Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

NCT00549848 | Completed Phase 3 Results DMC FDA Drug

• 8 other identifiers: TOTXVIR01CA140729F32CA141762R37CA036401R01CA090246Aspar PK-PD-T16NCI-2011-01254P50GM115279
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this study (TOTXVI) is to compare the clinical benefit, the pharmacokinetics, and the pharmacodynamics of polyethylene glycol-conjugated (PEG) asparaginase given in higher dose (HD PEG) versus those of PEG-asparaginase given in conventional dose (CD PEG) during the continuation phase. This study has several secondary objectives: Therapeutic Objectives: To estimate the event-free survival and overall survival of children with ALL who are treated with risk-directed therapy. To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 MRD \> 5%, will result in improved leukemia cytoreduction in this subgroup compared to TOTXV. To assess whether intensification of central nervous system (CNS)-directed intrathecal and systemic chemotherapy will improve outcome in patients at high risk of CNS relapse. Exploratory Pharmacologic Objectives: To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol. To compare the pharmacokinetics and pharmacodynamics of PEG-asparaginase given in higher dose (3,500 or 3,000 units/m2) versus those of PEG-asparaginase given in conventional dose (2,500 units/m2) in the continuation phase. Exploratory Biologic Objectives: To determine the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of remission induction. To validate new markers and methods for MRD detection. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and before reinduction, and to associate these features with treatment outcome. To identify new prognostic factors by applying new technologies to study patient material (e.g., stored plasma, serum, cerebrospinal fluid, and normal and leukemic cells). Exploratory Neuroimaging Objectives: To use quantitative MR measures (Diffusion Tensor Imaging and high resolution volumetric imaging) to assess differences in myelin and cortical thickness development in patients treated for ALL relative to healthy controls matched for age and gender. To assess the impact of folate pathway genetic polymorphisms on myelin and cortical thickness development and neurocognitive performance. To assess the impact of frontal-parietal lobe myelin and cortical thickness development on neurocognitive performance in attention, working memory, fluency, visual-spatial reasoning and processing speed.

Conditions

Acute Lymphoblastic Leukemia

Keywords

Leukemia

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Continuous Complete Remission of Patients Receiving High-dose and Conventional Dose PEG-asparaginase.

  The primary objective of this study is to compare the distributions of continuous complete remission of patients randomized on the first day of the continuation phase to receive a higher dose of PEG-asparaginase or to receive the conventional dose (2,500 units/m2). The randomization will occur on the starting day of the continuation phase, at which time all information necessary for performing the randomization should be available. In the rare case that immunophenotype and/or Day-15 MRD is not available, we will make the following assumptions: If immunophenotype is unknown at the time the randomization is to be executed, then it will be assumed B-lineage. If Day-15 MRD is unknown at the time of randomization, then it will be assumed negative (\<0.01%). Past experience indicate that few patients will fall into these unknown categories.

  3.5 years after the last enrollment up to 12.5 years

Secondary Outcomes (5)

• Probability of Event-free Survival

  For Total XVI: 3.5 years after the last enrollment, up to approximately 13.5 years For Total XV: patients are followed continuously, up to 20.5 years

• Probability of Overall Survival

  For Total XVI: 3.5 years after the last enrollment, up to approximately 13.5 years For Total XV: patients are followed continuously, up to 20.5 years

• Proportion of Participants With Minimal Residual Disease (MRD) on the 15th Day of Remission Induction ≥ 5%

  Middle of remission induction, Day 15 in Total XVI and Day 19 in Total XV

• Proportion of Participants With Minimal Residual Disease (MRD) at End of Remission Induction ≥ 0.01%

  End of remission induction; day 42 in Total XVI and day 46 in Total XV

• Probability of CNS Relapse

  For Total XVI: 3.5 years after the last enrollment, up to approximately 13.5 years For Total XV: patients are followed continuously, up to 20.5 years

Study Arms (2)

HD PEG

EXPERIMENTAL

Participants randomized to receive higher dose PEG-asparaginase during the continuation phase. Interventions: * Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine * Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine; Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

CD PEG

ACTIVE COMPARATOR

Participants randomized to receive conventional dose PEG-asparaginase during the continuation phase.. Interventions: * Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine * Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

Drug: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine; Drug: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

Interventions

Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine DRUG

See Detailed Description section for details of treatment interventions.

Also known as: Prednisone: prednisolone, Vincristine: Oncovin(R), Daunorubicin: daunomycin, Cerubidine(R), PEG-L-asparaginase: pegaspargase, Oncaspar(R), Erwinia L-Asparaginase: Erwinase(R), Doxorubicin: Adriamycin(R), Cyclophosphamide: Cytoxan(R), Cytarabine: Ara-C, Cytosar-U(R), Thioguanine: 6-TG

CD PEG; HD PEG

Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib DRUG

See Detailed Description section for details of treatment interventions.

Also known as: Clofarabine: clofarex, Clolar(TM), Methotrexate: MTX, Mercaptopurine: 6-MP, Purinethol(R), Dexamethasone: Decadron(R), Etoposide: VP-16, Vepesid(R), Dasatinib: Sprycel(R)

CD PEG; HD PEG

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Participant has a confirmed diagnosis of precursor B-cell or precursor T-cell acute lymphocytic leukemia (ALL) by immunophenotyping
• Participant is less than or equal to 18 years of age
• Limited prior therapy, including systemic glucocorticoids for one week or less, one dose of vincristine, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy. Other circumstances must be cleared by principal investigator (PI) or co-PI.
• Written, informed consent and assent following Institutional Review Board, NCI, FDA, and Office for Human Research Protections (OHRP) Guidelines.

