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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/NCT00666588




Registration number
NCT00666588
Ethics application status
Date submitted
24/04/2008
Date registered
25/04/2008
Date last updated
22/05/2018

Titles & IDs
Public title
Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia
Scientific title
A Phase II Pilot Study of Bortezomib (PS-341, Velcade) Combined With Reinduction Chemotherapy in Children and Young Adults With Recurrent, Refractory or Secondary Acute Myeloid Leukemia
Secondary ID [1] 0 0
U10CA098543
Secondary ID [2] 0 0
NCI-2009-00323
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adult Acute Monoblastic Leukemia (M5a) 0 0
Adult Acute Monocytic Leukemia (M5b) 0 0
Adult Acute Myeloblastic Leukemia With Maturation (M2) 0 0
Adult Acute Myeloblastic Leukemia Without Maturation (M1) 0 0
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities 0 0
Adult Acute Myeloid Leukemia With Del(5q) 0 0
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) 0 0
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) 0 0
Adult Acute Myelomonocytic Leukemia (M4) 0 0
Childhood Acute Basophilic Leukemia 0 0
Childhood Acute Eosinophilic Leukemia 0 0
Childhood Acute Erythroleukemia (M6) 0 0
Childhood Acute Megakaryocytic Leukemia (M7) 0 0
Childhood Acute Minimally Differentiated Myeloid Leukemia (M0) 0 0
Childhood Acute Monoblastic Leukemia (M5a) 0 0
Childhood Acute Monocytic Leukemia (M5b) 0 0
Childhood Acute Myeloblastic Leukemia With Maturation (M2) 0 0
Childhood Acute Myeloblastic Leukemia Without Maturation (M1) 0 0
Childhood Acute Myelomonocytic Leukemia (M4) 0 0
Recurrent Adult Acute Myeloid Leukemia 0 0
Recurrent Childhood Acute Myeloid Leukemia 0 0
Secondary Acute Myeloid Leukemia 0 0
Condition category
Condition code
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
Blood 0 0 0 0
Haematological diseases
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - idarubicin
Treatment: Drugs - cytarabine
Treatment: Drugs - bortezomib
Treatment: Drugs - etoposide
Other interventions - laboratory biomarker analysis

Experimental: Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure - Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age = 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.

Experimental: Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp - Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age = 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Experimental: Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp - Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age = 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).

Experimental: Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp - Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age = 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity


Treatment: Drugs: idarubicin
Given IV

Treatment: Drugs: cytarabine
Given IV or IT

Treatment: Drugs: bortezomib
Given IV

Treatment: Drugs: etoposide
Given IV

Other interventions: laboratory biomarker analysis
Correlative studies
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
Dose Limiting Toxicity
Timepoint [1] 0 0
During Course 1
Primary outcome [2] 0 0
Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1
Timepoint [2] 0 0
After course 1
Secondary outcome [1] 0 0
NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)
Timepoint [1] 0 0
At baseline, prior to and up to 24 hours after bortezomib treatment
Secondary outcome [2] 0 0
Proteasome Inhibition Activity
Timepoint [2] 0 0
At baseline
Secondary outcome [3] 0 0
Protein Expression Assessed by Western Blot
Timepoint [3] 0 0
At baseline, prior to and up to 24 hours after bortezomib treatment
Secondary outcome [4] 0 0
Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion
Timepoint [4] 0 0
At baseline and after completion of course 1

Eligibility
Key inclusion criteria
- Diagnosis of acute myeloid leukemia (AML) according to WHO classification

- At least 5% blasts in the bone marrow

- With or without extramedullary disease

- To be eligible for the dose-finding phase (closed as of 10/10) :

- Relapsed patients must meet the following criteria:

- Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21)
cytogenetics

- May be in first or any subsequent relapse

- If in first relapse, remission duration must be less than one year

- Refractory patients must meet the following criteria:

- Must have had a prior diagnosis of AML

- May have received one or more attempt at remission induction

- Patients with treatment-related AML may be previously treated or untreated for
secondary AML

- To be eligible for the efficacy phase:

- Relapsed patients must meet the following criteria:

- Must have had a prior diagnosis of AML, with no restriction on prior
cytogenetics

- Must be in first relapse

- Must not have received prior reinduction therapy

- Refractory patients must meet the following criteria:

- Must have had a prior diagnosis of AML

- Must not have received more than one attempt at remission induction (which
may consist of up to two therapy courses)

- Patients with treatment-related AML must be previously untreated for secondary
AML

- No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3)

- Patients with the following CNS status are eligible only in the absence of neurologic
symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

- CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin
preparation, regardless of the number of WBCs

- CNS 2, defined as presence of < 5/µL WBCs in CSF and cytospin positive for
blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

