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

NCT ID: NCT00666588

Last Updated: 2018-05-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2012-12-31

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.

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

idarubicin

Intervention Type: DRUG

Given IV

cytarabine

Intervention Type: DRUG

Given IV or IT

bortezomib

Intervention Type: DRUG

Given IV

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

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.

Group Type: EXPERIMENTAL

cytarabine

Intervention Type: DRUG

Given IV or IT

bortezomib

Intervention Type: DRUG

Given IV

etoposide

Intervention Type: DRUG

Given IV

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

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).

Group Type: EXPERIMENTAL

cytarabine

Intervention Type: DRUG

Given IV or IT

bortezomib

Intervention Type: DRUG

Given IV

etoposide

Intervention Type: DRUG

Given IV

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

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

Group Type: EXPERIMENTAL

cytarabine

Intervention Type: DRUG

Given IV or IT

bortezomib

Intervention Type: DRUG

Given IV

etoposide

Intervention Type: DRUG

Given IV

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

idarubicin

Given IV

Intervention Type: DRUG

cytarabine

Given IV or IT

Intervention Type: DRUG

bortezomib

Given IV

Intervention Type: DRUG

etoposide

Given IV

Intervention Type: DRUG

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

4-demethoxydaunorubicin; 4-DMDR; DMDR; IDA; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; LDP 341; MLN341; VELCADE; EPEG; VP-16; VP-16-213

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.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeffrey Moscow

Role: PRINCIPAL_INVESTIGATOR

Children's Oncology Group

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Phoenix Childrens Hospital

Phoenix, Arizona, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Southern California Permanente Medical Group

Downey, California, United States

Miller Children's Hospital

Long Beach, California, United States

Children's Hospital and Research Center at Oakland

Oakland, California, United States

Childrens Hospital of Orange County

Orange, California, United States

Packard Children's Hospital Stanford University

Palo Alto, California, United States

University of California San Francisco Medical Center

San Francisco, California, United States

Connecticut Children's Medical Center

Hartford, Connecticut, United States

Alfred I duPont Hospital for Children

Wilmington, Delaware, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Broward General Medical Center

Fort Lauderdale, Florida, United States

Lee Memorial Health System

Fort Myers, Florida, United States

Nemours Children's Clinic - Jacksonville

Jacksonville, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, United States

Nemours Childrens Clinic - Orlando

Orlando, Florida, United States

Nemours Children's Clinic - Pensacola

Pensacola, Florida, United States

All Children's Hospital

St. Petersburg, Florida, United States

Saint Joseph Children's Hospital of Tampa

Tampa, Florida, United States

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, United States

Memorial Health University Medical Center

Savannah, Georgia, United States

University of Hawaii

Honolulu, Hawaii, United States

Childrens Memorial Hospital

Chicago, Illinois, United States

Southern Illinois University

Springfield, Illinois, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

University of Kentucky

Lexington, Kentucky, United States

Tulane University Health Sciences Center

New Orleans, Louisiana, United States

Sinai Hospital of Baltimore

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

Michigan State University - Breslin Cancer Center

East Lansing, Michigan, United States

Helen DeVos Children's Hospital at Spectrum Health

Grand Rapids, Michigan, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota, United States

University of Minnesota Medical Center-Fairview

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

The Childrens Mercy Hospital

Kansas City, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Nevada Cancer Research Foundation CCOP

Las Vegas, Nevada, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

UMDNJ - Robert Wood Johnson University Hospital

New Brunswick, New Jersey, United States

Newark Beth Israel Medical Center

Newark, New Jersey, United States

Overlook Hospital

Summit, New Jersey, United States

University of New Mexico

Albuquerque, New Mexico, United States

Columbia University Medical Center

New York, New York, United States

State University of New York Upstate Medical University

Syracuse, New York, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Carolinas Medical Center

Charlotte, North Carolina, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

Children's Hospital Medical Center of Akron

Akron, Ohio, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

The Children's Medical Center of Dayton

Dayton, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Legacy Emanuel Hospital and Health Center

Portland, Oregon, United States

Penn State Hershey Children's Hospital

Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Palmetto Health Richland

Columbia, South Carolina, United States

Sanford University of South Dakota Medical Center

Sioux Falls, South Dakota, United States

East Tennessee Childrens Hospital

Knoxville, Tennessee, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Driscoll Children's Hospital

Corpus Christi, Texas, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

University of Texas Health Science Center

San Antonio, Texas, United States

Primary Children's Medical Center

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

Saint Vincent Hospital

Green Bay, Wisconsin, United States

Marshfield Clinic

Marshfield, Wisconsin, United States

Midwest Children's Cancer Center

Milwaukee, Wisconsin, United States

Princess Margaret Hospital for Children

Perth, Western Australia, Australia

CancerCare Manitoba

Winnipeg, Manitoba, Canada

IWK Health Centre

Halifax, Nova Scotia, Canada

Hospital for Sick Children

Toronto, Ontario, Canada

Hospital Sainte-Justine

Montreal, Quebec, Canada

Countries

United States; Australia; Canada

Other Identifiers

U10CA098543

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000594224

Identifier Type: REGISTRY

Identifier Source: secondary_id

COG-AAML07P1

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-2009-00323

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-2009-00323

Identifier Type: -

Identifier Source: org_study_id