Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

Monoclonal Antibody Therapy After Allogeneic Stem Cell Transplantation in Treating Patients With Persistent or Progressive Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Temporarily closed 14 and over NCI UCSD-040749 NCI-6082, NCT00060372, 6082

Objectives

1. Determine the optimal safe dose, in terms of incidence of grade 3 or 4 graft-versus-host disease, of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody administered to patients with persistent or progressive malignancies after allogeneic hematopoietic stem cell transplantation.
2. Determine the pharmacokinetics of this drug in these patients.
3. Determine the best dosing regimen of this drug when administered with donor lymphocyte infusions in these patients.
4. Determine, preliminarily, the efficacy of this drug in these patients.

Entry Criteria

Disease Characteristics:

• Diagnosis of persistent or progressive hematologic malignancy or solid tumor after allogeneic hematopoietic stem cell transplantation (AHSCT)
  • Patients are eligible for study entry at any time between post-transplantation day 90 and 3 years after withdrawal of immunosuppressive therapy



• The following malignancies are eligible:
  • Chronic myelogenous leukemia (CML) meeting the following criteria:
    • Cytogenetic progression or persistence as evidenced by 1 of the following:
      • Cytogenetic progression evidenced by an increase in the percentage of Philadelphia chromosome (Ph)1-positive metaphases (or Ph1-positive cells by fluorescent in situ hybridization) from complete cytogenetic response (CCR) (0% Ph1-positive cells) to partial response (PR) (1-34% Ph1-positive cells); PR to minor response (MR) (35-94% Ph1-positive cells); or MR to no response (95-100% Ph1-positive cells)
      • Cytogenetic persistence evidenced by any Ph1-positive metaphases in bone marrow after day 90 post-AHSCT
    • Resistance to imatinib mesylate, defined as disease progression (hematologic, cytogenetic, or molecular) during OR failure to respond to (i.e., lack of complete hematologic response after 3 months, lack of partial cytogenetic response after 6 months, or lack of complete cytogenetic response after 12 months) prior imatinib mesylate therapy
  
  
  
  • Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) that meets any of the following criteria:
    • Hematologic relapse by standard criteria
    • Hematologic persistence evidenced by bone marrow blasts > 10% after day 30 post-AHSCT
  
  
  
  • Myelodysplastic syndromes that meet any of the following criteria:
    • Hematologic relapse by standard criteria
    • Cytogenetic relapse evidenced by recurrence of clonal abnormality in patients who achieved CCR after AHSCT
    • Hematologic persistence evidenced by cytopenias not attributable to other post-transplant causes accompanied by characteristic morphological changes more than 90 days after AHSCT
    • Cytogenetic persistence evidenced by persistence of clonal abnormality more than 90 days after AHSCT
  
  
  
  • Chronic lymphocytic leukemia that meets any of the following criteria:
    • Greater than 25% increase in absolute lymphocytosis of > 5,000/mm³
    • Greater than 25% increase in measurable lymphadenopathy
    • Persistence of absolute lymphocytosis of > 5,000/mm³ at day 90 or later after AHSCT
    • Persistence of lymphadenopathy of ≥ 3 cm in diameter at day 90 or later after AHSCT
  
  
  
  • Agressive non-Hodgkin's lymphoma (e.g., diffuse large cell lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, or peripheral T cell lymphoma), Hodgkin's lymphoma, OR solid tumor that meets any of the following criteria:
    • Greater than 50% increase in measurable or evaluable disease
    • Persistence of measurable lesions > 3.0 cm in diameter at day 90 or later after AHSCT
    • Persistence of malignancy by biopsy or positron emission tomography scan unless there is clear evidence of progression
  
  
  
