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

NCT00440726 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: T2005-003
• Study Type: interventional
• Target: 31
• Locations: 4 countries
• Sites: 24

Brief 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). 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.

Conditions

Acute Lymphoblastic Leukemia

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

Outcome Measures

Primary Outcomes (2)

• 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.

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

• 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.

  Day 29 of Course 1

Study Arms (2)

Ph 1 Dose Escalation

EXPERIMENTAL

Intervention: 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.

Drug: Bortezomib; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Vincristine; Drug: Triple IT Therapy

Ph 2 Efficacy and Safety

EXPERIMENTAL

Intervention: 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.

Drug: Bortezomib; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Vincristine; Drug: Triple IT Therapy

Interventions

Bortezomib DRUG

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

Also known as: Velcade

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Dexamethasone DRUG

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

Also known as: Decadron

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

PEG-asparaginase DRUG

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

Also known as: Oncaspar

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Doxorubicin DRUG

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

Also known as: Adriamycin, Rubex

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Cytarabine DRUG

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

Also known as: Cytosar-U, Ara-C, Arabinosylcytosine

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Methotrexate DRUG

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

Also known as: Otrexup, Rasuvo, Rheumatrex, Trexall, Amethopterin

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Vincristine DRUG

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

Also known as: Oncovin, Leurocristine

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Triple IT Therapy DRUG

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

Ph 1 Dose Escalation; Ph 2 Efficacy and Safety

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead

Study Sites (24)

City of Hope

Duarte, California, 91010, United States

Location

Miller Children's Hospital

Long Beach, California, 90806, United States

Location

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital & Research Center Oakland

Oakland, California, 94618, United States

Location

Stanford University Medical Center

Palo Alto, California, 94304-1812, United States

Location

UCSF School of Medicine

San Francisco, California, 94143-0106, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

University of Miami Cancer Center

Miami, Florida, 33136, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

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

Chicago, Illinois, 60611, United States

Location

Johns Hopkins / Sydney Kimmel Cancer Center

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Center

Boston, Massachusetts, 02215, United States

Location

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109-0914, United States

Location

Childrens Hospital & Clinics of Minnesota

Minneapolis, Minnesota, 55404-4597, United States

Location

New York University Medical Center

New York, New York, 10016, United States

Location

Children's Hospital New York-Presbyterian

New York, New York, 10032, United States

Location

Levine Children's Hospital

Charlotte, North Carolina, 28203, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

Location

The Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Universidade Federale de Sao Paulo/Hospital Sao Paulo

São Paulo, 04023-062, Brazil

Location

Sick Kids

Toronto, Ontario, M5G1X8, Canada

Location

Related Publications (2)

• 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.

  PMID: 20582937 RESULT

• 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.

  PMID: 22653976 RESULT

Related Links

• Click here for more information about this protocol and the Therapeutic Advances in Childhood Leukemia Consortium

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Interventions

Bortezomib; Dexamethasone; Calcium Dobesilate; pegaspargase; Doxorubicin; Cytarabine; Methotrexate; Vincristine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines

Results Point of Contact

• Title: Peggy Romano, BA, CCRP
• Organization: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) / Children's Hospital Los Angeles

promano@chla.usc.edu

323-361-5505

Study Officials

• Yoav Messinger, MD

  Children's Hospital and Clinics of Minnesota

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2007
• First Posted: February 27, 2007
• Study Start: August 4, 2006
• Primary Completion: February 26, 2011
• Study Completion: February 26, 2011
• Last Updated: February 19, 2020
• Results First Posted: February 19, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); US (20); CA (1); BR (1)