Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

A Phase II Pilot Trial of Bortezomib (PS-341, Velcade) in Combination With Intensive Re-Induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL)

This pilot, phase II trial studies the side effects of giving bortezomib together with combination chemotherapy and to see how well it works in treating young patients with relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: L-asparaginase; Drug: doxorubicin hydrochloride; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Drug: cytarabine; Drug: prednisone; Drug: bortezomib; Drug: pegaspargase; Drug: methotrexate; Drug: etoposide phosphate; Drug: cyclophosphamide; Biological: filgrastim; Drug: leucovorin calcium; Drug: High Dose MTX

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the toxicity, second complete response (CR2) rate at the end of Block 1 therapy, and 4-month event-free survival (EFS) for pediatric and young adult patients with relapsed acute lymphoblastic leukemia (ALL) treated with bortezomib in combination with intensive re-induction chemotherapy.

II. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen.

SECONDARY OBJECTIVES:

I. To assess minimal residual disease (MRD) in bone marrow following completion of each therapy block.

II. To assess the feasibility of measuring leukemia initiating cells (LIC) in patient samples before and after chemotherapy.

III. To discover biologic pathways associated with response and drug resistance using gene and protein expression profiles at baseline and following initial exposure to chemotherapy.

IV. To determine if bortezomib inhibits lymphoblast nuclear factor (NF)-kappa (k)-B activity in leukemia patients.

OUTLINE:

REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; prednisone orally (PO) twice daily (BID) on days 1-28; bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) or IV over 1-2 hours on days 2, 8, 15, and 22. Patients with central nervous system (CNS)-negative disease (CNS1 or CNS2) also receive methotrexate IT on days 15 and 29; patients with CNS-positive disease (CNS3) receive triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and cytarabine IT on days 8, 15, 22, and 29. After completion of reinduction block 1, patients with ALL and M2 or M3 bone marrow proceed directly to reinduction block 2. Patients with ALL and M1 bone marrow or lymphoblastic lymphoma proceed to reinduction block 2 after blood counts recover. Patients with persistent cerebral spinal fluid (CSF) blasts after 6 doses of TIT or patients with progressive lymphoblastic lymphoma are removed from the study.

REINDUCTION BLOCK 2: Patients receive etoposide phosphate IV over 1-2 hours on days 1-5; cyclophosphamide IV over 15-30 minutes on days 1-5; bortezomib IV over 3-5 seconds on days 1, 4, and 8; filgrastim (G-CSF) subcutaneously (SC) or IV daily beginning on day 6 and continuing until blood counts recover*; high-dose methotrexate IV over 24 hours on day 22; and leucovorin calcium PO or IV every 6 hours on days 23 and 24. Patients with CNS-negative disease also receive methotrexate IT on days 1 and 22; patients with CNS-positive disease receive TIT on days 1 and 22. After completion of reinduction block 2, patients proceed to reinduction block 3 immediately or when blood counts recover. Patients with disease progression are removed from the study.

NOTE: *Patients do not receive G-CSF on day 8.

REINDUCTION BLOCK 3: Patients receive cytarabine IV over 3 hours BID on days 1, 2, 8, and 9; L-asparaginase IM on days 2 and 9; and G-CSF SC or IV daily beginning on day 10 and continuing until blood counts recover.

