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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00873093




Registration number
NCT00873093
Ethics application status
Date submitted
31/03/2009
Date registered
31/03/2009
Date last updated
30/11/2016

Titles & IDs
Public title
Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
Scientific title
A Phase II Pilot Trial of Bortezomib (PS-341, Velcade) in Combination With Intensive Re-Induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL)
Secondary ID [1] 0 0
NCI-2011-01908
Secondary ID [2] 0 0
NCI-2011-01908
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
B-cell Adult Acute Lymphoblastic Leukemia 0 0
B-cell Childhood Acute Lymphoblastic Leukemia 0 0
Recurrent Adult Acute Lymphoblastic Leukemia 0 0
Recurrent Adult Lymphoblastic Lymphoma 0 0
Recurrent Childhood Acute Lymphoblastic Leukemia 0 0
Recurrent Childhood Lymphoblastic Lymphoma 0 0
T-cell Adult Acute Lymphoblastic Leukemia 0 0
T-cell Childhood Acute Lymphoblastic Leukemia 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 - L-asparaginase
Treatment: Drugs - doxorubicin hydrochloride
Treatment: Drugs - therapeutic hydrocortisone
Treatment: Drugs - vincristine sulfate
Treatment: Drugs - cytarabine
Treatment: Drugs - prednisone
Treatment: Drugs - bortezomib
Treatment: Drugs - pegaspargase
Treatment: Drugs - methotrexate
Treatment: Drugs - etoposide phosphate
Treatment: Drugs - cyclophosphamide
Other interventions - filgrastim
Treatment: Drugs - leucovorin calcium
Other interventions - laboratory biomarker analysis
Treatment: Drugs - High Dose MTX

Experimental: Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs - Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.

Experimental: Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr - Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.

Experimental: Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs - Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.

Experimental: T-cell ALL (Chemotherapy) - Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.

Experimental: T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy) - Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.


Treatment: Drugs: L-asparaginase
Given IM 6000 IU/m2/dose Days 2 and 9

Treatment: Drugs: doxorubicin hydrochloride
Given IV 60 mg/m2/dose on Day 1

Treatment: Drugs: therapeutic hydrocortisone
Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22

Treatment: Drugs: vincristine sulfate
Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22

Treatment: Drugs: cytarabine
Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9

Treatment: Drugs: prednisone
Given PO or IV 40 mg/m2/day on Days 1-28

Treatment: Drugs: bortezomib
Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8

Treatment: Drugs: pegaspargase
Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22

Treatment: Drugs: methotrexate
Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22

Treatment: Drugs: etoposide phosphate
Given IV 100 mg/m2/dose on Days 1-5

Treatment: Drugs: cyclophosphamide
Given IV 440 mg/m2/dose on Days 1-5

Other interventions: filgrastim
Given IV or SC 5 micrograms/kg/dose Only on Day 6

Treatment: Drugs: leucovorin calcium
Given PO or IV 15mg/m2/dose q6h x 3 doses

Other interventions: laboratory biomarker analysis
Correlative studies

Treatment: Drugs: High Dose MTX
IV 5000 mg/m2/dose Block 2: Day 22

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy - The percentage of eligible and evaluable patients who have achieved complete response at the end Block 1 of re-induction therapy.
Timepoint [1] 0 0
The outcome is measured the end of Block 1 (Day 36 of Block 1) of re-induction therapy.
Primary outcome [2] 0 0
Event Free Survival - Percentage of patients who were event free at 4 months
Timepoint [2] 0 0
4 months after enrollment
Primary outcome [3] 0 0
Toxic Death Rate - The proportion of toxic death rate among all eligible patients.
Timepoint [3] 0 0
4 months
Primary outcome [4] 0 0
Severe Adverse Events (SAE) Rate. - The proportion of SAE rate among all eligible patients
Timepoint [4] 0 0
4 months
Secondary outcome [1] 0 0
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1 - Percentage of eligible and evaluable patients with MRD < 0.01% among those who had successful MRD determination at the end of Block 1.
Timepoint [1] 0 0
End of Block 1 (Day 36 of Block 1) of re-induction therapy
Secondary outcome [2] 0 0
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2 - Percentage of eligible and evaluable patients with MRD < 0.01% among those who had successful MRD determination at the end of Block 2.
Timepoint [2] 0 0
End of Block 2 (Day 36 of Block 2) of re-induction therapy
Secondary outcome [3] 0 0
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3 - Percentage of eligible and evaluable patients with MRD < 0.01% among those who had successful MRD determination at the end of Block 3.
Timepoint [3] 0 0
End of Block 3 (Day 36 of Block 3) of re-induction therapy

Eligibility
Key inclusion criteria
- Diagnosis

- Pre-B ALL in first early (< 36 months from diagnosis) isolated bone marrow (BM)
or combined BM/extramedullary relapse; or

- T-cell ALL in first isolated BM or combined relapse; or

- T-LL in first relapse

- Patients with leukemia must have had histologic verification of the malignancy at
relapse, including immunophenotyping to confirm diagnosis

- Patients with lymphoblastic lymphoma must have measurable disease documented by
clinical, radiographic, or histologic criteria; patients must have relapsed or become
refractory to conventional therapy

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Patients who relapse while receiving standard ALL maintenance chemotherapy will not be
required to have a waiting period before entry onto this study

