Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes
2 other identifiers
interventional
12
1 country
1
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_2
Started Oct 2006
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
October 1, 2006
CompletedFirst Submitted
Initial submission to the registry
October 25, 2006
CompletedFirst Posted
Study publicly available on registry
October 26, 2006
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 1, 2008
CompletedStudy Completion
Last participant's last visit for all outcomes
November 1, 2008
CompletedResults Posted
Study results publicly available
August 5, 2011
CompletedAugust 15, 2011
August 1, 2011
2.1 years
October 25, 2006
June 1, 2011
August 10, 2011
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Clinical Tumor Regression
Response Evaluation Criteria In Solid Tumors (RECIST). See the protocol Link module for full criteria if desired.
1-11 months
The Number of Participants With Adverse Events
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.
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.
Secondary Outcomes (1)
In Vivo Survival of T-cell Receptor (TCR) Gene-engineered Cells in Participants
3-12 months
Study Arms (2)
Patients with metastatic melanoma
EXPERIMENTALMelanoma is a serious form of skin cancer that develops in the skin cells that make our skin color (melanocytes).
Patients with other metastatic cancers
EXPERIMENTALInterventions
Peripheral blood lymphocytes are harvested by lymphapheresis and engineered to express a T cell receptor that binds to P53.
720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days
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.
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.
25 mg/m2/day intravenously piggyback (IVPB) daily over 30 minutes for 5 days.
Eligibility Criteria
You may qualify if:
- 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.
- +3 more criteria
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
National Institutes of Health
Bethesda, Maryland, 20892, United States
Related Publications (3)
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenberg SA. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3515-9. doi: 10.1073/pnas.91.9.3515.
PMID: 8170938BACKGROUNDKawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, Appella E, Rosenberg SA. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994 Jul 1;180(1):347-52. doi: 10.1084/jem.180.1.347.
PMID: 7516411BACKGROUNDKawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, Yannelli JR, Adema GJ, Miki T, Rosenberg SA. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6458-62. doi: 10.1073/pnas.91.14.6458.
PMID: 8022805BACKGROUND
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Steven Rosenberg, M.D., Ph.D.
- Organization
- National Cancer Institute (NCI), National Institutes of Health (NIH)
Study Officials
- PRINCIPAL INVESTIGATOR
Steven A Rosenberg, M.D., Ph.D
NCI, NIH
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
Study Record Dates
First Submitted
October 25, 2006
First Posted
October 26, 2006
Study Start
October 1, 2006
Primary Completion
November 1, 2008
Study Completion
November 1, 2008
Last Updated
August 15, 2011
Results First Posted
August 5, 2011
Record last verified: 2011-08