- CNS 2a: < 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts

- CNS 2b: = 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts

- CNS 2c: = 10/µL RBCs; = 5/µL WBCs and cytospin positive for blasts but
negative by Steinherz/Bleyer algorithm

- Patients with CNS3 disease (presence of = 5/µL WBCs in CSF and cytospin positive for
blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS
leukemia) are not eligible

- CNS toxicity = grade 2

- Lansky (patients = 16 years of age) or Karnofsky (patients > 16 years of age)
performance status (PS) 50-100%

- ECOG PS 0-2

- No Down syndrome

- No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone
marrow failure syndrome

- No evidence of active graft-vs-host disease

- Creatinine clearance or radioisotope glomerular filtration rate = 70 mL/min OR serum
creatinine based on age/gender as follows:

- 0.4 mg/dL for patients 1 month to < 6 months of age

- 0.5 mg/dL for patients 6 months to < 1 year of age

- 0.6 mg/dL for patients 1 to < 2 years of age

- 0.8 mg/dL for patients 2 to < 6 years of age

- 1 mg/dL for patients 6 to < 10 years of age

- 1.2 mg/dL for patients 10 to < 13 years of age

- 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age

- 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients = 16 years of age

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

- ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement)

- Shortening fraction = 27% by ECHO OR LVEF = 50% by gated radionuclide

- Normal respiratory rate and pulse oximetry > 94% on room air

- FEV_1 = 80% of predicted

- FVC and DLCO > 50% (corrected for hemoglobin)

- Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because
of young age) will be excluded provided they have a medical history of
significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia
requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or
pulmonary toxin exposure)

- Children with histories of resolved bronchiolitis, resolved viral pneumonias and
well-controlled asthma are eligible, even if they are unable to perform PFTs

- Patients with seizure disorder may be enrolled if on a non-enzyme-inducing
anticonvulsant and if seizures are well-controlled

- No uncontrolled infection

- No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Concurrent radiotherapy allowed for patients who present with a chloroma that is
producing or threatens to produce an irreversible neurologic deficit

- Recovered from all prior chemotherapy, immunotherapy, or radiotherapy

- More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas),
except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study
drug, and intrathecal chemotherapy, which is allowed immediately up to administration
of study drug

- Prior steroid allowed as clinically indicated for patients with asthma

- Hydrocortisone and methylprednisolone allowed as premedication in patients with a
history of severe allergic reactions

- At least 7 days since prior biologic agents, such as steroids, retinoids, or donor
lymphocyte infusion without conditioning

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 8 weeks since prior craniospinal radiotherapy or = 50% radiation of pelvis

- At least 6 weeks since prior other bone marrow radiation

- At least 1 day since prior green tea containing products, any products containing
vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and
foods with high vitamin C content

- No prior radiotherapy to > 25% of lung volume

- No prior total-body irradiation as part of a hematopoietic stem cell conditioning
regimen

- At least 2 months since prior stem cell transplantation

- No concurrent graft-vs-host disease prophylactic medication

- No prior bortezomib or other proteasome inhibitors

- No other concurrent investigational drugs

- More than 4 days since prior growth factors that support platelet or white cell number
or function

- No concurrent enzyme-inducing anticonvulsant medications known to be potent inducers
of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital

- Concurrent benzodiazepines and gabapentin allowed

- No concurrent grapefruit juice with bortezomib

- No other concurrent cancer chemotherapy or immunomodulating agents

- No concurrent corticosteroids as anti-emetic therapy

- Concurrent corticosteroids therapy allowed as treatment or prophylaxis for
anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for
presumptive bortezomib-induced pulmonary toxicity.
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

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
Parallel
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
1/04/2008
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/12/2012
Sample size
Target
Accrual to date
Final
52
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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United States of America
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Arizona
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Arkansas
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California
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Connecticut
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Delaware
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District of Columbia
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United States of America
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Florida
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Georgia
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Hawaii
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Illinois
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Indiana
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Kentucky
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Louisiana
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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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Missouri
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Nebraska
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Nevada
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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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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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Rhode Island
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South Carolina
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South Dakota
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Tennessee
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Texas
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Utah
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Washington
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Wisconsin
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Canada
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Manitoba
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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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Canada
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Quebec

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

Ethics approval
Ethics application status

Summary
Brief summary
This phase II trial is studying the side effects and best dose of bortezomib and to see how
well it works when given together with combination chemotherapy in treating younger patients
with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop
the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used
in chemotherapy, such as idarubicin, cytarabine, and etoposide, work in different ways to
stop the growth of cancer cells, either by killing the cells or by stopping them from
dividing. Giving more than one drug (combination chemotherapy) together with bortezomib may
kill more cancer cells
Trial website
https://clinicaltrials.gov/ct2/show/NCT00666588
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jeffrey Moscow
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

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT00666588