After completion of study treatment, patients are followed every 6 months for 3 years and then annually for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Newfoundland and Labrador
    • Saint John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Child Health Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3G9
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Hamilton, Ontario, Canada, L8S 4L8
      • Chedoke-McMaster Hospitals
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • The Montreal Children's Hospital of the MUHC
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• Puerto Rico
  • San Juan, Puerto Rico, 00912
    • San Jorge Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • Duarte, California, United States, 91010
      • City of Hope
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93636-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center at Oakland
    • Orange, California, United States, 92868-3874
      • Childrens Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • Sacramento, California, United States, 95817
      • University of California at Davis Cancer Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20057
      • Lombardi Comprehensive Cancer Center at Georgetown University
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward Health Medical Center
    • Fort Myers, Florida, United States, 33908
      • Golisano Children's Hospital of Southwest Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Healthcare System - Joe DiMaggio Children's Hospital
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville South
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Orlando, Florida, United States, 32803
      • Florida Hospital
    • Orlando, Florida, United States, 32806
      • UF Cancer Center at Orlando Health
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • Saint Joseph Children's Hospital of Tampa
    • West Palm Beach, Florida, United States, 33407
      • Saint Mary's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
    • Savannah, Georgia, United States, 31404
      • Memorial University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Mountain States Tumor Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Hospital and Health Services
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Children's Hospital
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital New Orleans
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital for Children at Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48236
      • Saint John Hospital and Medical Center
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • East Lansing, Michigan, United States, 48824-7016
      • Michigan State University Clinical Center
    • Flint, Michigan, United States, 48502
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49008
      • Kalamazoo Center for Medical Studies
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Columbia Regional
    • Kansas City, Missouri, United States, 64108
      • The Childrens Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Saint John's Mercy Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center of Omaha
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Nevada Cancer Research Foundation CCOP
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Morristown, New Jersey, United States, 07962
      • Morristown Memorial Hospital
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • UMDNJ - Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Paterson, New Jersey, United States, 07503
      • Saint Joseph's Regional Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center - Moses Campus
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital-Memorial Campus
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Medical Center-Fargo
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
    • Toledo, Ohio, United States, 43606
      • The Toledo Hospital/Toledo Children's Hospital
    • Toledo, Ohio, United States, 43608
      • Mercy Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at Saint Francis
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Children's Hospital
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-2001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health Richland
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Cancer Treatment Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T C Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Childrens Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Science Center-Amarillo
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Norfolk, Virginia, United States, 23507
      • Childrens Hospital-King's Daughters
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Roanoke, Virginia, United States, 24014
      • Carilion Clinic Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center and Children's Hospital
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University Charleston
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 31 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis

  • Pre-B ALL in first early (< 36 months from diagnosis) isolated bone marrow (BM) or combined BM/extramedullary relapse; or
  • T-cell ALL in first isolated BM or combined relapse; or
  • T-LL in first relapse
• Patients with leukemia must have had histologic verification of the malignancy at relapse, including immunophenotyping to confirm diagnosis
• Patients with lymphoblastic lymphoma must have measurable disease documented by clinical, radiographic, or histologic criteria; patients must have relapsed or become refractory to conventional therapy
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study
• Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• At least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy
• At least 7 days since the completion of therapy with a biologic agent or donor lymphocyte infusions (DLI); for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• No evidence of active graft-vs-host disease (GVHD) and >= 4 months must have elapsed; must not be receiving GVHD prophylaxis

