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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: 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

Intervention: idarubicin (Drug); cytarabine (Drug); bortezomib (Drug); etoposide (Drug); laboratory biomarker analysis (Other)

Phase: Phase 2

Status: Completed

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Jeffrey Moscow, Principal Investigator, Affiliation: Children's Oncology Group

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

Clinical Details

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

Primary outcome:

Dose Limiting Toxicity

Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1

Secondary outcome:

NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)

Proteasome Inhibition Activity

Protein Expression Assessed by Western Blot

Feasibility of Stem Cell Quantitation

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

Minimum age: 1 Year. Maximum age: 21 Years. Gender(s): Both.

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.

Locations and Contacts

University of Alabama at Birmingham, Birmingham, Alabama 35293, United States

Phoenix Childrens Hospital, Phoenix, Arizona 85016, United States

University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States

Southern California Permanente Medical Group, Downey, California 90242, United States

Miller Children's Hospital, Long Beach, California 90806, United States

Children's Hospital and Research Center at Oakland, Oakland, California 94609-1809, United States

Childrens Hospital of Orange County, Orange, California 92868-3874, United States

Packard Children's Hospital Stanford University, Palo Alto, California 94304, United States

University of California San Francisco Medical Center, San Francisco, California 94143, United States

Connecticut Children's Medical Center, Hartford, Connecticut 06106, United States

Alfred I duPont Hospital for Children, Wilmington, Delaware 19803, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

Broward General Medical Center, Fort Lauderdale, Florida 33316, United States

Lee Memorial Health System, Fort Myers, Florida 33901, United States

Nemours Children's Clinic - Jacksonville, Jacksonville, Florida 32207-8426, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center, Miami, Florida 33136, United States

Nemours Childrens Clinic - Orlando, Orlando, Florida 32806, United States

Nemours Children's Clinic - Pensacola, Pensacola, Florida 32504, United States

All Children's Hospital, Saint Petersburg, Florida 33701, United States

Saint Joseph Children's Hospital of Tampa, Tampa, Florida 33607, United States

Children's Healthcare of Atlanta - Egleston, Atlanta, Georgia 30322, United States

Memorial Health University Medical Center, Savannah, Georgia 31403, United States

University of Hawaii, Honolulu, Hawaii 96813, United States

Childrens Memorial Hospital, Chicago, Illinois 60614, United States

Southern Illinois University, Springfield, Illinois 62702, United States

Riley Hospital for Children, Indianapolis, Indiana 46202, United States

University of Kentucky, Lexington, Kentucky 40536, United States

Tulane University Health Sciences Center, New Orleans, Louisiana 70112, United States

CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada

Sinai Hospital of Baltimore, Baltimore, Maryland 21215, United States

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States

C S Mott Children's Hospital, Ann Arbor, Michigan 48109, United States

Michigan State University - Breslin Cancer Center, East Lansing, Michigan 48824-1313, United States

Helen DeVos Children's Hospital at Spectrum Health, Grand Rapids, Michigan 49503, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States

University of Minnesota Medical Center-Fairview, Minneapolis, Minnesota 55455, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

University of Mississippi Medical Center, Jackson, Mississippi 39216, United States

The Childrens Mercy Hospital, Kansas City, Missouri 64108, United States

Washington University School of Medicine, Saint Louis, Missouri 63110, United States

University of Nebraska Medical Center, Omaha, Nebraska 68198-7830, United States

Nevada Cancer Research Foundation CCOP, Las Vegas, Nevada 89106, United States

Hackensack University Medical Center, Hackensack, New Jersey 07601, United States

UMDNJ - Robert Wood Johnson University Hospital, New Brunswick, New Jersey 08903, United States

Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States

Overlook Hospital, Summit, New Jersey 07902, United States

University of New Mexico, Albuquerque, New Mexico 87106, United States

Columbia University Medical Center, New York, New York 10032, United States

State University of New York Upstate Medical University, Syracuse, New York 13210, United States

University of North Carolina, Chapel Hill, North Carolina 27599, United States

Carolinas Medical Center, Charlotte, North Carolina 28203, United States

Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, United States

IWK Health Centre, Halifax, Nova Scotia B3J 3G9, Canada

Children's Hospital Medical Center of Akron, Akron, Ohio 44308, United States

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, United States

Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States

Rainbow Babies and Childrens Hospital, Cleveland, Ohio 44106, United States

Nationwide Children's Hospital, Columbus, Ohio 43205, United States

The Children's Medical Center of Dayton, Dayton, Ohio 45404, United States

University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, United States

Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Legacy Emanuel Hospital and Health Center, Portland, Oregon 97227, United States

Penn State Hershey Children's Hospital, Hershey, Pennsylvania 17033, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

Childrens Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224, United States

Hospital Sainte-Justine, Montreal, Quebec H3T 1C5, Canada

Rhode Island Hospital, Providence, Rhode Island 02903, United States

Palmetto Health Richland, Columbia, South Carolina 29203, United States

Sanford University of South Dakota Medical Center, Sioux Falls, South Dakota 57117-5134, United States

East Tennessee Childrens Hospital, Knoxville, Tennessee 37916, United States

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States

Driscoll Children's Hospital, Corpus Christi, Texas 78411, United States

University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States

Cook Children's Medical Center, Fort Worth, Texas 76104, United States

Baylor College of Medicine, Houston, Texas 77030, United States

University of Texas Health Science Center, San Antonio, Texas 78229-3900, United States

Primary Children's Medical Center, Salt Lake City, Utah 84113, United States

Seattle Children's Hospital, Seattle, Washington 98105, United States

Princess Margaret Hospital for Children, Perth, Western Australia 6008, Australia

Saint Vincent Hospital, Green Bay, Wisconsin 54301, United States

Marshfield Clinic, Marshfield, Wisconsin 54449, United States

Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: April 2008
Last updated: May 13, 2014

Page last updated: August 23, 2015

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