Clinical trial NCT00440726: Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)
Official title: A Study of Bortezomib With Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Sponsor class: OTHER
First posted: 2007-02-27
Enrollment: 31
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria

The eligibility criteria listed below are interpreted literally and cannot be waived.

1. Age Patients must be \< 21 years of age when originally diagnosed with ALL. Patient must be \> 1 year of age at study entry.
2. 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.
3. Performance Level Karnofsky \> 50% for patients \> 10 years of age and Lansky \> 50% for patients \< 10 years of age.
4. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

   1. Prior anthracycline exposure: Patients must have less than 400mg/m2 lifetime exposure of anthracycline chemotherapy.
   2. 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).
   3. Patients should not have received previous therapy using bortezomib (Velcdade® or PS-341).
   4. 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.
   5. 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)
   6. 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.
5. Reproductive Function

   1. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
   2. Female patients with infants must agree not to breastfeed their infants while on this study.
   3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.

Exclusion Criteria

1. Drug Allergies

   Patients will be excluded if they have allergies to the following:
   * Asparaginase products
   * Boron
   * Mannitol
2. 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.
3. Liver/Pancreatic Function

   1. 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.
   2. SGPT (ALT) \> 4 x institutional ULN
   3. Grade 3 or greater pancreatitis as defined by the CTCAE v3.0
   4. History of any L-asparaginase induced pancreatitis
   5. Amylase or Lipase \> 2 x institutional ULN
4. Cardiac Function Patients will be excluded if their shortening fraction by echocardiogram is less than 30%.
5. Patients with Down Syndrome are excluded.
6. 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.
7. Patients with grade 2 or greater motor or sensory neuropathy per CTC 3.0 criteria.
8. 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.)
9. Patients planning on receiving other anti-cancer therapies while on this study. Hydroxyurea for cyto-reduction is allowed prior to the start of therapy.
10. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
11. 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.

Primary outcomes:
measure: Occurrence of a Dose-Limiting Toxicity (Phase 1)
timeFrame: Beginning with the first dose of investigational product until 30 days following the last dose of bortezomib
measure: Achievement of Complete Remission (CR)
timeFrame: Day 29 of Course 1
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Long Beach
country: United States
facility: Miller Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Oakland
country: United States
facility: Children's Hospital & Research Center Oakland
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF School of Medicine
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins / Sydney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Childrens Hospital & Clinics of Minnesota
state: Minnesota
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Children's Hospital New York-Presbyterian
state: New York
city: Charlotte
country: United States
facility: Levine Children's Hospital
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: São Paulo
country: Brazil
facility: Universidade Federale de Sao Paulo/Hospital Sao Paulo
city: Toronto
country: Canada
facility: Sick Kids
state: Ontario
Study officials:
affiliation: Children's Hospital and Clinics of Minnesota
name: Yoav Messinger, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.