- Patients who relapse on therapy other than standard ALL maintenance therapy must have
fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy,
or radiotherapy prior to entering this study

- At least 14 days since the completion of cytotoxic therapy with the exception of
hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy

- At least 7 days since the completion of therapy with a biologic agent or donor
lymphocyte infusions (DLI); for agents that have known adverse events occurring beyond
7 days after administration, this period must be extended beyond the time during which
adverse events are known to occur

- No evidence of active graft-vs-host disease (GVHD) and >= 4 months must have elapsed;
must not be receiving GVHD prophylaxis

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- 1 month to < 6 months (0.4 male, 0.4 female)

- 6 months to < 1 year (0.5 male, 0.5 female)

- 1 to < 2 years (0.6 male, 0.6 female)

- 2 to < 6 years (0.8 male, 0.8 female)

- 6 to < 10 years (1 male, 1 female)

- 10 to < 13 years (1.2 male, 1.2 female)

- 13 to < 16 years (1.5 male, 1.4 female)

- >= 16 years (1.7 male, 1.4 female)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x
ULN for age, unless elevation due to leukemia infiltration

- Shortening fraction of >= 27% by echocardiogram, or

- Ejection fraction of >= 50% by gated radionuclide study

- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry >= 94%
at sea level (> 90% if at high altitude)

- No evidence of acute pulmonary infiltrates on chest radiograph

- Patients with seizure disorder may be enrolled if on allowed anticonvulsants and well
controlled; benzodiazepines and gabapentin are acceptable

- Central nervous system (CNS) toxicity =< grade 2

- Peripheral nervous system (PNS) toxicity < grade 3

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, FDA, and National Cancer Institute (NCI) requirements for human
studies must be met
Minimum age
1 Year
Maximum age
31 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patients with Philadelphia chromosome positive ALL are not eligible unless refractory
to at least one tyrosine kinase inhibitor (TKI) therapy; patients that are unable to
tolerate TKI therapy due to toxicity are eligible

- Patients with mature B-cell ALL, ie, leukemia with B-cell (soluble immunoglobulin
[sIg] positive and kappa or lambda restricted positivity) ALL, with
French-American-British (FAB) L3 morphology and/or a myc translocation, are not
eligible

- Extramedullary disease status: patients with isolated CNS disease or isolated
testicular disease are not eligible

- Patients with known optic nerve and/or retinal involvement are not eligible; patients
presenting with visual disturbances should have an ophthalmological exam and, if
indicated, an magnetic resonance imaging (MRI) to determine optic nerve or retinal
involvement

- Patients with concomitant genetic syndrome: patients with Down syndrome, Fanconi
anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure
syndrome are not eligible

- Cumulative prior anthracycline exposure must not exceed 400 mg/m^2

- Patients taking anticonvulsants known to activate the cytochrome p450 system, in
particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are
not eligible; benzodiazepines and gabapentin are acceptable

- Patients who have previously received bortezomib or other proteasome inhibitors are
not eligible

- Patients who have a known allergy to doxorubicin, cytarabine, both etoposide and
etopophos, boron, mannitol or bortezomib are not eligible

- Patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or
Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or
other toxicity) are not eligible; patients who initially receive asparaginase, but
must discontinue due to toxicity, remain eligible; patients with clinically
significant prior allergies to pegaspargase are eligible if Erwinia L-asparaginase can
be substituted

- Patients who are pregnant or breast-feeding are not eligible for this study; negative
pregnancy tests must be obtained in girls who are post-menarchal; males or females of
reproductive potential may not participate unless they have agreed to use an effective
birth control method

- Patients must not have received any prior re-induction attempts and must not have
received treatment for prior extramedullary relapse; patients with primary induction
failure are not eligible

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
6008 - Perth
Recruitment outside Australia
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United States of America
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Alabama
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Arizona
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Arkansas
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California
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Colorado
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Connecticut
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Delaware
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District of Columbia
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Florida
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Georgia
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Hawaii
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Idaho
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Illinois
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Indiana
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Iowa
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Kentucky
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Louisiana
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Maine
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Maryland
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Massachusetts
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Michigan
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Minnesota
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Mississippi
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Nebraska
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Nevada
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New Hampshire
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New Jersey
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New Mexico
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New York
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North Carolina
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North Dakota
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Ohio
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Oklahoma
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Oregon
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Vermont
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West Virginia
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Wisconsin
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Canada
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British Columbia
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Canada
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Manitoba
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Canada
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Newfoundland and Labrador
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Canada
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Nova Scotia
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Canada
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Ontario
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Quebec
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Saskatchewan
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Puerto Rico
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San Juan

Funding & Sponsors
Primary sponsor type
Government body
Name
National Cancer Institute (NCI)
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This pilot, phase II trial studies the side effects of giving bortezomib together with
combination chemotherapy and to see how well it works in treating young patients with
relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. Bortezomib may stop the
growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in
chemotherapy work in different ways to stop the growth of cancer cells, either by killing the
cells or by stopping them from dividing. Giving bortezomib together with combination
chemotherapy may kill more cancer cells.
Trial website
https://clinicaltrials.gov/show/NCT00873093
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Terzah Horton, MD PhD
Address 0 0
Children's Oncology Group
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

Summary results
Other publications