Clinical trial NCT00704938: Gene-Modified Lymphocytes, High-Dose Aldesleukin, and Vaccine Therapy in Treating Patients With Progressive or Recurrent Metastatic Cancer
Official title: Phase II Study of Metastatic Cancer That Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes and Dendritic Cell Vaccination
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Kidney Cancer
Melanoma (Skin)
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: recurrent renal cell cancer
stage IV renal cell cancer
recurrent melanoma
stage IV melanoma
unspecified adult solid tumor, protocol specific
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-06-25
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Gene-modified lymphocytes may stimulate the immune system in different ways and stop tumor cells from growing. High-dose aldesleukin may stimulate lymphocytes to kill tumor cells. Vaccines made from a gene modified virus and a person's dendritic cells may help the body build an effective immune response to kill tumor cells. Giving gene-modified lymphocytes together with high-dose aldesleukin and vaccine therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving gene-modified lymphocytes together with high-dose aldesleukin and vaccine therapy works in treating patients with progressive or recurrent metastatic cancer.

Detailed description: OBJECTIVES:

Primary

* Determine if the administration of anti-p53 T-cell receptor (TCR) gene-engineered peripheral blood lymphocytes, high-dose aldesleukin, and adenovirus p53 dendritic cell (DC) vaccine after a nonmyeloablative, but lymphoid-depleting, preparative regimen will result in clinical tumor regression in patients with metastatic cancer that overexpresses p53.

Secondary

* Determine the in vivo survival of T-cell receptor (TCR) gene-engineered cells.
* Determine the ability of a dendritic cell (DC) vaccine to restimulate TCR gene-engineered cells in vivo.
* Determine the toxicity profile of this treatment regimen.

OUTLINE: Patients are stratified according to type of metastatic cancer (melanoma or renal cell cancer vs all other cancers).

* Peripheral blood mononuclear cell (PBMC) collection: Patients undergo PBMC collection via leukapheresis for the generation of the adenovirus p53 dendritic cell vaccine as well as anti-p53 T-cell receptor (TCR) gene-engineered peripheral blood lymphocytes.
* Nonmyeloablative lymphocyte-depleting preparative regimen: Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30 minutes on days -5 to -1.
* Peripheral blood lymphocyte infusion: Patients receive anti-p53 TCR gene-engineered peripheral blood lymphocytes IV over 20-30 minutes on day 0. Patients receive filgrastim (growth colony stimulating factor (G-CSF)) subcutaneously (SC) once daily beginning on day 1 or 2 and continuing until blood counts recover.
* High-dose aldesleukin: Patients receive high-dose aldesleukin IV over 15 minutes three times daily on days 0-4 for up to 15 doses.
* Dendritic cell vaccine: Patients receive adenovirus p53 dendritic cell vaccine SC on days 0, 7, 14, and 28.

Patients may receive one re-treatment course as above (nonmyeloablative preparative regimen, peripheral blood lymphocyte infusion, high-dose aldesleukin, and dendritic cell vaccinations) beginning 6-8 weeks after the last dose of high-dose aldesleukin.

After completion of study treatment, patients are followed periodically for up to 15 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of metastatic cancer
* Tumor overexpresses p53 as assessed by immunohistochemistry (i.e., ≥ 5% tumor cells stain positive for p53)

  * Biopsy must be available to evaluate p53 expression
* Human leukocyte antigens 0201 (HLA-A\*0201) positive
* Progressive or recurrent disease after prior standard therapy for metastatic disease

  * Patients with melanoma or renal cell cancer must have previously received aldesleukin
  * Patients with other histologies, not including hematologic malignancies, must have previously received first-line and second-line or higher systemic standard therapy (or effective salvage chemotherapy regimens)

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Life expectancy \> 3 months
* Absolute neutrophil count \> 1,000/mm\^3
* White blood cell (WBC) \> 3,000/mm\^3
* Platelet count \> 100,000/mm\^3
* Hemoglobin \> 8.0 g/dL
* Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal
* Serum creatinine ≤ 1.6 mg/dL
* Total bilirubin ≤ 2.0 mg/dL (\< 3.0 mg/dL in 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
* Patients who have previously received ipilimumab or ticilimumab must have a normal colonoscopy with normal colonic biopsies
* Human immunodeficiency virus (HIV) antibody negative
* Hepatitis B antigen and hepatitis C antibody negative (unless antigen negative)
* No primary immunodeficiency (e.g., severe combined immunodeficiency disease)
* No active systemic infections
* No history of severe immediate hypersensitivity reaction to any of the agents used in this study
* No coagulation disorders
* No myocardial infarction or cardiac arrhythmias
* No history of coronary revascularization
* No obstructive or restrictive pulmonary disease
* No contraindications for high-dose aldesleukin administration
* Left ventricular ejection fraction (LVEF) ≥ 45% in patients meeting any of the following criteria:

  * History of ischemic heart disease,
  * chest pain,
  * or clinically significant atrial and/or ventricular arrhythmias including, but not limited to, atrial fibrillation,
  * ventricular tachycardia,
  * or second- or third-degree heart block
  * At least 60 years of age
* Forced expiratory volume 1 (FEV_1) \> 60% predicted in patients meeting any of the following criteria:

  * Prolonged history of cigarette smoking (\> 20 pack/year within the past 2 years)
  * Symptoms of respiratory dysfunction
* No other major medical illness of the cardiovascular,

  * respiratory,
  * or immune system

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Recovered from prior therapy
* More than 4 weeks since prior and no concurrent systemic steroid therapy
* More than 4 weeks since other prior systemic therapy
* More than 6 weeks since prior ipilimumab

Primary outcomes:
measure: Clinical Response (Complete Response + Partial Response)
timeFrame: 5 months
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 5 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
Study officials:
affiliation: NCI - Surgery Branch
name: Steven A. Rosenberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: