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

Unspecified Adult Solid Tumor, Protocol Specific Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00704938
• Other study ID #: 080155
• Secondary ID: NCI-08-C-0155NCI
• Status: Terminated
• Phase: Phase 2
• First received: June 24, 2008
• Last updated: October 6, 2015
• Start date: June 2008
• Est. completion date: August 2009

Study information

• Verified date: September 2015
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: August 2009
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Cancer
• Melanoma (Skin)
• Neoplasm Metastasis
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

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

Drug:
• cyclophosphamide
60mg/kg/day (Days-7,-6)
• fludarabine phosphate
25mg/m^2 (Days -5, -4, -3, -2, and -1)

Locations

Country	Name	City	State
United States	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Bethesda	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
National Institutes of Health Clinical Center (CC)	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Response (Complete Response + Partial Response)	Clinical response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all lesions. Partial response is a 30% decrease in the sum of the longest diameter (LD) of target lesions.	5 months	No
Secondary	Number of Participants With Adverse Events	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse events module.	5 months	Yes