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

  • 1 month to < 6 months (0.4 male, 0.4 female)
  • 6 months to < 1 year (0.5 male, 0.5 female)
  • 1 to < 2 years (0.6 male, 0.6 female)
  • 2 to < 6 years (0.8 male, 0.8 female)
  • 6 to < 10 years (1 male, 1 female)
  • 10 to < 13 years (1.2 male, 1.2 female)
  • 13 to < 16 years (1.5 male, 1.4 female)
  • >= 16 years (1.7 male, 1.4 female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x ULN for age, unless elevation due to leukemia infiltration
• Shortening fraction of >= 27% by echocardiogram, or
• Ejection fraction of >= 50% by gated radionuclide study
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry >= 94% at sea level (> 90% if at high altitude)
• No evidence of acute pulmonary infiltrates on chest radiograph
• Patients with seizure disorder may be enrolled if on allowed anticonvulsants and well controlled; benzodiazepines and gabapentin are acceptable
• Central nervous system (CNS) toxicity =< grade 2
• Peripheral nervous system (PNS) toxicity < grade 3
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, FDA, and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Patients with Philadelphia chromosome positive ALL are not eligible unless refractory to at least one tyrosine kinase inhibitor (TKI) therapy; patients that are unable to tolerate TKI therapy due to toxicity are eligible
• Patients with mature B-cell ALL, ie, leukemia with B-cell (soluble immunoglobulin [sIg] positive and kappa or lambda restricted positivity) ALL, with French-American-British (FAB) L3 morphology and/or a myc translocation, are not eligible
• Extramedullary disease status: patients with isolated CNS disease or isolated testicular disease are not eligible
• Patients with known optic nerve and/or retinal involvement are not eligible; patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, an magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
• Patients with concomitant genetic syndrome: patients with Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome are not eligible
• Cumulative prior anthracycline exposure must not exceed 400 mg/m^2
• Patients taking anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible; benzodiazepines and gabapentin are acceptable
• Patients who have previously received bortezomib or other proteasome inhibitors are not eligible
• Patients who have a known allergy to doxorubicin, cytarabine, both etoposide and etopophos, boron, mannitol or bortezomib are not eligible
• Patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or other toxicity) are not eligible; patients who initially receive asparaginase, but must discontinue due to toxicity, remain eligible; patients with clinically significant prior allergies to pegaspargase are eligible if Erwinia L-asparaginase can be substituted
• Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective birth control method
• Patients must not have received any prior re-induction attempts and must not have received treatment for prior extramedullary relapse; patients with primary induction failure are not eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs; Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.	Other: laboratory biomarker analysis; Correlative studies; Drug: L-asparaginase; Given IM 6000 IU/m2/dose Days 2 and 9; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: doxorubicin hydrochloride; Given IV 60 mg/m2/dose on Day 1; Other Names: ADM; ADR; Adria; Drug: therapeutic hydrocortisone; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22; Other Names: Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; Drug: vincristine sulfate; Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Drug: cytarabine; Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: prednisone; Given PO or IV 40 mg/m2/day on Days 1-28; Other Names: DeCortin; Deltra; Drug: bortezomib; Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8; Other Names: MLN341; LDP 341; VELCADE; Drug: pegaspargase; Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Drug: methotrexate; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Drug: etoposide phosphate; Given IV 100 mg/m2/dose on Days 1-5; Other Names: Etopophos; ETOP; Drug: cyclophosphamide; Given IV 440 mg/m2/dose on Days 1-5; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given IV or SC 5 micrograms/kg/dose Only on Day 6; Other Names: G-CSF; Neupogen; Drug: leucovorin calcium; Given PO or IV 15mg/m2/dose q6h x 3 doses; Other Names: CF; CFR; LV; Drug: High Dose MTX; IV 5000 mg/m2/dose Block 2: Day 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; methotrexate
Experimental: Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr; Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.	Other: laboratory biomarker analysis; Correlative studies; Drug: L-asparaginase; Given IM 6000 IU/m2/dose Days 2 and 9; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: doxorubicin hydrochloride; Given IV 60 mg/m2/dose on Day 1; Other Names: ADM; ADR; Adria; Drug: therapeutic hydrocortisone; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22; Other Names: Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; Drug: vincristine sulfate; Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Drug: cytarabine; Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: prednisone; Given PO or IV 40 mg/m2/day on Days 1-28; Other Names: DeCortin; Deltra; Drug: bortezomib; Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8; Other Names: MLN341; LDP 341; VELCADE; Drug: pegaspargase; Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Drug: methotrexate; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Drug: etoposide phosphate; Given IV 100 mg/m2/dose on Days 1-5; Other Names: Etopophos; ETOP; Drug: cyclophosphamide; Given IV 440 mg/m2/dose on Days 1-5; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given IV or SC 5 micrograms/kg/dose Only on Day 6; Other Names: G-CSF; Neupogen; Drug: leucovorin calcium; Given PO or IV 15mg/m2/dose q6h x 3 doses; Other Names: CF; CFR; LV; Drug: High Dose MTX; IV 5000 mg/m2/dose Block 2: Day 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; methotrexate
