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

Acute Lymphoblastic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00440726
• Other study ID #: T2005-003
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 4, 2006
• Est. completion date: February 26, 2011

Study information

• Verified date: February 2020
• Source: Therapeutic Advances in Childhood Leukemia Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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). 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: February 26, 2011
• Est. primary completion date: February 26, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Bortezomib
Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.
• Dexamethasone
10 mg/m2/day divided BID, oral administration for 14 days.
• PEG-asparaginase
2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22
• Doxorubicin
60 mg/m2/day IV over 15 minutes on Day 1
• Cytarabine
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
• Methotrexate
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
• Vincristine
1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22.
• Triple IT Therapy
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

Locations

Country	Name	City	State
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Brazil	Universidade Federale de Sao Paulo/Hospital Sao Paulo	São Paulo
Canada	Sick Kids	Toronto	Ontario
United States	C.S. Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Johns Hopkins / Sydney Kimmel Cancer Center	Baltimore	Maryland
United States	Dana Farber Cancer Center	Boston	Massachusetts
United States	Levine Children's Hospital	Charlotte	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	City of Hope	Duarte	California
United States	Miller Children's Hospital	Long Beach	California
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	University of Miami Cancer Center	Miami	Florida
United States	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital New York-Presbyterian	New York	New York
United States	New York University Medical Center	New York	New York
United States	Children's Hospital & Research Center Oakland	Oakland	California
United States	Stanford University Medical Center	Palo Alto	California
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	UCSF School of Medicine	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Therapeutic Advances in Childhood Leukemia Consortium

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada, 

References & 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 re — View 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 leuke — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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

External Links

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