  • Multiple myeloma with demonstrated resistance to or intolerance of prior thalidomide and bortezomib unless these agents are contraindicated (e.g., due to peripheral neuropathy) and meeting any of the following criteria:
    • Greater than 25% increase in paraprotein band, abnormal quantitative immunoglobulin level, or urine protein excretion
    • Greater than 25% increase in percent of plasma cells in the bone marrow (if > 15%)
    • Presence of new lytic bone lesions
    • New extramedullary lesions OR ≥ 25% enlargement of existing extramedullary lesions
    • Persistence of paraprotein band, abnormally elevated quantitative immunoglobulin level, or bone marrow plasmacytosis > 15% for a period of at least 90 days after AHSCT
  
  
  



• Measurable or evaluable disease
  • At least 1 bidimensionally measurable lesion ≥ 1.5 cm in diameter
  • Evaluable disease is defined as disease that is assessable for response (e.g., pleural effusion, elevated serum tumor)
  • Bone metastases that can be assessed by CT scan or MRI considered evaluable
  • Leukemia is considered evaluable disease
  • Patients who met criteria for persistence or progression with AML, ALL, CML, or aggressive NHL AND are currently in complete remission after reinduction therapy do not require measurable or evaluable disease to be eligible



• At least 50% donor chimerism in the T-cell lineage OR full (≥ 90%) donor chimerism in unseparated blood on last assessment within 3 months before study entry
  • No evidence on consecutive testing of > 10% decline in T-cell chimerism beyond the error of the test

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics
• No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010)

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• At least 6 weeks since prior immunosuppressive agents
• At least 2 weeks since prior imatinib mesylate
• No concurrent imatinib mesylate
• At least 6 weeks since prior and no concurrent immunosuppressive agents for clinically active graft-versus-host disease (GVHD) prophylaxis or treatment
• No other concurrent investigational agents

Patient Characteristics:

Age

• 14 and over

Performance status

• ECOG 0-2

Life expectancy

• More than 3 months

Hematopoietic

• See Disease Characteristics
• Absolute lymphocyte count > 250/mm³

Hepatic

• Bilirubin ≤ 2.0 mg/dL*
• AST and ALT ≤ 3 times upper limit of normal*
• Chronic hepatitis B or C infection allowed provided other hepatic function criteria are met

 [Note: *Unless due to the malignancy]

Renal

• Creatinine ≤ 2.0 mg/dL (unless due to the malignancy)

Immunologic

• No prior grade 3 or 4 acute graft-vs-host disease
• No concurrent autoimmune diseases requiring the chronic use of immunosuppressive medications
  • Active connective tissue disease
  • CNS disease including multiple sclerosis or demyelinating disease
  • Inflammatory bowel disease
  • Autoimmune hepatitis
• No ongoing serious infection
• No known history of HIV

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 4 months after study therapy
• No other serious ongoing medical condition that would preclude study participation
• No other malignancy within the past 5 years
• No psychological or psychiatric condition that would preclude study participation

Expected Enrollment

A total of 18-21 patients will be accrued for this study within 24-30 months.

Outline

This is a dose-escalation, multicenter study.

Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) IV over 90 minutes.

Cohorts of 3-6 patients receive escalating doses of MDX-010 until the maximum tolerated dose (MTD) is determined. The MTD is the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients with persistent or progressive disease at 60 days after MDX-010 administration and no evidence of graft-versus-host disease receive donor lymphocyte infusions every 60 days for a total of 3 infusions.

Patients are followed at 4, 5, 6, 9, and 12 months and then annually thereafter.

Trial Contact Information

Trial Lead Organizations

Rebecca and John Moores UCSD Cancer Center

Asad Bashey, MD, PhD, Protocol chair		Ph: 404-255-1930

Registry Information
Official Title		CTLA-4 Blockade With MDX-010 To Induce Graft - Versus - Malignancy Effects Following Allogeneic Hematopoietic Stem Cell Transplantation
Trial Start Date		2003-04-04
Trial Completion Date		2004-02-13 (estimated)
Registered in ClinicalTrials.gov		NCT00060372
Date Submitted to PDQ		2003-03-31
Information Last Verified		2008-12-21
NCI Grant/Contract Number		CA93891

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