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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03117751




Registration number
NCT03117751
Ethics application status
Date submitted
27/03/2017
Date registered
18/04/2017
Date last updated
5/03/2024

Titles & IDs
Public title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Scientific title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Secondary ID [1] 0 0
NCI-2017-00582
Secondary ID [2] 0 0
TOT17
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Lymphoblastic Leukemia 0 0
Acute Lymphoblastic Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Prednisone
Treatment: Drugs - Vincristine
Treatment: Drugs - Daunorubicin
Treatment: Drugs - Pegaspargase
Treatment: Drugs - Erwinase®
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Cytarabine
Treatment: Drugs - Mercaptopurine
Treatment: Drugs - Dasatinib
Treatment: Drugs - Methotrexate
Treatment: Drugs - Blinatumomab
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - Bortezomib
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Etoposide
Treatment: Drugs - Clofarabine
Treatment: Drugs - Vorinostat
Treatment: Drugs - Idarubicin
Treatment: Drugs - Nelarabine
Treatment: Drugs - Thioguanine
Treatment: Drugs - Asparaginase Erwinia chrysanthemi (recombinant)-rywn
Treatment: Drugs - Calaspargase Pegol

Experimental: B-ALL and B-LLy, Low-risk - 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.

Experimental: B-ALL and B-LLy, Standard-risk - 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

Experimental: B-ALL and B-LLy, High-risk - 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.

Experimental: T-ALL and T-LLy, Standard-risk - 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.

Experimental: T-ALL and T-LLy, High-risk - 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..

Experimental: ALL, CEP72 T/T, Vincristine - 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.

Experimental: ALL, CEP72 C/T or C/C, Vincristine - 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.


Treatment: Drugs: Prednisone
Given orally (PO).

Treatment: Drugs: Vincristine
Given intravenously (IV).

Treatment: Drugs: Daunorubicin
Given IV.

Treatment: Drugs: Pegaspargase
Given IV or intramuscularly (IM) .

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

Treatment: Drugs: Cyclophosphamide
Given IV.

Treatment: Drugs: Cytarabine
Given IV or by subcutaneous injection (SQ).

Treatment: Drugs: Mercaptopurine
Given PO.

Treatment: Drugs: Dasatinib
Given PO.

Treatment: Drugs: Methotrexate
Given IV.

Treatment: Drugs: Blinatumomab
Given IV.

Treatment: Drugs: Ruxolitinib
Given PO.

Treatment: Drugs: Bortezomib
Given IV or subcutaneously (SQ).

Treatment: Drugs: Dexamethasone
Given PO.

Treatment: Drugs: Doxorubicin
Given IV.

Treatment: Drugs: Etoposide
Given IV.

Treatment: Drugs: Clofarabine
Given IV.

Treatment: Drugs: Vorinostat
Given PO.

Treatment: Drugs: Idarubicin
Given IV.

Treatment: Drugs: Nelarabine
Given IV.

Treatment: Drugs: Thioguanine
Participants with mercaptopurine-related pancreatitis. Given PO.

Treatment: Drugs: 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).

Treatment: Drugs: Calaspargase Pegol
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free survival of ALL patients (EFS)
Timepoint [1] 0 0
At 3.5 years after enrollment of the last participant
Primary outcome [2] 0 0
Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation
Timepoint [2] 0 0
At 6 months after the last randomized patient completes Continuation Treatment (Week 120).
Primary outcome [3] 0 0
Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype
Timepoint [3] 0 0
After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy
Secondary outcome [1] 0 0
5-year overall survival (OS) of ALL patients compared to historical controls
Timepoint [1] 0 0
3.5 years after enrollment of the last patient
Secondary outcome [2] 0 0
EFS of LLy patients
Timepoint [2] 0 0
3.5 years after enrollment of the last patient
Secondary outcome [3] 0 0
5-year OS of LLy patients
Timepoint [3] 0 0
3.5 years after enrollment of the last patient
Secondary outcome [4] 0 0
The efficacy of blinatumomab in B-ALL patients
Timepoint [4] 0 0
3.5 years after enrollment of the last patient
Secondary outcome [5] 0 0
Comparison of MRD measurements between flow cytometry and sequencing
Timepoint [5] 0 0
From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)
Secondary outcome [6] 0 0
Log hazard ratio of the association of low level of MRD and treatment outcome
Timepoint [6] 0 0
3.5 years after enrollment of the last patient
Secondary outcome [7] 0 0
Comparison of bone marrow and peripheral blood MRD
Timepoint [7] 0 0
From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)
Secondary outcome [8] 0 0
Isolated CNS relapse in CNS1b patients
Timepoint [8] 0 0
3.5 years after enrollment of the last patient
Secondary outcome [9] 0 0
Level of clonal diversity and rise of leukemic clones during treatment
Timepoint [9] 0 0
From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)
Secondary outcome [10] 0 0
Number and type of germline or somatic genomic variants associated with drug resistance
Timepoint [10] 0 0
3.5 years after enrollment of the last participant
Secondary outcome [11] 0 0
Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo
Timepoint [11] 0 0
5 years after enrollment of the last participant
Secondary outcome [12] 0 0
Change in bone mineral density (BMD) in the tibia
Timepoint [12] 0 0
From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
Secondary outcome [13] 0 0
Change in markers of bone turnover
Timepoint [13] 0 0
From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)

Eligibility
Key inclusion criteria
- Diagnosis of B- or T-ALL or LLy by immunophenotyping:

- LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by
morphology and flow cytometry. If any of these show =25% blasts, patient will be
considered to have leukemia. Patients with MPAL are eligible.

- Age 1-18 years (inclusive).

- No prior therapy, or limited prior therapy, including systemic glucocorticoids for one
week or less, one dose of vincristine, emergency radiation therapy (e.g., to the
mediastinum, head and neck, orbit, etc.) and one dose of intrathecal chemotherapy.

- Written, informed consent and assent following Institutional Review Board (IRB),
National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of
Human Research Protections (OHRP) Guidelines.
Minimum age
1 Year
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participants who are pregnant or lactating. Males or females of reproductive potential
must agree to use effective contraception for the duration of study participation.

- Inability or unwillingness of research participant or legal guardian/representative to
give written informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
29/03/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/03/2028
Actual
Sample size
Target
Accrual to date
Final
790
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
The Royal Children's Hospital Melbourne - Parkville
Recruitment postcode(s) [1] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Michigan
Country [4] 0 0
United States of America
State/province [4] 0 0
North Carolina
Country [5] 0 0
United States of America
State/province [5] 0 0
Tennessee
Country [6] 0 0
United States of America
State/province [6] 0 0
Texas

Funding & Sponsors
Primary sponsor type
Other
Name
St. Jude Children's Research Hospital
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Incyte Corporation
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Amgen
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Servier
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03117751
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Hiroto Inaba, MD, PhD
Address 0 0
St. Jude Children's Research Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries