Gene-Modified Lymphocytes, High-Dose Aldesleukin, and Vaccine Therapy in Treating Patients With Progressive or Recurrent Metastatic Cancer

NCT ID: NCT00704938

Last Updated: 2015-10-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-06-30
• Study Completion Date: 2009-08-31

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.

Conditions

Kidney Cancer; Melanoma (Skin); Unspecified Adult Solid Tumor, Protocol Specific

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

anti-p53 TCR PBL + DC + IL-2: Melanoma/RCC

Patients with melanoma and renal cell cancer will receive anti-p53 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + dendritic cells (DC) + interleukin-2 (IL-2)

Group Type: EXPERIMENTAL

aldesleukin

Intervention Type: BIOLOGICAL

Intravenous (IV) aldesleukin 720,000 IU/kg every 8 hours for a maximum of 15 doses.

anti-p53 T-cell receptor-transduced peripheral blood lymphocytes

Intervention Type: BIOLOGICAL

Intravenous (IV) anti-p53 TCR transduced PBL will be administered at a a dose of 1 x 10\^8 cells to 5 x 10\^10 cells.

autologous dendritic cell-adenovirus p53 vaccine

Intervention Type: BIOLOGICAL

Ad-p53 DC vaccine, up to 2 x 10\^8 ad-p53 DCs per dose will be administered subcutaneously, divided into 4 injections, one into each of the 4 extremities. Ad-p53 DCs will be administered subcutaneously on day 7 (± 2 days), day 14 (between day 14 and day 18), and day 28 (between day 25 and day 42) post T cell infusion.

filgrastim

Intervention Type: BIOLOGICAL

subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day).

cyclophosphamide

Intervention Type: DRUG

60mg/kg/day (Days-7,-6)

fludarabine phosphate

Intervention Type: DRUG

25mg/m\^2 (Days -5, -4, -3, -2, and -1)

anti-p53 TCR PBL + DC + IL-2: Other histology

Patients with other histologies, such as breast cancer, will receive anti-p53 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + dendritic cells (DC) + interleukin-2 (IL-2)

Group Type: EXPERIMENTAL

aldesleukin

Intervention Type: BIOLOGICAL

Intravenous (IV) aldesleukin 720,000 IU/kg every 8 hours for a maximum of 15 doses.

anti-p53 T-cell receptor-transduced peripheral blood lymphocytes

Intervention Type: BIOLOGICAL

Intravenous (IV) anti-p53 TCR transduced PBL will be administered at a a dose of 1 x 10\^8 cells to 5 x 10\^10 cells.

autologous dendritic cell-adenovirus p53 vaccine

Intervention Type: BIOLOGICAL

Ad-p53 DC vaccine, up to 2 x 10\^8 ad-p53 DCs per dose will be administered subcutaneously, divided into 4 injections, one into each of the 4 extremities. Ad-p53 DCs will be administered subcutaneously on day 7 (± 2 days), day 14 (between day 14 and day 18), and day 28 (between day 25 and day 42) post T cell infusion.

filgrastim

Intervention Type: BIOLOGICAL

subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day).

cyclophosphamide

Intervention Type: DRUG

60mg/kg/day (Days-7,-6)

fludarabine phosphate

Intervention Type: DRUG

25mg/m\^2 (Days -5, -4, -3, -2, and -1)

Interventions

aldesleukin

Intravenous (IV) aldesleukin 720,000 IU/kg every 8 hours for a maximum of 15 doses.

Intervention Type: BIOLOGICAL

anti-p53 T-cell receptor-transduced peripheral blood lymphocytes

Intravenous (IV) anti-p53 TCR transduced PBL will be administered at a a dose of 1 x 10\^8 cells to 5 x 10\^10 cells.

Intervention Type: BIOLOGICAL

autologous dendritic cell-adenovirus p53 vaccine

Ad-p53 DC vaccine, up to 2 x 10\^8 ad-p53 DCs per dose will be administered subcutaneously, divided into 4 injections, one into each of the 4 extremities. Ad-p53 DCs will be administered subcutaneously on day 7 (± 2 days), day 14 (between day 14 and day 18), and day 28 (between day 25 and day 42) post T cell infusion.

Intervention Type: BIOLOGICAL

filgrastim

subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day).

Intervention Type: BIOLOGICAL

cyclophosphamide

60mg/kg/day (Days-7,-6)

Intervention Type: DRUG

fludarabine phosphate

25mg/m\^2 (Days -5, -4, -3, -2, and -1)

Intervention Type: DRUG

Other Intervention Names

Proleukin; growth colony stimulating factor (GCSF); Cytoxan; Fludara

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Institutes of Health Clinical Center (CC)

NIH

Sponsor Role: lead

Responsible Party

Steven Rosenberg, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven A. Rosenberg, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

NCI - Surgery Branch

Locations

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office

Bethesda, Maryland, United States

Countries

United States

Other Identifiers

NCI-08-C-0155

Identifier Type: -

Identifier Source: secondary_id

NCI-P07215

Identifier Type: -

Identifier Source: secondary_id

080155

Identifier Type: -

Identifier Source: org_study_id