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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


Phase 2
1 Year
21 Years
Not Enrolling
Both
Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myelomonocytic Leukemia (M4), Childhood Acute Basophilic Leukemia, Childhood Acute Eosinophilic Leukemia, Childhood Acute Erythroleukemia (M6), Childhood Acute Megakaryocytic Leukemia (M7), Childhood Acute Minimally Differentiated Myeloid Leukemia (M0), Childhood Acute Monoblastic Leukemia (M5a), Childhood Acute Monocytic Leukemia (M5b), Childhood Acute Myeloblastic Leukemia With Maturation (M2), Childhood Acute Myeloblastic Leukemia Without Maturation (M1), Childhood Acute Myelomonocytic Leukemia (M4), Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

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Trial Information

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


PRIMARY OBJECTIVES:

I. To determine the toxicities and tolerability of bortezomib in combination with
standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in
pediatric and young adult patients with relapsed or primary-refractory or secondary AML.

II. To estimate the complete response rate to the Arm A and Arm B regimens.

SECONDARY OBJECTIVES:

I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces
apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of
measuring AML stem cells in relapsed and recovering bone marrow.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified
according to anthracycline*-equivalent cumulative exposure (≤ 400 mg/m² vs > 400 mg/m²).
Patients are assigned to 1 of 2 groups.

GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative
exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days
1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and
8.

GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with > 400
mg/m² anthracycline*-equivalent cumulative exposure): Patients receive etoposide IV over 1
hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and
bortezomib IV on days 1, 4, and 8.

NOTE: * Anthracycline restriction no longer required for group 2 as of 10/02/10.

All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms,
treatment repeats every 28 days for up to 2 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study therapy, patients are followed periodically for at least 5 years.


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 traumaticlumbar 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 aspremedication 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 containingproducts, any products containing
vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbalsupplements), 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 P450system, 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose (MTD) of bortezomib when given with chemotherapy regimen

Outcome Time Frame:

Weekly during courses 1 and 2

Safety Issue:

No

Principal Investigator

Jeffrey Moscow

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00323

NCT ID:

NCT00666588

Start Date:

April 2008

Completion Date:

Related Keywords:

  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Childhood Acute Basophilic Leukemia
  • Childhood Acute Eosinophilic Leukemia
  • Childhood Acute Erythroleukemia (M6)
  • Childhood Acute Megakaryocytic Leukemia (M7)
  • Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Childhood Acute Monoblastic Leukemia (M5a)
  • Childhood Acute Monocytic Leukemia (M5b)
  • Childhood Acute Myeloblastic Leukemia With Maturation (M2)
  • Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
  • Childhood Acute Myelomonocytic Leukemia (M4)
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Basophilic, Acute
  • Leukemia, Eosinophilic, Acute
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Hypereosinophilic Syndrome

Name

Location

Baylor College of MedicineHouston, Texas  77030
Cleveland Clinic FoundationCleveland, Ohio  44195
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Rhode Island HospitalProvidence, Rhode Island  02903
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Marshfield ClinicMarshfield, Wisconsin  54449
Newark Beth Israel Medical CenterNewark, New Jersey  07112
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's National Medical CenterWashington, District of Columbia  20010-2970
Broward General Medical CenterFort Lauderdale, Florida  33316
All Children's HospitalSt. Petersburg, Florida  33701
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Overlook HospitalSummit, New Jersey  07902-0220
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Lee Memorial Health SystemFort Myers, Florida  33902
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Connecticut Children's Medical CenterHartford, Connecticut  06106
University of North CarolinaChapel Hill, North Carolina  27599
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
University of Texas Health Science CenterSan Antonio, Texas  78284
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
University of New MexicoAlbuquerque, New Mexico  87131
Tulane University Health Sciences CenterNew Orleans, Louisiana  70112
Memorial Health University Medical CenterSavannah, Georgia  31404
Seattle Children's HospitalSeattle, Washington  98105
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
University of HawaiiHonolulu, Hawaii  96813
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
Sanford University of South Dakota Medical CenterSioux Falls, South Dakota  57117-5134
Saint Vincent HospitalGreen Bay, Wisconsin  54301
Cook Children's Medical CenterFort Worth, Texas  76104
The Children's Medical Center of DaytonDayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
University of California San Francisco Medical CenterSan Francisco, California  94143
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
Childrens Hospital of PittsburghPittsburgh, Pennsylvania  15213
Riley Hospital for ChildrenIndianapolis, Indiana  46202
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Phoenix Childrens HospitalPhoenix, Arizona  85016
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916