Experimental: Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs; Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.	Other: laboratory biomarker analysis; Correlative studies; Drug: L-asparaginase; Given IM 6000 IU/m2/dose Days 2 and 9; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: doxorubicin hydrochloride; Given IV 60 mg/m2/dose on Day 1; Other Names: ADM; ADR; Adria; Drug: therapeutic hydrocortisone; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22; Other Names: Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; Drug: vincristine sulfate; Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Drug: cytarabine; Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: prednisone; Given PO or IV 40 mg/m2/day on Days 1-28; Other Names: DeCortin; Deltra; Drug: bortezomib; Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8; Other Names: MLN341; LDP 341; VELCADE; Drug: pegaspargase; Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Drug: methotrexate; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Drug: etoposide phosphate; Given IV 100 mg/m2/dose on Days 1-5; Other Names: Etopophos; ETOP; Drug: cyclophosphamide; Given IV 440 mg/m2/dose on Days 1-5; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given IV or SC 5 micrograms/kg/dose Only on Day 6; Other Names: G-CSF; Neupogen; Drug: leucovorin calcium; Given PO or IV 15mg/m2/dose q6h x 3 doses; Other Names: CF; CFR; LV; Drug: High Dose MTX; IV 5000 mg/m2/dose Block 2: Day 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; methotrexate
Experimental: T-cell ALL (Chemotherapy); Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.	Other: laboratory biomarker analysis; Correlative studies; Drug: L-asparaginase; Given IM 6000 IU/m2/dose Days 2 and 9; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: doxorubicin hydrochloride; Given IV 60 mg/m2/dose on Day 1; Other Names: ADM; ADR; Adria; Drug: therapeutic hydrocortisone; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22; Other Names: Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; Drug: vincristine sulfate; Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Drug: cytarabine; Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: prednisone; Given PO or IV 40 mg/m2/day on Days 1-28; Other Names: DeCortin; Deltra; Drug: bortezomib; Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8; Other Names: MLN341; LDP 341; VELCADE; Drug: pegaspargase; Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Drug: methotrexate; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Drug: etoposide phosphate; Given IV 100 mg/m2/dose on Days 1-5; Other Names: Etopophos; ETOP; Drug: cyclophosphamide; Given IV 440 mg/m2/dose on Days 1-5; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given IV or SC 5 micrograms/kg/dose Only on Day 6; Other Names: G-CSF; Neupogen; Drug: leucovorin calcium; Given PO or IV 15mg/m2/dose q6h x 3 doses; Other Names: CF; CFR; LV; Drug: High Dose MTX; IV 5000 mg/m2/dose Block 2: Day 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; methotrexate
Experimental: T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy); Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.	Other: laboratory biomarker analysis; Correlative studies; Drug: L-asparaginase; Given IM 6000 IU/m2/dose Days 2 and 9; Other Names: Elspar; Colaspase; L-ASP; ASNase; Crasnitin; Drug: doxorubicin hydrochloride; Given IV 60 mg/m2/dose on Day 1; Other Names: ADM; ADR; Adria; Drug: therapeutic hydrocortisone; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22; Other Names: Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; Drug: vincristine sulfate; Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Drug: cytarabine; Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: prednisone; Given PO or IV 40 mg/m2/day on Days 1-28; Other Names: DeCortin; Deltra; Drug: bortezomib; Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8; Other Names: MLN341; LDP 341; VELCADE; Drug: pegaspargase; Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22; Other Names: Oncaspar; L-asparaginase with polyethylene glycol; PEG-ASP; PEG-L-asparaginase; Drug: methotrexate; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Drug: etoposide phosphate; Given IV 100 mg/m2/dose on Days 1-5; Other Names: Etopophos; ETOP; Drug: cyclophosphamide; Given IV 440 mg/m2/dose on Days 1-5; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Biological: filgrastim; Given IV or SC 5 micrograms/kg/dose Only on Day 6; Other Names: G-CSF; Neupogen; Drug: leucovorin calcium; Given PO or IV 15mg/m2/dose q6h x 3 doses; Other Names: CF; CFR; LV; Drug: High Dose MTX; IV 5000 mg/m2/dose Block 2: Day 22; Other Names: amethopterin; Folex; methylaminopterin; Mexate; methotrexate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy	The percentage of eligible and evaluable patients who have achieved complete response at the end Block 1 of re-induction therapy.	The outcome is measured the end of Block 1 (Day 36 of Block 1) of re-induction therapy.
Event Free Survival	Percentage of patients who were event free at 4 months	4 months after enrollment
Toxic Death Rate	The proportion of toxic death rate among all eligible patients.	4 months
Severe Adverse Events (SAE) Rate.	The proportion of SAE rate among all eligible patients	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1	Percentage of eligible and evaluable patients with MRD < 0.01% among those who had successful MRD determination at the end of Block 1.	End of Block 1 (Day 36 of Block 1) of re-induction therapy
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2	Percentage of eligible and evaluable patients with MRD < 0.01% among those who had successful MRD determination at the end of Block 2.	End of Block 2 (Day 36 of Block 2) of re-induction therapy
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3	Percentage of eligible and evaluable patients with MRD < 0.01% among those who had successful MRD determination at the end of Block 3.	End of Block 3 (Day 36 of Block 3) of re-induction therapy

