early Intensification

Additional therapy for patients with standard/high-risk or low-risk with specific MRD levels

4 weeks

Frequent visits for monitoring and drug administration

Consolidation

High dose methotrexate and other drugs to consolidate remission

8 weeks

Bi-weekly visits for high dose methotrexate

Continuation

Long-term risk-directed therapy to maintain remission

120 weeks

Regular visits for ongoing treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Asparaginase Erwinia chrysanthemi (recombinant)-rywn
• Blinatumomab
• Bortezomib
• Calaspargase Pegol
• CAR T-cell / Blinatumomab
• Clofarabine
• Cyclophosphamide
• Cytarabine
• Dasatinib
• Daunorubicin
• Dexamethasone
• Doxorubicin
• Erwinase®
• Idarubicin
• Mercaptopurine
• Methotrexate
• Nelarabine
• Pegaspargase
• Quality-of-Life Assessment
• Ruxolitinib
• Thioguanine
• Vorinostat

Trial Overview The study tests a combination of drugs like Calaspargase Pegol and Bortezomib among others, aiming to improve survival rates by targeting specific genetic features of the leukemia. It includes precision medicine strategies and therapies such as CAR T cells for certain patients.

Participant Groups

Group I: T-ALL and T-LLy, Standard-risk Experimental Treatment 18 Interventions

Induction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Continuation (120 wks). During Remission Induction therapy, prednisone dose is 60mg/m\^2 and 3 doses daunorubicin are given. Dasatinib is given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib is given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5% and all patients with ETP and T/M MPAL and LLy patients who don't qualify for complete response at end of Remission Induction. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD ≥ 5%. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin, nelarabine, thioguanine.

Group II: T-ALL and T-LLy, High-risk Experimental Treatment 21 Interventions

Induction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Reintensification. During Remission Induction therapy, prednisone dose is 60mg/m\^2 and 3 doses daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib given as done for patients with standard-risk T-ALL but are discontinued in Reintensification therapy. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, etoposide, dexamethasone, clofarabine, vorinostat, idarubicin, nelarabine, thioguanine..

Group III: B-ALL and B-LLy, Standard-risk Experimental Treatment 18 Interventions

Induction (6wks), Early Intensification (4wks), Consolidation (8wks) and Continuation (120 wks). Remission Induction: Prednisone dose is 40mg/m\^2 and 2 doses daunorubicin are given. Dasatinib: given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib: given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5%, LLy patients who don't qualify for complete response at end of Remission Induction and all patients with ETP and T/M MPAL. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD \>5%. Blinatumomab will be given to patients with residual disease at the end of induction (≥0.01% and \<1%), certain genetic subtypes and Down syndrome. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, thioguanine, methotrexate, dexamethasone, doxorubicin

Group IV: B-ALL and B-LLy, Low-risk Experimental Treatment 15 Interventions

Patients with low-risk B ALL and LLy will have Induction (6 weeks), Consolidation (8 weeks), and Continuation (120 weeks). During Remission Induction therapy, prednisone dose is 40mg/m\^2 and 1-2 doses of daunorubicin (based on day 8 peripheral blood MRD in patients with ETV6-RUNX1 or hyperdiploid) are given. Dasatinib is given for patients with ABL-class fusion. Blinatumomab will be given to patients with certain genetic subtypes and those with Down syndrome. Interventions: Prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, thioguanine, methotrexate, dexamethasone, blinatumomab.

Group V: B-ALL and B-LLy, High-risk Experimental Treatment 19 Interventions

Induction (6 weeks), Early Intensification (4 weeks), Consolidation (8 weeks), and Immunotherapy (chimeric antigen receptor \[CAR\] T cells). Patients who do not respond to Immunotherapy will receive Reintensification therapy. During Remission Induction therapy, prednisone dose is 40mg/m\^2 and 2 doses of daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib are given as done for patients with standard-risk B-ALL but are discontinued in Immunotherapy and Reintensification therapy. Blinatumomab will be given to patients who are not able to receive CAR T cell therapy and patients with certain genetic subtypes and those with Down syndrome. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, etoposide, dexamethasone, clofarabine, thioguanine, methotrexate.

Group VI: ALL, CEP72 T/T, Vincristine Experimental Treatment 1 Intervention

Patients with the CEP72 rs904627T/T genotype (\~16% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive either 1.5 mg/m\^2 or 1 mg/m\^2 of vincristine after Continuation Week 1. Patients in low- risk will complete vincristine in Week 49 and those in standard/high-risk will complete in Week 101. Intervention: vincristine.

Group VII: ALL, CEP72 C/T or C/C, Vincristine Experimental Treatment 4 Interventions

Patients with either a CEP72 rs904627 C/T or C/C genotype (\~84% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive vincristine (2 mg/m\^2 per dose except during Reinduction I and Reinduction II when 3 weekly doses of 1.5 mg/m\^2 will be given) and dexamethasone pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation Treatment. Patients at low-risk will complete vincristine in Week 49. Interventions: vincristine, dexamethasone, methotrexate, mercaptopurine.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Servier

Industry Sponsor

Trials

55

Recruited

45,600+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Amgen

Industry Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

References

1. Italy pubmed.ncbi.nlm.nih.gov

Back to the future: the amazing journey of the therapeutic anti-leukemia enzyme asparaginase Erwinia chrysanthemi. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: A report from the Children's Oncology Group. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to E. coli-derived asparaginase. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Asparaginase Erwinia chrysanthemi (Erwinaze®): a guide to its use in acute lymphoblastic leukemia in the USA. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Optimizing asparaginase therapy for acute lymphoblastic leukemia. [2020]

7. Greece pubmed.ncbi.nlm.nih.gov

Pharmacoanalytical assays of Erwinia asparaginase (erwinase) and pharmacokinetic results in high-risk acute lymphoblastic leukemia (HR ALL) patients: simulations of erwinase population PK-PD models. [2007]