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

Alternate Title

Cyclophosphamide and Fludarabine Followed By White Blood Cell Infusion and High-Dose Aldesleukin in Treating Patients With Metastatic Cancer That Overexpresses p53

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	18 and over	NCI	NCI-07-C-0003 NCI-P6850, NCT00393029

Special Category: NCI Web site featured trial

Objectives

Primary

1. Determine clinical tumor regression in patients with metastatic cancer that overexpresses p53 treated with nonmyeloablative lymphodepleting chemotherapy comprising cyclophosphamide and fludarabine phosphate followed by anti-p53 T-cell receptor (TCR)-transduced peripheral blood lymphocytes and high-dose aldesleukin (IL-2).

Secondary

1. Determine the in vivo survival of TCR gene-engineered cells.
2. Determine the toxicity profile of this regimen in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed metastatic cancer
  • Tumor overexpresses p53 as determined by immunohistochemistry



• Patients with melanoma or renal cell cancer must have received prior aldesleukin and have either progressive or recurrent disease



• Patients with other histologies, not including hematologic cancer, must have received first-line and second-line or higher systemic standard therapy (or effective salvage chemotherapy regimens) for metastatic disease and have either progressive or recurrent disease



• HLA-A*0201-positive

Prior/Concurrent Therapy:

• Recovered (i.e., ≤ grade 1) from prior toxicity except for alopecia or vitiligo
• More than 4 weeks since prior systemic therapy
• More than 6 weeks since prior MDX-010
  • Patients who have had prior treatment with MDX-010 must have a normal colonoscopy with normal colonic biopsies
• No concurrent systemic steroids

Patient Characteristics:

• ECOG performance status 0-1
• Life expectancy > 3 months
• Platelet count > 100,000/mm³
• Absolute neutrophil count > 1,000/mm³
• WBC > 3,000/mm³
• Hemoglobin > 8.0 g/dL
• ALT and AST < 3 times upper limit of normal
• Creatinine ≤ 1.6 mg/dL
• Total bilirubin ≤ 1.5 mg/dL (< 3.0 mg/dL for patients with Gilbert's syndrome)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 months after completion of study treatment
• HIV negative
• Hepatitis B antigen negative
• Hepatitis C antibody or antigen negative
• No active systemic infections
• No form of primary immunodeficiency OR severe combined immunodeficiency disease or AIDS
• No known opportunistic infections
• No history of severe immediate hypersensitivity reaction to any of the study drugs
• No coagulation disorders
• LVEF ≥ 45% by cardiac stress test (e.g., stress thallium, stress MUGA, dobutamine echocardiogram, or other stress test) for patients meeting any of the following criteria:
  • History of EKG abnormalities
  • Symptoms of cardiac ischemia or arrhythmia
  • At least 50 years of age and over
• No myocardial infarction
• No cardiac arrhythmias
• No obstructive or restrictive pulmonary disease
• Patients with a prolonged history of cigarette smoking (i.e., > 20 pack/year within the past 2 years) or symptoms of respiratory dysfunction (e.g., grade 2 dyspnea or hypoxia) must have a normal pulmonary function test (i.e., FEV₁ ≥ 60% of predicted)
• No other major medical illness of the cardiovascular, respiratory, or immune system
• No other contraindication to high-dose aldesleukin (IL-2) administration

Expected Enrollment

A total of 82 patients will be accrued for this study.

Outcomes

Clinical tumor regression

In vivo survival of T-cell receptor gene-engineered cells
Toxicity

Outline

Patients are stratified according to diagnosis (metastatic melanoma or renal cell cancer vs other types of metastatic cancer).

• Leukapheresis and T-cell transduction: Patients undergo leukapheresis to collect peripheral blood mononuclear cells (PBMC). PBMCs are then cultured in the presence of anti-CD3 (OKT3) and aldesleukin (IL-2) to stimulate T-cell growth. The T cells are transduced with the anti-p53 T-cell receptor (TCR) retroviral vector. Once the transduced T cells are biologically active, patients proceed to nonmyeloablative lymphodepleting chemotherapy:



• Nonmyeloablative lymphodepleting chemotherapy: Patients receive cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30 minutes on days -5 to -1.



• Autologous anti-p53 TCR-transduced peripheral blood lymphocyte reinfusion: Patients receive anti-p53 TCR-transduced peripheral blood lymphocyte infusion over 20-30 minutes on day 0. Patients then receive filgrastim (G-CSF) subcutaneously beginning on day 1 or 2 and continuing until blood counts recover.



• High-dose IL-2: Patients receive high-dose IL-2 IV over 15 minutes 3 times daily on days 0-4 (up to 15 doses).

Patients are evaluated 4-6 weeks after completion of high-dose IL-2. Patients achieving a response may receive up to 1 retreatment course comprising nonmyeloablative lymphodepleting chemotherapy, anti-p53 TCR-transduced peripheral blood lymphocyte infusion, and high-dose IL-2 as above, beginning 6-8 weeks after completion of high-dose IL-2.

After completion of study treatment, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Steven Rosenberg, MD, PhD, Principal investigator		Ph: 301-496-4164 Email: sar@nih.gov

Related Information

Featured trial article
Web site for additional information

Registry Information
Official Title		Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes
Trial Start Date		2006-09-25
Trial Completion Date		2008-10-24
Registered in ClinicalTrials.gov		NCT00393029
Date Submitted to PDQ		2006-10-12
Information Last Verified		2008-11-30

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