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Acute Lymphoblastic LeukemiaPhase 1/2NCT00440726

Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)

A Phase 1/2 study testing Bortezomib, Dexamethasone and PEG-asparaginase in people with Acute Lymphoblastic Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 24 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This is a Phase I/II study of a drug called bortezomib given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). Read more about this study

Who is it for?
Ages 1 year to 21 years
Conditions the study is for
Acute Lymphoblastic Leukemia
What is being tested?
Bortezomib, Dexamethasone and PEG-asparaginase
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
24 sitesin 4 countries
Study dates
4 Aug 2006to 26 Feb 2011
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • The eligibility criteria listed below are interpreted literally and cannot be waived.
  • Age Patients must be < 21 years of age when originally diagnosed with ALL. Patient must be > 1 year of age at study entry.
  • Diagnosis Patients must have relapsed or refractory ALL with a M3 marrow (marrow blasts >25%). Patients with CNS I, II or III or testicular disease are eligible.
  • Performance Level Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients < 10 years of age.
  • Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
  • Prior anthracycline exposure: Patients must have less than 400mg/m2 lifetime exposure of anthracycline chemotherapy.
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  • Stem Cell Transplant (SCT): Patients are eligible after allogeneic stem cell transplant as long as patients are not actively being treated for graft-versus-host-disease (GvHD).
  • Patients should not have received previous therapy using bortezomib (Velcdade® or PS-341).
  • During the phase I portion of the trial, there is no limit on the number of prior treatment regimens. Patients with persistent disease after an induction attempt are eligible.
  • During the phase II portion of the trial, patients must have had two or more prior therapeutic attempts defined as:
  • Persistent initial disease after two induction attempts, or
  • Relapse after one-reinduction attempt (2nd relapse), or
  • Persistent disease after first relapse and initial re-induction attempt
  • (Patients in first relapse are not eligible for the phase II portion of the study)
  • During the phase II portion of the trial, patients must have no more than 3 prior therapeutic attempts and it must be at least 3 months since the last treatment with a "VPLD" induction/re-induction regimen.
  • Reproductive Function
  • Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
  • Female patients with infants must agree not to breastfeed their infants while on this study.
  • Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.

Who cannot join

  • Drug Allergies
  • Patients will be excluded if they have allergies to the following:
  • Asparaginase products
  • Boron
  • Mannitol
  • Renal Function Patients will be excluded if their serum creatinine is > 2 x the upper limit of normal for age at the institution's laboratory.
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  • Liver/Pancreatic Function
  • Direct bilirubin > 1.5x the institutional ULN for age. A total bilirubin result that is less than 1.5 times the institutional ULN for age may be used for eligibility if a direct bilirubin result is not available.
  • SGPT (ALT) > 4 x institutional ULN
  • Grade 3 or greater pancreatitis as defined by the CTCAE v3.0
  • History of any L-asparaginase induced pancreatitis
  • Amylase or Lipase > 2 x institutional ULN
  • Cardiac Function Patients will be excluded if their shortening fraction by echocardiogram is less than 30%.
  • Patients with Down Syndrome are excluded.
  • Infection
  • Patients will be excluded if they have an active uncontrolled infection.
  • Patients will be excluded if they have had a positive culture within 2 weeks of study entry.
  • Patients with grade 2 or greater motor or sensory neuropathy per CTC 3.0 criteria.
  • Patients planning on receiving other investigational agents while on this study. (An investigational agent is defined as any drug not currently approved for use in humans.)
  • Patients planning on receiving other anti-cancer therapies while on this study. Hydroxyurea for cyto-reduction is allowed prior to the start of therapy.
  • Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
  • Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure.

Trial locations and contacts

24 sites in 4 countries.

