Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Closed 21 and under NCI CCG-0901 CCG-0901

Objectives

I.  Evaluate the toxicity and tolerance of seven dose levels of murine 
monoclonal antibody 14G2A (MOAB 14G2A) combined with a well tolerated and 
characterized regimen of interleukin-2 (IL-2) in children with refractory 
neuroblastoma or melanoma.

II.  Determine, by in vitro testing, whether and when conditions in the blood 
duplicate those that enable in vitro augmented tumor cell destruction via 
antibody-dependent cellular cytotoxicity.

III.  Evaluate whether treatment with MOAB 14G2A influences the magnitude of 
well characterized immune response changes induced by IL-2.

IV.  Evaluate the influence of IL-2 on induction of human antimouse antibody 
induced by MOAB 14G2A, and compare this to antibody induction by MOAB 14G2A 
alone.

V.  Document, by immunohistology, in vivo tumor binding of MOAB 14G2A in 
selected patients.

VI.  Use this protocol, upon identifying the MTD, to design a Phase II trial 
in which this regimen of IL-2 plus MOAB 14G2A is tested for antitumor effects 
in patients with refractory neuroblastoma or melanoma.

VII.  Observe all patients, when possible, for evidence of clinically 
measurable antitumor responses.

VIII.  Evaluate, by means of serial bone marrow aspirations, the cellular 
response of neuroblastoma-infiltrated bone marrow to combined IL-2/MOAB 14G2A 
given with granulocyte-macrophage colony stimulating factor (GM-CSF).

IX.  Determine the toxicity of GM-CSF when added to IL-2.

X.  Determine the toxicity of adding GM-CSF to combined IL-2/MOAB 14G2A.

Entry Criteria

Disease Characteristics:

Biopsy-proven, refractory neuroblastoma or melanoma, i.e.:
  Failure to achieve a complete response after aggressive
  chemotherapy (including autologous bone marrow transplant)

  Response to re-induction therapy but considered likely to
  relapse

  Progression following aggressive chemotherapy

Other GD2-positive tumors (e.g., peripheral primitive
neuroectodermal tumors and osteogenic sarcoma) eligible
provided the tumor is shown to be GD2-positive by monoclonal
antibody 14G2A immunoperoxidase staining

Measurable disease by standard CCG criteria required
  Measurable disease not required for patients who experienced
  a relapse following aggressive chemotherapy and responded to
  re-induction therapy yet are likely to relapse

  Evaluable metastatic disease required for melanoma

No intracerebral metastases

No requirement for immediate palliative chemotherapy or
radiotherapy

Prior/Concurrent Therapy:

Biologic therapy:
  No prior murine monoclonal antibody
  No prior human-mouse chimeric monoclonal antibody
  Prior interleukin-2 allowed
     Dosages of 1.5-3.0 MU/sqm/day given 4 days/week for 3
     weeks must have been tolerated
  At least 2 weeks since biologic therapy, with recovery
     required

Chemotherapy:
  At least 1 prior multiagent chemotherapy regimen required
  At least 2 weeks since cytotoxic therapy, with recovery
     required
  No immediate requirement for palliative chemotherapy

Endocrine therapy:
  Not specified

Radiotherapy:
  At least 2 weeks since radiotherapy, with recovery required
  No immediate requirement for palliative radiotherapy

Surgery:
  At least 21 days since major surgery

Other:
  Prior autologous bone marrow transplant (ABMT) allowed
  No prior allogeneic bone marrow transplant

Patient Characteristics:

Age:
  No greater than 21 at initial diagnosis

Performance status:
  CCG 0-2

Life expectancy:
  Greater than 3 months

Hematopoietic:
  In patients with no bone marrow involvement and no prior
  autologous bone marrow transplantation:
     WBC at least 1,500
     AGC at least 1,000
     Platelets greater than 75,000 (transfusion-independent)
     Hb at least 10 g/dl (may transfuse)

  In patients with bone marrow involvement:
     Platelets greater than 50,000 (may transfuse)
     Hb greater than 10 g/dl (may transfuse)

  In patients with prior bone marrow transplantation but no
  marrow involvement:
     Platelets greater than 50,000 (transfusion-independent)

Hepatic:
  Bilirubin less than 2.0 mg/dl
  SGOT less than 3 x normal

Renal:
  Creatinine less than 2.0 mg/dl OR
  Creatinine clearance greater than 60 ml/min

Cardiovascular:
  EKG and echocardiogram normal

Pulmonary:
  In patients with suspected pulmonary insufficiency (testing
  not required in the absence of clinical suspicion of
  pulmonary dysfunction and with less than 25% loss of lung
  volume by chest x-ray):
     FEV1/FVC at least 60% of predicted

     In children less than 4 years of age unable to cooperate
     with pulmonary function testing:
        No evidence of dyspnea at rest
        No exercise intolerance
        No greater than 25% loss of lung volume to tumor on
           radiographic analysis
        At least 93% oxygen saturation

Other:
  No serious infection (requiring intravenous antibiotics)
     within 14 days prior to entry
  No requirement for concurrent aspirin or NSAIDs
  No requirement for concurrent corticosteroids
  No organ allografts other than ABMT
  No psychiatric disabilities or seizure disorders
  No known HIV positivity
  No pregnant women
  Effective contraception required of fertile patients

Expected Enrollment

It is anticipated that 21-30 patients will be studied to determine the MTD of 
MOAB 14G2A given with IL-2 and 12-24 patients will be studied to determine the 
MTD of GM-CSF in combination with IL-2 and MOAB 14G2A.  Both portions of the 
study are expected to require 12-18 months to complete.

Outline

Nonrandomized study.  The first four cohorts of patients are treated on 
Regimen A; the fifth cohort is treated on Regimen B.  Patients with no 
measurable disease by virtue of a response to re-induction therapy following 
relapse after aggressive front-line chemotherapy are treated on Regimen B.  
Melanoma and neuroblastoma patients with bone marrow involvement detectable by 
standard bone marrow aspiration cytology or by immunohistochemistry who agree 
to the required bone marrow aspirations are entered on Regimen C, while those 
without bone marrow involvement are entered on Regimen B.  Patients with other 
GD2-positive tumors (e.g., peripheral primitive neuroectodermal tumors and 
osteogenic sarcoma) are treated on Regimen C.

Regimen A:  Biological Response Modifier Therapy.  Murine Monoclonal Anti-GD2 
Antibody 14G2A, MOAB 14G2A, NSC-624345; Recombinant Interleukin-2 (Hoffmann-La 
Roche), IL-2, NSC-600664.

Regimen B:  Biological Response Modifier Therapy.  MOAB 14G2A; followed (in 
responding and stable patients) by MOAB 14G2A; IL-2.

Regimen C:  Biological Response Modifier Therapy plus Growth Factor Therapy.  
MOAB 14G2A; IL-2; plus Granulocyte-Macrophage Colony Stimulating Factor 
(Schering/Sandoz), GM-CSF, NSC-617589.

Frost JD, Hank JA, Reaman GH, et al.: A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children's Cancer Group. Cancer 80 (2): 317-33, 1997.[PUBMED Abstract]

Hank JA, Surfus J, Gan J, et al.: Treatment of neuroblastoma patients with antiganglioside GD2 antibody plus interleukin-2 induces antibody-dependent cellular cytotoxicity against neuroblastoma detected in vitro. J Immunother Emphasis Tumor Immunol 15 (1): 29-37, 1994.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Cancer Group

Paul Sondel, MD, PhD, Protocol chair		Ph: 608-263-9069; 800-622-8922 Email: pmsondel@facstaff.wisc.edu