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
NF-kB Activity	NF-kB activity will be measured as a continuous variable (ng NF-kB/ug protein). Differences in NF-kB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range.	Up to 5 years
Expression of Apoptotic and Cell Cycle Proteins Assessed by Using Gene and Tissue Microarrays and Immunoblots	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. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.	Up to 5 years
Change in Stem Cell Percentage	Will use descriptive statistics to assess mean +/- standard deviation for stem cell percentage before and after bortezomib treatment. If there appears to be a difference in responders vs. non-responders, stem cell percentage differences between responders and non-responders will be compared using a paired t-test or equivalent nonparametric test.	Baseline to post-treatment with bortezomib
Plasma Concentration-time Profiles	Will be analyzed using descriptive statistics and will be graphically displayed by age group and stratum. PK data will be analyzed using methods such as nonlinear mixed effects modeling to estimate bortezomib clearance and volume of distribution (and the associated 95% confidence intervals) in each age group (2-11 years and 12-16 years of age).	Up to day 8 of block 2
Pharmacokinetics (PK) of Bortezomib in Patients Receiving Multi-agent Combination Therapy.	This outcome measure cannot be reported due to the data used for analysis was not collected.	Day 8 of blocks 1 and 2

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Terzah Horton, MD PhD, Children's Oncology Group

Publications and helpful links

General Publications

• Horton TM, Whitlock JA, Lu X, O'Brien MM, Borowitz MJ, Devidas M, Raetz EA, Brown PA, Carroll WL, Hunger SP. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol. 2019 Jul;186(2):274-285. doi: 10.1111/bjh.15919. Epub 2019 Apr 7.
• Hanley MJ, Mould DR, Taylor TJ, Gupta N, Suryanarayan K, Neuwirth R, Esseltine DL, Horton TM, Aplenc R, Alonzo TA, Lu X, Milton A, Venkatakrishnan K. Population Pharmacokinetic Analysis of Bortezomib in Pediatric Leukemia Patients: Model-Based Support for Body Surface Area-Based Dosing Over the 2- to 16-Year Age Range. J Clin Pharmacol. 2017 Sep;57(9):1183-1193. doi: 10.1002/jcph.906. Epub 2017 Apr 18.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: March 31, 2009
• First Submitted That Met QC Criteria: March 31, 2009
• First Posted (Estimate): April 1, 2009

Study Record Updates

• Last Update Posted (Estimate): January 27, 2017
• Last Update Submitted That Met QC Criteria: November 30, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Lymphoma; Leukemia; Recurrence; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Etoposide; Etoposide phosphate; Leucovorin; Levoleucovorin; Prednisone; Bortezomib; Doxorubicin; Liposomal doxorubicin; Cytarabine; Methotrexate; Vincristine; Asparaginase; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Pegaspargase
• Other Study ID Numbers: NCI-2011-01908 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180886 (U.S. NIH Grant/Contract); U10CA098543 (U.S. NIH Grant/Contract); AALL07P1 (Other Identifier: CTEP)