24 sites in 4 countries

United States20 sites

  • C.S. Mott Children's Hospital

    Ann Arbor, Michigan, 48109-0914

  • Children's Healthcare of Atlanta

    Atlanta, Georgia, 30322

  • Johns Hopkins / Sydney Kimmel Cancer Center

    Baltimore, Maryland, 21231

  • Dana Farber Cancer Center

    Boston, Massachusetts, 02215

  • Levine Children's Hospital

    Charlotte, North Carolina, 28203

  • Ann & Robert H. Lurie Children's Hospital of Chicago

    Chicago, Illinois, 60611

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • City of Hope

    Duarte, California, 91010

  • Miller Children's Hospital

    Long Beach, California, 90806

  • Childrens Hospital Los Angeles

    Los Angeles, California, 90027

  • University of Miami Cancer Center

    Miami, Florida, 33136

  • Childrens Hospital & Clinics of Minnesota

    Minneapolis, Minnesota, 55404-4597

  • New York University Medical Center

    New York, New York, 10016

  • Children's Hospital New York-Presbyterian

    New York, New York, 10032

  • Children's Hospital & Research Center Oakland

    Oakland, California, 94618

  • Stanford University Medical Center

    Palo Alto, California, 94304-1812

  • Primary Children's Hospital

    Salt Lake City, Utah, 84113

  • UCSF School of Medicine

    San Francisco, California, 94143-0106

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

Australia2 sites

  • Sydney Children's Hospital

    Randwick, New South Wales, 2031

  • The Children's Hospital at Westmead

    Westmead, New South Wales, 2145

Other trials in Australia

Brazil1 site

  • Universidade Federale de Sao Paulo/Hospital Sao Paulo

    São Paulo, 04023-062

Other trials in Brazil

Canada1 site

  • Sick Kids

    Toronto, Ontario, M5G1X8

Other trials in Canada

About this study

Official title: A Study of Bortezomib With Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

This is a Phase I/II study of a drug called bortezomib given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). Bortezomib is a drug that has been approved by the Food and Drug Administration (FDA) for treating adults with multiple myeloma which is a type of blood cancer. Bortezomib has been shown to cause cancer cells to die in studies done on animals (mice). Studies have been done that have shown that some adults and children with cancer have shown a response to bortezomib when it is used alone. Studies have also been done in adults to evaluate the dose of bortezomib that can be safely given in combination with other chemotherapy drugs.

Read the detailed description

All patients will receive 1 course of chemotherapy unless medical complications prevent the administration of some of the drugs. Treatment will last about 1 month.

Treatment on this study will consist of a combination of 7 anti-cancer medications. The 7 anti-cancer medicines are bortezomib, vincristine, dexamethasone, PEG-asparaginase, doxorubicin, cytarabine (Ara-C), and methotrexate (MTX).

If you are in the Phase I portion of this study, you will be given an assigned dose of bortezomib. The dose of bortezomib will be based on doses given in previous studies done with adults and children. At each dose level of bortezomib, between 3 and 6 children will receive bortezomib in combination with chemotherapy. If the side effects are not too severe, the next group of children will receive a higher dose. The dose will continue to be increased until we find the dose that causes serious side effects. Your dose of bortezomib will not be increased. If you have bad side effects, your dose may be decreased.

The dose used during the Phase 2 part of this study will be determined by the outcome of the Phase I study. The highest dose used in Phase I that was tolerated without serious side effects will be the one used in Phase 2.

Being tested
Bortezomib, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine
Keywords
Acute Lymphoblastic Leukemia, Pediatrics, Relapsed, Recurrence, Bortezomib, Velcade, Therapeutic Advances in Childhood Leukemia, Investigational, Childhood, ALL, Relapsed ALL, Refractory ALL, Relapsed pediatric ALL, Refractory pediatric ALL, TACL, Recurrent Pediatric ALL
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BortezomibDrug

    Also called Velcade

    Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.

  • DexamethasoneDrug

    Also called Decadron

    10 mg/m2/day divided BID, oral administration for 14 days.

  • PEG-asparaginaseDrug

    Also called Oncaspar

    2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22

  • DoxorubicinDrug

    Also called Adriamycin, Rubex

    60 mg/m2/day IV over 15 minutes on Day 1

  • CytarabineDrug

    Also called Cytosar-U, Ara-C, Arabinosylcytosine

    Given intrathecally on Day 1 of course 1 at the dose defined by age below.

    • 30 mg for patients age 1-1.99
    • 50 mg for patients age 2-2.99
    • 70 mg for patients >3 years of age

  • MethotrexateDrug

    Also called Otrexup, Rasuvo, Rheumatrex, Trexall

    Given intrathecally to all patients who are CNS 1 at study entry on Day 15 at the dose defined by age below.

    • 8 mg for patients age 1-1.99
    • 10 mg for patients age 2-2.99
    • 12 mg for patients 3-8.99 years of age
    • 15 mg for patients >9 years of age

  • VincristineDrug

    Also called Oncovin, Leurocristine

    1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22.