You may not qualify if:

• Participants with prior therapy, other than that listed above
• Pregnant or lactating
• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• National Cancer Institute (NCI): collaborator
• Enzon Pharmaceuticals, Inc.: collaborator
• National Institute of General Medical Sciences (NIGMS): collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Publications (9)

• Purvis K, Zhou Y, Karol SE, Rubnitz JE, Ribeiro RC, Lee S, Yang JJ, Bowman WP, Wang L, Dixon SB, Roberts KG, Gao Q, Cheng C, Mullighan CG, Jeha S, Pui CH, Inaba H. Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies. Blood. 2025 Jan 9;145(2):190-201. doi: 10.1182/blood.2024024936.

  PMID: 39316653 DERIVED

• Chang TC, Chen W, Qu C, Cheng Z, Hedges D, Elsayed A, Pounds SB, Shago M, Rabin KR, Raetz EA, Devidas M, Cheng C, Angiolillo A, Baviskar P, Borowitz M, Burke MJ, Carroll A, Carroll WL, Chen IM, Harvey R, Heerema N, Iacobucci I, Wang JR, Jeha S, Larsen E, Mattano L, Maloney K, Pui CH, Ramirez NC, Salzer W, Willman C, Winick N, Wood B, Hunger SP, Wu G, Mullighan CG, Loh ML. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. J Clin Oncol. 2024 Oct 10;42(29):3491-3503. doi: 10.1200/JCO.23.02238. Epub 2024 Aug 9.

  PMID: 39121442 DERIVED

• Panetta JC, Liu Y, Bottiglieri T, Arning E, Cheng C, Karol SE, Yang JJ, Zhou Y, Inaba H, Pui CH, Jeha S, Relling MV. Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase. Cancer Chemother Pharmacol. 2021 Oct;88(4):655-664. doi: 10.1007/s00280-021-04315-0. Epub 2021 Jun 25.

  PMID: 34170389 DERIVED

• Finch ER, Smith CA, Yang W, Liu Y, Kornegay NM, Panetta JC, Crews KR, Molinelli AR, Cheng C, Pei D, Ramsey LB, Karol SE, Inaba H, Sandlund JT, Metzger M, Evans WE, Jeha S, Pui CH, Relling MV. Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2020 Jan;67(1):e28040. doi: 10.1002/pbc.28040. Epub 2019 Oct 14.

  PMID: 31612640 DERIVED

• Liu Y, Smith CA, Panetta JC, Yang W, Thompson LE, Counts JP, Molinelli AR, Pei D, Kornegay NM, Crews KR, Swanson H, Cheng C, Karol SE, Evans WE, Inaba H, Pui CH, Jeha S, Relling MV. Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge. J Clin Oncol. 2019 Aug 10;37(23):2051-2061. doi: 10.1200/JCO.18.02439. Epub 2019 Jun 12.

  PMID: 31188727 DERIVED

• Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW. Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. Clin Infect Dis. 2018 Aug 1;67(4):541-548. doi: 10.1093/cid/ciy153.

  PMID: 29518185 DERIVED

• Wolf J, Tang L, Flynn PM, Pui CH, Gaur AH, Sun Y, Inaba H, Stewart T, Hayden RT, Hakim H, Jeha S. Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia. Clin Infect Dis. 2017 Nov 13;65(11):1790-1798. doi: 10.1093/cid/cix644.

  PMID: 29020310 DERIVED

• Bhojwani D, Darbandi R, Pei D, Ramsey LB, Chemaitilly W, Sandlund JT, Cheng C, Pui CH, Relling MV, Jeha S, Metzger ML. Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. Eur J Cancer. 2014 Oct;50(15):2685-94. doi: 10.1016/j.ejca.2014.06.023. Epub 2014 Jul 30.

  PMID: 25087182 DERIVED

• Fernandez CA, Smith C, Yang W, Date M, Bashford D, Larsen E, Bowman WP, Liu C, Ramsey LB, Chang T, Turner V, Loh ML, Raetz EA, Winick NJ, Hunger SP, Carroll WL, Onengut-Gumuscu S, Chen WM, Concannon P, Rich SS, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Relling MV. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014 Aug 21;124(8):1266-76. doi: 10.1182/blood-2014-03-563742. Epub 2014 Jun 26.

  PMID: 24970932 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia

Interventions

Prednisone; Vincristine; Daunorubicin; pegaspargase; asparaginase erwinia chrysanthemi recombinant; Doxorubicin; Cyclophosphamide; Cytarabine; Thioguanine; 6-thioguanylic acid; Clofarabine; Methotrexate; Mercaptopurine; Dexamethasone; Etoposide; Dasatinib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Purines; Adenine Nucleotides; Purine Nucleotides; Nucleotides; Ribonucleotides; Aminopterin; Pterins; Pteridines; Sulfhydryl Compounds; Sulfur Compounds; Pregnadienetriols; Steroids, Fluorinated; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Thiazoles; Azoles

Results Point of Contact

• Title: Sima Jeha, MD
• Organization: St. Jude Children's Research Hospital

sima.jeha@stjude.org

(901) 595-3901

Study Officials

• Sima Jeha, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 25, 2007
• First Posted: October 26, 2007
• Study Start: October 29, 2007
• Primary Completion: September 26, 2020
• Study Completion: March 26, 2022
• Last Updated: August 23, 2022
• Results First Posted: February 10, 2022

Record last verified: 2022-07

Locations

US (1)