Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

Recurrent Adult Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00666588
• Other study ID #: NCI-2009-00323
• Secondary ID: U10CA098543CDR00
• Status: Completed
• Phase: Phase 2
• Start date: April 2008
• Est. completion date: December 2012

Study information

• Verified date: May 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• 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)
• Hypereosinophilic Syndrome
• Leukemia
• Leukemia, Erythroblastic, Acute
• Leukemia, Megakaryoblastic, Acute
• Leukemia, Monocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Neoplasm Metastasis
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia

Intervention

Drug:
• idarubicin
Given IV
• cytarabine
Given IV or IT
• bortezomib
Given IV
• etoposide
Given IV

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Hospital Sainte-Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	University of New Mexico	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Childrens Memorial Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	The Children's Medical Center of Dayton	Dayton	Ohio
United States	Southern California Permanente Medical Group	Downey	California
United States	Michigan State University - Breslin Cancer Center	East Lansing	Michigan
United States	Broward General Medical Center	Fort Lauderdale	Florida
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	University of Hawaii	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	University of Kentucky	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Miller Children's Hospital	Long Beach	California
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Childrens Hospital of Orange County	Orange	California
United States	Nemours Childrens Clinic - Orlando	Orlando	Florida
United States	Packard Children's Hospital Stanford University	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	University of Texas Health Science Center	San Antonio	Texas
United States	University of California San Francisco Medical Center	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford University of South Dakota Medical Center	Sioux Falls	South Dakota
United States	Southern Illinois University	Springfield	Illinois
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Saint Joseph Children's Hospital of Tampa	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicity	Number of participants with dose limiting toxicity.	During Course 1
Primary	Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1	Overall response (complete remission [CR] and CR with partial recovery [CRp]) during course 1.	After course 1
Secondary	NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)	NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-?B activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response.	At baseline, prior to and up to 24 hours after bortezomib treatment
Secondary	Proteasome Inhibition Activity	Mean and standard deviation of ß1 and ß5- Results are ratios (proteasome subunit/ß-actin based on loading of 15 µg total protein, normalized to CEM).	At baseline
Secondary	Protein Expression Assessed by Western Blot	Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.	At baseline, prior to and up to 24 hours after bortezomib treatment
Secondary	Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion	Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion.	At baseline and after completion of course 1