  • Triple IT TherapyDrug

    Triple IT therapy will be given intrathecally on Day 8, 15, and 22 for patients who are CNS 2 and CNS 3 at study entry. Regimen/dosing as follows:

    Methotrexate-

    • <2 years: 8 mg
    • 2 - <3 y: 10 mg
    • 3 - <9 y: 12 mg
    • >=9 y: 15 mg

    Cytarabine:

    • <2 years: 16 mg
    • 2 - <3 y: 20 mg
    • 3 - <9 y: 24 mg
    • >=9 y: 30 mg

    Hydrocortisone:

    • <2 years: 8 mg
    • 2 - <3 y: 10 mg
    • 3 - <9 y: 12 mg
    • >=9 y: 15 mg
Study groups in NCT00440726
Study groupRoleWhat they receive
Ph 1 Dose EscalationExperimentalIntervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. 3+3 escalation design.
Receives: Drug: Bortezomib; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Vincristine; Drug: Triple IT Therapy
Ph 2 Efficacy and SafetyExperimentalIntervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. Patients receive bortezomib at maximum tolerated dose (as established in the Phase 1 portion of the study) and are assessed for response and toxicity.
Receives: Drug: Bortezomib; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Vincristine; Drug: Triple IT Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Occurrence of a Dose-Limiting Toxicity (Phase 1)

    Toxicity will be graded using the CTCAE criteria, version 3.0. Dose-limiting toxicity will be defined as any of the following events that are deemed by the investigator as possibly, probably or definitely attributable to bortezomib: Grade 3 or 4 Sensory Neuropathy; Grade 3 or 4 Neuropathic pain (Neuralgia or peripheral nerve) lasting longer than 24 hours despite medical intervention; Marrow hypoplasia, which continues 6 weeks from the start of each course (less than 10% cellularity); and Grade 4 Non-Hematologic Toxicity excluding the following: Infection (septic shock, typhlitis), Fever/Neutropenia, Fatigue, Electrolyte abnormalities, Hyper/Hypoglycemia, Nausea or Vomiting, AST/ALT/Bilirubin elevations that return to grade 1 by the time of the next course.

    Measured: Beginning with the first dose of investigational product until 30 days following the last dose of bortezomib

  2. Achievement of Complete Remission (CR)

    • Complete Remission (CR): M1 (< 5% blasts) BM with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC>750/uL and platelet count >75 000/uL);
    • Complete Remission without Platelet Recovery (CRp): M1 BM with no circulating blasts or extramedullary disease and recovery of ANC (>750/uL) but insufficient recovery of platelets (<75 000/uL).
    • Partial Remission (PR): the disappearance of circulating blasts and achievement of M2 (5%-25% blasts) marrow status, without new sites of extramedullary disease, and with recovery of ANC (>750/uL).
    • Stable disease (SD): not satisfying the criterion for progressive disease (PD), or a recovery of ANC (>750/uL) but fails to qualify for CR, CRp, or PR.
    • Progressive Disease (PD): increase of at least 25% in the absolute number of circulating leukemia cells, development of new sites of extramedullary disease, or other lab or clinical evidence of PD, with or without recovery of ANC or platelets.

    Measured: Day 29 of Course 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Feb 2007 (estimated)
  2. Study start4 Aug 2006
  3. Primary completion26 Feb 2011
  4. Study completion26 Feb 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00440726
Sponsor's protocol ID
T2005-003
Status last verified
Feb 2020
First submitted
23 Feb 2007
Last updated
19 Feb 2020
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Messinger Y, Gaynon P, Raetz E, Hutchinson R, Dubois S, Glade-Bender J, Sposto R, van der Giessen J, Eckroth E, Bostrom BC. Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood Cancer. 2010 Aug;55(2):254-9. doi: 10.1002/pbc.22456.

    PubMed 20582937

  • Messinger YH, Gaynon PS, Sposto R, van der Giessen J, Eckroth E, Malvar J, Bostrom BC; Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood. 2012 Jul 12;120(2):285-90. doi: 10.1182/blood-2012-04-418640. Epub 2012 May 31.

    PubMed 22653976

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Bortezomib, Dexamethasone and PEG-asparaginase in people with Acute Lymphoblastic Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 24 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, Australia, Brazil, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Occurrence of a Dose-Limiting Toxicity (Phase 1) (time frame: Beginning with the first dose of investigational product until 30 days following the last dose of bortezomib). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00440726, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Feb 2020.

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