Calaspargase Pegol or Pegaspargase in Treating Younger Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Supportive care, Treatment365 days to 18 years11-001
NCI-2012-00825, NCT01574274

Trial Description

Summary

This partially randomized phase II trial studies how well calaspargase pegol or pegaspargase works in treating younger patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as calaspargase pegol and pegaspargase, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether calaspargase pegol or pegaspargase works better in treating patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma.

Further Study Information

PRIMARY OBJECTIVES:

I. To assess the safety and feasibility associated with the administration of intravenous (IV) calaspargase pegol 2500 IU/m^2 given as a single dose during remission induction and every 3-weeks for 30 weeks during post-induction therapy in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL).

II. To assess the toxicity associated with IV calaspargase pegol administration and determine if it is significantly different than toxicity associated with IV Oncaspar (pegaspargase).

III. To determine the serum asparaginase activity (SAA) levels associated with IV calaspargase pegol administered as a single dose during remission induction and every 3-weeks for 30 consecutive weeks during post-induction therapy, and to compare them to the SAA associated with IV Oncaspar administered as a single dose during remission induction and every 2-weeks for 30 consecutive weeks during post-induction therapy.

SECONDARY OBJECTIVES:

I. To assess the frequency of bacteremia, fungemia and invasive fungal infections during the remission induction phase in patients receiving antibiotic prophylaxis.

II. To describe the outcome of children and adolescents with lymphoblastic lymphoma treated with a Dana-Farber Cancer Institute (DFCI) ALL Consortium treatment regimen.

III. To explore the impact on outcome of changing therapy for very high risk patients, defined as: i) B-precursor ALL patients with high end-induction minimal residual disease (MRD); ii) patients with mixed-lineage leukemia (MLL)-gene rearrangements or low hypodiploidy; or iii) T cell (T)-ALL/ lymphoblastic lymphoma patients with early T-cell precursor (ETP) phenotype.

IV. To assess the feasibility of vitamin D screening and supplementation in children and adolescents undergoing treatment for ALL in the context of a multi-institutional trial.

V. To determine the prevalence of vitamin D deficiency in children and adolescents with ALL at the following time-points: at diagnosis, at the end of remission induction, at the start of continuation, and at the conclusion of therapy.

VI. To assess the feasibility of correcting vitamin D deficiency with supplementation of vitamin D and calcium in patients found to have vitamin D deficiency.

VII. To explore the relationship between vitamin D status and skeletal toxicity (fracture and osteonecrosis) in children and adolescents undergoing therapy for ALL.

VIII. To explore risk factors for vitamin D deficiency, including demographic variables such as age, sex, and ethnicity, as well as geographic location (geographic latitude) and season of measurement.

IX. To determine the feasibility of prospective screening for absence of biallelic T cell receptor (TCR) gamma deletions (ABGD) via quantitative polymerase chain reaction (qPCR) in patients with T-ALL.

X. To determine the frequency of ABGD in patients with T-cell ALL at diagnosis.

XI. To explore the correlation between early T-cell precursor (ETP) phenotype and ABGD.

XII. To determine the feasibility of prospective screening for abnormalities (e.g., mutations, deletions, rearrangements) of IKAROS family zinc finger 1 (IKZF1), cytokine receptor-like factor 2 (CRLF2) and Janus kinase (JAK)1/2 in patients with newly diagnosed B-cell (B)-ALL.

XIII. To determine the frequency of these abnormalities in standard-risk and high-risk patients.

XIV. To explore the correlation between the presence of these abnormalities and end-induction MRD levels.

XV. To explore the relationship between mitochondrial B-cell CLL/lymphoma 2 (BCL-2) family preconditions and response to chemotherapy as measured by induction response, end-induction MRD level and event-free survival (EFS).

XVI. To obtain patient samples for the development of primary xenograft mouse models with the goal of identifying novel therapies for high-risk (including those with high end-induction MRD, T-ALL with ABGD) and relapsed patients.

OUTLINE:

STEROID PROPHASE: Patients receive methylprednisolone IV every 8 hours (or thrice daily [TID]) on days 1-3 and cytarabine intrathecally (IT) on day 1. Patients with central nervous system (CNS) leukemia or cranial nerve palsy also receive cytarabine IT twice weekly beginning on days 4-6 until the cerebrospinal fluid (CSF) is clear, and then receive 2 additional doses.

REMISSION INDUCTION: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive prednisone orally (PO) twice daily (BID) or TID or methylprednisolone IV every 8 hours on days 4-32; vincristine sulfate IV on days 4, 11, 18, and 25; doxorubicin hydrochloride IV over 15 minutes on days 4 and 5; methotrexate IV on day 6, calaspargase pegol IV over 1 hour on day 7; methotrexate IT on day 18 and 32; therapeutic hydrocortisone IT on day 18; and cytarabine IT on day 18. High risk and very high risk patients also receive dexrazoxane hydrochloride IV on days 4 and 5.

ARM II: Patients receive prednisone PO BID or TID or methylprednisolone IV every 8 hours (or TID) on days 4-32; vincristine sulfate IV on days 4, 11, 18, and 25; doxorubicin hydrochloride IV over 15 minutes on days 4 and 5; methotrexate IV on day 6; pegaspargase* IV over 1 hour on day 7; methotrexate IT on day 18 and 32; therapeutic hydrocortisone IT on day 18; and cytarabine IT on day 18. High risk and very high risk patients also receive dexrazoxane hydrochloride IV on days 4 and 5.

CONSOLIDATION I: Patients receive vincristine sulfate IV on day 1, mercaptopurine PO QD on days 1-14, methotrexate IT on day 1, high dose methotrexate IV over 48 hours on days 1-2, and leucovorin calcium IV every 6 hours beginning 36 hours after the start of high dose methotrexate administration. High risk patients also receive dexrazoxane hydrochloride IV over 15 minutes on day 1 and doxorubicin hydrochloride IV on day 1.

Consolidation I therapy for very high risk patients consists of 3 phases:

CONSOLIDATION IA: Patients receive vincristine sulfate IV on day 1, mercaptopurine PO QD on days 1-14, dexrazoxane hydrochloride IV over 15 minutes on day 1, doxorubicin hydrochloride IV on day 1, methotrexate IT on day 1, high-dose methotrexate IV over 48 hours between 8 and 24 hours following the dose of doxorubicin hydrochloride, and leucovorin calcium IV beginning 36 hours after the start of high dose methotrexate administration.

CONSOLIDATION IB: Patients receive cyclophosphamide IV over 1 hour on day 1, cytarabine IV on days 2-5 and 9-12, mercaptopurine PO QD on days 1-14, and methotrexate IT on day 1.

CONSOLIDATION IC: Patients receive high-dose cytarabine IV every 12 hours on days 1-2; etoposide IV over 1 hour on days 3, 4, and 5; and dexamethasone PO or IV BID on days 1-5. Beginning on day 8, patients receive calaspargase pegol IV over 1 hour every 3 weeks or pegaspargase* IV over 1 hour every 2 weeks according to randomization.

CNS PHASE: Patients receive vincristine sulfate IV on day 1, mercaptopurine PO QD on days 1-14, dexamethasone PO BID on days 1-5, methotrexate IT twice weekly for 4 doses, cytarabine IT twice weekly for 4 doses, and therapeutic hydrocortisone twice weekly for 4 doses. Patients receive calaspargase pegol IV over 1 hour on day 1 or pegaspargase* IV over 1 hour on day 1 according to randomization. High risk and very high risk patients also receive dexrazoxane hydrochloride IV over 15 minutes on day 1 and doxorubicin hydrochloride IV on day 1 and undergo cranial radiation therapy daily for 8 days.

CONSOLIDATION II: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; mercaptopurine PO QD on days 1-14; methotrexate IV or intramuscularly (IM) on days 1, 8, and 15; methotrexate IT every 9 weeks for 6 doses; cytarabine IT every 9 weeks for 6 doses; and therapeutic hydrocortisone every 9 weeks for 6 doses. Patients receive calaspargase pegol IV over 1 hour every 3 weeks for 30 weeks or pegaspargase* IV over 1 hour every 2 weeks for 30 weeks according to randomization. High risk and very high risk patients also receive dexrazoxane hydrochloride IV over 15 minutes on day 1 and doxorubicin hydrochloride IV on day 1.

CONTINUATION: Patients receive vincristine sulfate IV on day 1; dexamethasone PO PID on days 1-5; mercaptopurine PO QD on days 1-14; methotrexate IV or IM on days 1, 8, and 15; methotrexate IT every 18 weeks; cytarabine every 18 weeks; and therapeutic hydrocortisone IT every 18 weeks. Courses repeat every 3 weeks for 2 years.

* NOTE: Patients experiencing sensitivity to pegaspargase may receive asparaginase Erwinia chrysanthemi IM twice weekly or IV over 1 hour thrice weekly.

After completion of study treatment, patients are followed up periodically.

Eligibility Criteria

Inclusion Criteria:

For lymphoblastic lymphoma: diagnosis may be made by i) biopsy of involved site (e.g., node, mediastinal mass), or ii) by cytology from pleural fluid or other fluid collection or iii) by marrow aspirate/biopsy demonstrating < 30% involvement by lymphoblasts (confirmed by flow cytometry, immunohistochemistry, cytogenetics and/or FISH studies) in a patient with evidence of lymphomatous masses by radiographic studies; note: marrow aspirate and/or biopsy must be performed in patients with lymphoblastic lymphoma prior to study entry to confirm that patient does not meet definition of ALL; in rare circumstances, lymphoblastic lymphoma patients may be registered prior to marrow aspirate/biopsy if it is felt that the procedure cannot be safely performed; permission in advance by principal investigator or designee is required

Ability of parent or guardian to understand and the willingness to sign a written informed consent document

For acute lymphoblastic leukemia: diagnosis should be made by bone marrow aspirate or biopsy demonstrating >= 30% involvement by lymphoblasts, with flow cytometry or immunohistochemistry confirming B-precursor or T-ALL phenotype; while myeloid co-expression on blasts determined to be primarily lymphoid is allowed, patients with leukemia of ambiguous lineage are not eligible

Note: patients with mature B-cell (Burkitt's) ALL are excluded from study; mature B-cell is defined by the presence of surface immunoglobulin and/or the t(8;14)(q24;q32), t(8;22), or t(2;8) translocation and/or c-myc-gene rearrangement by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR)

Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L); note: a total bilirubin of < 1.4 mg/dL (23.9 micromoles/L) is acceptable to meet this requirement

No prior therapy is allowed except for the following:

Corticosteroids: short courses of corticosteroid (defined as =< 7 days of corticosteroids within the 4 weeks preceding registration) are allowed prior to registration; note: if patient has received pre-treatment with corticosteroids, they should not receive steroid prophase

  • Participants who have been on corticosteroids chronically (defined as more than 7 days of corticosteroids within the 4 weeks preceding registration or more than 28 days of corticosteroids over the preceding 6 months) are not eligible

IT cytarabine: a single dose of intrathecal cytarabine (at the time of the diagnostic lumbar puncture) is allowed prior to registration; if patient has received IT cytarabine prior to registration, day 1 IT cytarabine should not be administered

Emergent radiation therapy: emergent radiation to the mediastinum or other life-threatening masses is allowed prior to registration

Confirmed diagnosis of acute lymphoblastic leukemia or lymphoblastic lymphoma

For patients with circulating blasts in the peripheral blood, flow cytometry confirmation of B-precursor or T-ALL phenotype is sufficient for registration onto the study; bone marrow aspirate and/or biopsy should be performed as soon as feasible, preferably prior to the initiation of any therapy

Exclusion Criteria:

Participants who have received any chemotherapy or radiotherapy for previous malignancy are not eligible; participants who have ever previously received any anti-neoplastic agent, including methotrexate, 6-mercaptopurine, 6-thioguanine, vincristine cyclophosphamide, cytarabine (except for IT cytarabine), or any anthracycline, for any reason (e.g., rheumatologic or autoimmune condition) are not eligible

Participants may not be receiving any other investigational agents

Individuals with a history of a previous malignancy are ineligible; also, exposure to previous anti-neoplastic treatment may alter the ability to tolerate or respond to the agents utilized in this protocol; exception: individuals with a previous malignancy treated with surgery only (no chemotherapy or radiotherapy) more than 5 years prior to registration may be enrolled

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is enrolled

Participants known to be human immunodeficiency virus (HIV)-positive are excluded (note: HIV testing is not required prior to enrollment)

Uncontrolled intercurrent illness including, but not limited to ongoing infection with vital sign instability (hypotension, respiratory insufficiency), life-threatening acute tumor lysis syndrome (e.g., with renal failure), symptomatic congestive heart failure, cardiac arrhythmia, intracranial or other uncontrolled bleeding, or psychiatric illness/social situations that would limit compliance with study requirements

Participants who have received more than 7 days of corticosteroids in the preceding 4 weeks or more than 28 days of corticosteroids in the preceding 6 months are not eligible

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Dana-Farber Harvard Cancer Center

  • National Cancer Institute
Lewis Barry Silverman, Principal Investigator

Trial Sites

U.S.A.

Massachusetts
Boston

Boston Children's Hospital

Amy Louise Billett
Ph: 866-790-4500
Email: amy_billett@dfci.harvard.edu

Amy Louise Billett
Principal Investigator

Brigham and Women's Hospital

Lewis Barry Silverman
Ph: 617-632-6191
Email: lewis_silverman@dfci.harvard.edu

Lewis Barry Silverman
Principal Investigator

Dana-Farber Cancer Institute

Lewis Barry Silverman
Ph: 617-632-6191
Email: lewis_silverman@dfci.harvard.edu

Lewis Barry Silverman
Principal Investigator

Massachusetts General Hospital Cancer Center

Jeffrey Supko
Ph: 617-724-1970
Email: jsupko@partners.org

Jeffrey Supko
Principal Investigator

New York
Bronx

Montefiore Medical Center - Moses Campus

Peter David Cole
Ph: 718-741-2342
Email: pcole@aecom.yu.edu

Peter David Cole
Principal Investigator

New York

Children's Hospital of New York Presbyterian

Kara M. Kelly
Ph: 212-305-8615
Email: kk291@columbia.edu

Kara M. Kelly
Principal Investigator

Columbia University Medical Center

Kara M. Kelly
Ph: 212-305-8615
Email: kk291@columbia.edu

Kara M. Kelly
Principal Investigator

PR
San Juan

San Jorge Children's Hospital

Luis A. Clavell
Ph: 787-728-1575
Email: luisclavell@sjcms.com

Luis A. Clavell
Principal Investigator

Rhode Island
Providence

Hasbro Children’s Hospital

Jennifer J. Greene Welch
Ph: 401-444-1488
Email: jwelch@lifespan.org

Jennifer J. Greene Welch
Principal Investigator

Rhode Island Hospital

Lewis Barry Silverman
Ph: 617-632-6191
Email: lewis_silverman@dfci.harvard.edu

Lewis Barry Silverman
Principal Investigator

Canada

Ontario
Hamilton

Chedoke Hospital at Hamilton Health Sciences

Lewis Barry Silverman
Ph: 617-632-6191
Email: lewis_silverman@dfci.harvard.edu

Lewis Barry Silverman
Principal Investigator

McMaster Children's Hospital at Hamilton Health Sciences

Uma H. Athale
Email: athaleu@mcmaster.ca

Uma H. Athale
Principal Investigator

Quebec
Montreal

Centre Hospitalier Universitaire Sainte-Justine

Caroline Laverdiere
Ph: 514-345-4931
Email: caroline.laverdiere@umontreal.ca

Caroline Laverdiere
Principal Investigator

Quebec

Centre Hospitalier Universitaire de Quebec

Bruno Michon
Ph: 418-525-4444
Email: bruno.michon@mail.chuq.qc.ca

Bruno Michon
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01574274

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.