Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT00393029 |
|
Recruitment Status :
Completed
First Posted : October 26, 2006
Results First Posted : August 5, 2011
Last Update Posted : August 15, 2011
|
Sponsor:
National Cancer Institute (NCI)
Information provided by:
National Institutes of Health Clinical Center (CC)
- Study Details
- Tabular View
- Study Results
- Disclaimer
- How to Read a Study Record
Brief Summary:
Background:
The p53 gene normally suppresses tumor growth, but when it is mutated, or damaged, tumors can grow unchecked.
In cancers where the p53 gene has mutated, an increased level of p53(overexpression of p53) can be measured in the tumor.
Objectives To determine whether advanced cancers that overexpress p53 can be treated effectively with lymphocytes (white blood cells) that have been genetically engineered to contain an anti-p53 protein.
Eligibility Patients 18 years of age and older with metastatic cancer (cancer that has spread beyond the original site) Patient's tumor overexpresses p53 Patient's leukocyte antigen type is HLA-A 0201 Design
Patients undergo the following procedures:
Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the anti-p53 protein is inserted into the cells using an inactivated (harmless)virus in a process called transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.
Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) for 1 week to suppress the immune system so that the patients immune cells do not interfere with the treatment.
Treatment with anti-p53 cells. Patients receive an IV infusion of the transduced cells containing anti-p53 protein, followed by infusions of a drug called IL-2, which helps boost the effectiveness of the transduced white cells.
Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue). Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans 4 to 6 weeks after treatment and then once a month 3 to 4 months to determine the response to treatment.
Patients have blood tests at 1, 3, 6 and 12 months and then annually for the next 10 years.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Anti-p53 TCR-Gene | Biological: anti-protein 53 or tumor protein 53 (p53) T-cell receptor transduced peripheral blood lymphocytes Biological: aldesleukin Biological: filgrastim Drug: cyclophosphamide Drug: fludarabine phosphate | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 12 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase II Study of Metastatic Cancer That Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-p53 T Cell Receptor (TCR)-Gene Engineered Lymphocytes |
| Study Start Date : | October 2006 |
| Actual Primary Completion Date : | November 2008 |
| Actual Study Completion Date : | November 2008 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Genes and Gene Therapy
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Patients with metastatic melanoma
Melanoma is a serious form of skin cancer that develops in the skin cells that make our skin color (melanocytes).
|
Biological: anti-protein 53 or tumor protein 53 (p53) T-cell receptor transduced peripheral blood lymphocytes
Peripheral blood lymphocytes are harvested by lymphapheresis and engineered to express a T cell receptor that binds to P53.
Other Names:
Biological: aldesleukin 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days
Other Names:
Biological: filgrastim Beginning on day 1 or 2, administered subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day); continue daily until neutrophil count > 1.0 x 10^9/L x 3 days or > 5.0 x 10^9/L.
Other Names:
Drug: cyclophosphamide 60 mg/kg/day x 2 days intravenously in 250ml dextrose 5% in water (D5W) with mesna 15 mg/kg/day x 2 days over 1 hour.
Other Names:
Drug: fludarabine phosphate 25 mg/m2/day intravenously piggyback (IVPB) daily over 30 minutes for 5 days.
Other Name: Fludara |
| Experimental: Patients with other metastatic cancers |
Biological: anti-protein 53 or tumor protein 53 (p53) T-cell receptor transduced peripheral blood lymphocytes
Peripheral blood lymphocytes are harvested by lymphapheresis and engineered to express a T cell receptor that binds to P53.
Other Names:
Biological: aldesleukin 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days
Other Names:
Biological: filgrastim Beginning on day 1 or 2, administered subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day); continue daily until neutrophil count > 1.0 x 10^9/L x 3 days or > 5.0 x 10^9/L.
Other Names:
Drug: cyclophosphamide 60 mg/kg/day x 2 days intravenously in 250ml dextrose 5% in water (D5W) with mesna 15 mg/kg/day x 2 days over 1 hour.
Other Names:
Drug: fludarabine phosphate 25 mg/m2/day intravenously piggyback (IVPB) daily over 30 minutes for 5 days.
Other Name: Fludara |
Primary Outcome Measures :
- Clinical Tumor Regression [ Time Frame: 1-11 months ]
Response Evaluation Criteria In Solid Tumors (RECIST).
See the protocol Link module for full criteria if desired.
- The Number of Participants With Adverse Events [ Time Frame: events related to all components of the treatment regimen were reported from the start of the non-myeloablative conditioning regiment through 30 days following treatment or resolution. ]Here are the total number of participants with adverse events. Adverse events were described using the Common Terminology Criteria for Adverse Events (CTCAE) version 3. For the detailed list of adverse events see the adverse event module.
