Clinical trial NCT00666588: Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-04-25
Enrollment: 52
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Dose Limiting Toxicity
timeFrame: During Course 1
measure: Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1
timeFrame: After course 1
Secondary outcomes:
measure: NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)
timeFrame: At baseline, prior to and up to 24 hours after bortezomib treatment
measure: Proteasome Inhibition Activity
timeFrame: At baseline
measure: Protein Expression Assessed by Western Blot
timeFrame: At baseline, prior to and up to 24 hours after bortezomib treatment
measure: Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion
timeFrame: At baseline and after completion of course 1
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Long Beach
country: United States
facility: Miller Children's Hospital
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Packard Children's Hospital Stanford University
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Broward General Medical Center
state: Florida
city: Fort Myers
country: United States
facility: Lee Memorial Health System
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic - Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Orlando
country: United States
facility: Nemours Childrens Clinic - Orlando
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Saint Joseph Children's Hospital of Tampa
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Childrens Memorial Hospital
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: East Lansing
country: United States
facility: Michigan State University - Breslin Cancer Center
state: Michigan
city: Grand Rapids
country: United States
facility: Helen DeVos Children's Hospital at Spectrum Health
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson University Hospital
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Summit
country: United States
facility: Overlook Hospital
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: The Children's Medical Center of Dayton
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Legacy Emanuel Hospital and Health Center
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Childrens Hospital of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Columbia
country: United States
facility: Palmetto Health Richland
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford University of South Dakota Medical Center
state: South Dakota
city: Knoxville
country: United States
facility: East Tennessee Childrens Hospital
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Corpus Christi
country: United States
facility: Driscoll Children's Hospital
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Green Bay
country: United States
facility: Saint Vincent Hospital
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hospital Sainte-Justine
state: Quebec
Study officials:
affiliation: Children's Oncology Group
name: Jeffrey Moscow
role: PRINCIPAL_INVESTIGATOR
References: