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Leukemia & Lymphoma

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AALL07P1: A Phase II Pilot Trial of Bortezomib (PS-341, Velcade®, IND #58,443) in Combination with Intensive Re-Induction Therapy for Children
With Relapsed Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic
Lymphoma (LL)

Date Last Modified:
Date First Published: 5/28/2009

Type Status Age Range Sponsors Protocol ID
Interventional Open 1 to 31 years
  • COG
  • NCI
 AALL07P1

Outline

This is a multicenter study.

  • Reinduction block 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; oral prednisone twice daily on days 1-29; bortezomib IV on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22. Patients with CNS-negative disease (CNS1 or CNS2) also receive methotrexate IT on days 15 and 29; patients with CNS-positive disease (CNS3) receive triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and cytarabine IT on days 8, 15, 22, and 29. After completion of reinduction block 1, patients with acute lymphoblastic leukemia (ALL) and M2 or M3 bone marrow proceed directly to reinduction block 2. Patients with ALL and M1 bone marrow or acute lymphoblastic lymphoma proceed to reinduction block 2 after blood counts recover
    Patients with persistent CSF blasts after 6 doses of TIT or patients with progressive acute lymphoblastic lymphoma are removed from the study.
  • Reinduction block 2: Patients receive etoposide phosphate IV over 1-2 hours on days 1-5; cyclophosphamide IV over 1 hour on days 1-5; bortezomib IV on days 1, 4, and 8; filgrastim (G-CSF) subcutaneously (SC) or IV daily beginning on day 6 and continuing until blood counts recover*; high-dose methotrexate IV on day 22; and leucovorin calcium orally or IV every 6 hours on days 23 and 24. Patients with CNS-negative disease also receive methotrexate IT on days 1 and 22; patients with CNS-positive disease receive TIT on days 1 and 22. After completion of reinduction block 2, patients proceed to reinduction block 3 immediately or when blood counts recover. Patients with disease progression are removed from the study
    NOTE: *Patients do not receive G-CSF on day 8.
  • Reinduction block 3: Patients receive cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9; L-asparaginase IM on days 2 and 9; and G-CSF SC or IV daily beginning on day 10 and continuing until blood counts recover. After completion of study treatment, patients are followed every 6 months for 3 years and then annually for 2 years

Objectives

Primary

  1. To estimate the toxicity of bortezomib in combination with intensive reinduction chemotherapy in young patients with relapsed acute lymphoblastic leukemia or acute lymphoblastic lymphoma
  2. To estimate the second complete remission rate at the end of block 1 reinduction chemotherapy and the 4-month event-free survival of these patients

Secondary

  1. To assess minimal residual disease in bone marrow following completion of each block of reinduction chemotherapy

Projected Accrual

The maximum number of people enrolled on this study is expected to be around 90. About 22-31 people are expected to participate at Cincinnati Children’s Hospital Medical Center. This total includes both leukemia and lymphoma patients.

Mechanism of Action

Bortezomib is a dipeptide boronic acid analogue with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy.

Entry Criteria

Disease Characteristics:

  • Diagnosis of 1 of the following:
    • Pre-B acute lymphoblastic leukemia (ALL) in first early (< 36 months from diagnosis) isolated bone marrow or combined bone marrow/extramedullary relapse as documented by histology and immunophenotyping
    • T-cell ALL in first isolated bone marrow or combined relapse as documented by histology and immunophenotyping
    • T-cell acute lymphoblastic lymphoma in first relapse as documented by histology
      • Measurable disease as documented by clinical, radiographic, or histologic criteria
  • Relapsed or refractory to conventional therapy
  • No Ph+ ALL unless refractory to ≥ 1 tyrosine kinase inhibitor therapy
    • Patients who are unable to tolerate tyrosine kinase inhibitor therapy due to toxicity are eligible
  • No mature B-cell ALL (i.e., sIg positive and kappa or lambda restricted positivity) with FAB L3 morphology and/or myc translocation)
  • No known optic nerve and/or retinal involvement
    • Patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, an MRI to determine optic nerve or retinal involvement
  • No extramedullary disease (i.e., isolated CNS disease or isolated testicular disease)
  • No concurrent genetic syndrome (e.g., Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome)

Patient Characteristics:

Age

  • 1 year to 31 years

Performance Status

  • Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)

Hepatic

  • Total bilirubin ≤ 1.5 times ULN for age
  • ALT < 3 times ULN for age (unless elevation due to leukemia infiltration)

Renal

  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR maximum serum creatinine based on age/gender as follows:
    • 0.4 mg/dL (for patients 1 to 5 months of age)
    • 0.5 mg/dL (for patients 6 to 11 months of age)
    • 0.6 mg/dL (for patients 1 year of age)
    • 0.8 mg/dL (for patients 2 to 5 years of age)
    • 1 mg/dL (for patients 6 to 9 years of age)
    • 1.2 mg/dL (for patients 10 to 12 years of age)
    • 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)
    • 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age)

Cardiovascular

  • Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by gated radionuclide study

Pulmonary

  • Pulse oximetry ≥ 94% at sea level (> 90% if at high altitude)
  • No evidence of acute pulmonary infiltrates on chest radiograph

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No evidence of dyspnea at rest or exercise intolerance
  • No known allergy to doxorubicin, cytarabine, etoposide, etoposide phosphate, boron, mannitol, or bortezomib
  • No CNS toxicity > grade 2
  • Seizure disorder allowed provided patient is on anticonvulsants (e.g., benzodiazepines or gabapentin) and it is well controlled
  • Able to receive asparaginase (i.e., no prior severe pancreatitis, stroke, or other toxicity)
    • Patients who initially receive asparaginase but discontinue drug due to toxicity are eligible
    • Patients with prior allergies to pegaspargase that are clinically significant are eligible provided Erwinia L-asparaginase can be substituted

Prior Concurrent Therapy

Biologic Therapy

  • At least 7 days since prior anticancer biologic agents or donor lymphocyte infusions

Chemotherapy

  • No prior cumulative anthracycline exposure > 400 mg/m²

Endocrine Therapy

  • No concurrent corticosteroids (including steroids as antiemetics) except as treatment or prophylaxis for anaphylactic reactions

      OR

  • treatment for pulmonary toxicity

Other

  • Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy (for patients who relapse on therapy other than standard ALL maintenance therapy)
  • No prior bortezomib or other proteasome inhibitors
  • No prior reinduction attempts or treatment for prior extramedullary relapse
    • Patients with primary induction failure are not eligible
  • At least 4 months since prior stem cell transplant or rescue
    • No evidence of active graft-vs-host disease (GVHD)
  • No concurrent GVHD prophylaxis
  • No concurrent anticonvulsants known to activate the cytochrome p450 system (e.g., phenytoin, carbamazepine, and phenobarbital)
    • Concurrent benzodiazepines or gabapentin allowed
  • No other concurrent anticancer chemotherapy or immunomodulating agents NOTE: *Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to undergo a waiting period prior to entry onto this study
  • At least 14 days since prior cytotoxic therapy (24 hours for hydroxyurea)

For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org