Secondary Outcome Measures :
- In Vivo Survival of T-cell Receptor (TCR) Gene-engineered Cells in Participants [ Time Frame: 3-12 months ]Survival of TCR gene-engineered cells is defined as >10% murine TCR positive cells.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patients must have metastatic cancer that overexpresses p53 as assessed by immunohistochemistry, as determined by positive staining of tumor sample. when compared to negative controls per procedure in Appendix 1. The immunohistochemical staining will be performed in the Pathology Laboratory Center for Cancer Research (CCR), National Cancer Institute (NCI) on fresh or archival tissue and will be supervised by Dr. Maria Merino. The criteria used to determine overexpression will be that used in the Laboratory of Dr. Curt Harris. Ten fields will be evaluated at 40 X magnification and if greater than 5% of cells stain positive, the tumor will be categorized as an overexpressor.
- Patients with melanoma or renal cell cancer must have previously received interleukin-2 (IL-2) and have been either non-responders (progressive disease) or have recurred. Patients with other histologies,not including hematologic malignancies, must have previously received first line and second line or higher systemic standard care(or effective salvage chemotherapy regimens) for metastatic disease,if known to be effective for that disease and have been either non-responders (progressive disease) or have recurred.
- Age greater than or equal to 18 years.
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 1.
- Life expectancy of greater than three months.
- Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental and more susceptible to its toxicities).
- Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.
- Patients must be human leukocyte antigen A(HLA-A) 0201 positive.
- Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
- Absolute neutrophil count greater than 1000/mm^3, and normal white blood cells (WBC) (greater than 3000/mm^3).
- Platelet count greater than 100,000/mm^3.
- Hemoglobin greater than 8.0 g/dl.
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than the upper limit of normal.
- Serum creatinine less than or equal to 1.6 mg/dl.
- Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
- More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Six weeks must have elapsed since prior Ipilimumab (MDX-010) therapy to allow antibody levels to decline, and patients who have previously received MDX-010 must have a normal colonoscopy with normal colonic biopsies.
- Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
- A biopsy must be evaluable to evaluate p53 expression and to confirm the diagnosis by the Laboratory of Pathology, CCR, NCI.
Exclusion Criteria:
- Patients requiring systemic steroid therapy
- Patients with active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
- Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and acquired immune deficiency syndrome (AIDS)). Patients with opportunistic infections will be excluded. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
- Patients with history of severe immediate hypersensitivity reaction to any of the agents used in this study.
- Patient is not willing to sign a durable power of attorney.
- Patient is not able to understand and sign the Informed Consent Document.
- Since aldesleukin will be excluded if they have a history of electrocardio- gram (EKG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) less than 45% on a cardiac stress test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram, or other stress test).
- Similarly, patients who are greater than or equal to 50 years old with a LVEF less than 45% will be excluded.
- Patients with a prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years) or symptoms of respiratory dysfunction (e.g. grade 2 dyspnea or hypoxia) who do not have a normal pulmonary function test as evidenced by a FEV(1) less than 60% predicted will be excluded.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00393029
Locations
| United States, Maryland | |
| National Institutes of Health | |
| Bethesda, Maryland, United States, 20892 | |
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Steven A Rosenberg, M.D., Ph.D | NCI, NIH |
Additional Information:
Publications:
Publications:
| Responsible Party: | Steven A. Rosenberg, M.D., Ph.D., National Cancer Institute, National Institutes of Health |
| ClinicalTrials.gov Identifier: | NCT00393029 |
| Other Study ID Numbers: |
070003 070003 ( Other Identifier: National Institutes of Health (NIH) ) 07-C-0003 ( Other Identifier: National Institutes of Health (NIH) ) |
| First Posted: | October 26, 2006 Key Record Dates |
| Results First Posted: | August 5, 2011 |
| Last Update Posted: | August 15, 2011 |
| Last Verified: | August 2011 |
Keywords provided by National Institutes of Health Clinical Center (CC):
|
Tumor Regression In Vivo Cell Survival Toxicity Profile |
Metastatic Renal Cell Cancer Cancer Metastatic Cancer |
Additional relevant MeSH terms:
|
Neoplasm Metastasis Neoplastic Processes Neoplasms Pathologic Processes Aldesleukin Cyclophosphamide Fludarabine Fludarabine phosphate Interleukin-2 Lenograstim Sargramostim Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents |
Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antimetabolites, Antineoplastic Antimetabolites Adjuvants, Immunologic Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents |