Brief Title
CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer
Official Title
Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-mesothelin Gene Engineered Lymphocytes
Brief Summary
Background:
The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for
treating patients with metastatic cancer that involves taking white blood cells from the
patient, growing them in the laboratory in large numbers, genetically modifying these
specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then
giving the cells back to the patient. This type of therapy is called gene transfer. In this
protocol, we are modifying the patients white blood cells with a retrovirus that has the gene
for anti-mesothelin incorporated in the retrovirus.
Objective:
The purpose of this study is to determine a safe number of these cells to infuse and to see
if these tumor fighting cells (anti-mesothelin cells) cause metastatic cancer tumors to
shrink.
Eligibility:
- Adults age 18-70 with metastatic cancer expressing the mesothelin molecule.
Design:
Work up stage: Patients will be seen as an outpatient at the National Institutes of Health
(NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab
tests, and other tests as needed
Leukapheresis: If the patients meet all of the requirements for the study they will undergo
leukapheresis to obtain white blood cells to make the anti-mesothelin cells. {Leukapheresis
is a common procedure, which removes only the white blood cells from the patient.}
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the
conditioning chemotherapy, the anti-mesothelin cells, and aldesleukin. They will stay in the
hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
year as long as their tumors are shrinking. Follow up visits will take up to 2 days.
Detailed Description
Background:
- We have constructed a single retroviral vector that contains a chimeric T cell receptor
(CAR) that recognizes mesothelin, which can be used to mediate genetic transfer of this
CAR with high efficiency (> 50%) without the need to perform any selection.
- In co-cultures with mesothelin expressing cells, anti-mesothelin transduced T cells
secreted significant amounts of interferon (IFN)-gamma with high specificity.
Objectives:
Primary Objectives:
- To evaluate the safety of the administration of anti-mesothelin CAR engineered
peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning
regimen, and aldesleukin.
- Determine if the administration anti-mesothelin CAR engineered peripheral blood
lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid
depleting preparative regimen will result in clinical tumor regression in patients with
metastatic cancer.
Eligibility:
Patients who are 18 years of age or older must have
- Metastatic or unresectable cancer that expresses mesothelin;
- Previously received and have been a non-responder to or recurred after standard care;
Patients may not have:
-Contraindications for low dose aldesleukin administration.
Design:
- Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in
order to stimulate T-cell growth.
- Transduction is initiated by exposure of approximately 10^8 to 5 X 10^8 cells to
retroviral vector supernatant containing the anti-mesothelin CAR.
- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex
vivo CAR gene-transduced PBMC plus low dose intravenous (IV) aldesleukin
- Patients will undergo complete evaluation of tumor with physical examination, Computed
tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four
to six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage,
repeat complete evaluations will be performed every 1-3 months. After the first year,
patients continuing to respond will continue to be followed with this evaluation every
3-4 months until off study criteria are met.
- The study will be conducted using a Phase I/II optimal design. The protocol will proceed
in a phase 1 dose escalation design. Once the maximum tolerated dose (MTD) has been
determined, the study then would proceed to the phase II portion. Patients will be
entered into two cohorts based on histology: cohort 1 will include patients with
mesothelioma, and cohort 2 will include patients with other types of cancer that express
mesothelin.
- For each of the 2 strata evaluated, the study will be conducted using a phase II optimal
design where initially 21 evaluable patients will be enrolled. For each of these two
arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no
further patients will be enrolled but if 2 or more of the first 21 evaluable patients
enrolled have a clinical response, then accrual will continue until a total of 41
evaluable patients have been enrolled in that stratum.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Number of Patients With Objective Tumor Regression
Condition
Cervical Cancer
Intervention
Fludarabine
Study Arms / Comparison Groups
1/Phase I
Description: Non-myeloablative but lymphodepleting preparative regimen of cyclophosphamide and fludarabine plus anti-mesothelin chimeric T cell receptor (CAR) transduced peripheral blood lymphocytes (PBL) plus low dose aldesleukin.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
15
Start Date
May 4, 2012
Completion Date
December 17, 2018
Primary Completion Date
December 17, 2018
Eligibility Criteria
- INCLUSION CRITERIA:
1. Metastatic or unresectable measurable cancers that express mesothelin. As in
other protocols conducted by Dr. Hassan in the National Cancer Institute (NCI),
epithelial mesotheliomas and pancreatic cancers do not need to be assessed for
mesothelin expression since all of these tumors have been shown to express
mesothelin. Other metastatic or unresectable cancers must be shown to expresses
mesothelin as assessed by reverse transcription polymerase chain reaction
(RT-PCR) or immunohistochemistry on tumor tissue. Bi-phasic mesotheliomas must
express mesothelin on greater than 50% of the cells in the epithelial component.
Diagnosis will be confirmed by the Laboratory of Pathology, NCI.
2. Patients must have previously received at least one systemic standard care (or
effective salvage chemotherapy regimens) for metastatic or unresectable disease,
if known to be effective for that disease, and have been either non-responders
(progressive disease) or have recurred.
3. Greater than or equal to 18 years of age and less than or equal to 70 years of
age.
4. Willing to sign a durable power of attorney
5. Able to understand and sign the Informed Consent Document
6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
7. Patients of both genders must be willing to practice birth control from the time
of enrollment on this study and for up to four months after treatment.
8. Serology:
1. 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 treatment and
more susceptible to its toxicities.)
2. Seronegative for hepatitis B antigen, and seronegative for hepatitis C
antibody. If hepatitis C antibody test is positive, then patient must be
tested for the presence of antigen by RT-PCR and be Hepatitis C virus
ribonucleic acid (HCV RNA) negative.
9. Women of child-bearing potential must have a negative pregnancy test because of
the potentially dangerous effects of the treatment on the fetus.
10. Hematology:
1. Absolute neutrophil count greater than 1000/mm(3) without the support of
filgrastim.
2. White blood cell (WBC) (> 3000/mm(3)).
3. Platelet count greater than 100,000/mm(3).
4. Hemoglobin greater than 8.0 g/dl.
11. Chemistry:
1. Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) less or
equal to 2.5 times the upper limit of normal.
2. Serum creatinine less than or equal to 1.6 mg/dl.
3. 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.
12. More than four weeks must have elapsed since any prior systemic therapy at the
time the patient receives the preparative regimen, and patient's toxicities must
have recovered to a grade 1 or less (except for toxicities such as alopecia or
vitiligo).
Note: Patients may have undergone minor surgical procedures within the past 3
weeks, as long as all toxicities have recovered to grade 1 or less.
13. Subject's must be co-enrolled in protocol 03-C-0277.
EXCLUSION CRITERIA:
1. Patients with sarcomatoid mesothelioma as mesothelin is not expressed in this type of
mesothelioma.
2. Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
3. Patients with known brain metastases.
4. Patients receiving full dose anticoagulative therapy.
5. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation
disorders or any other major medical illnesses.
6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
7. Concurrent opportunistic infections (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).
8. Patients with diabetic retinopathy.
9. Concurrent Systemic steroid therapy.
10. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
11. History of coronary revascularization or ischemic symptoms.
12. Documented left ventricular ejection fraction (LVEF) of less than or equal to 45%
tested in patients with:
- Clinically significant atrial and/or ventricular arrhythmias including but not
limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree
heart block, chest pain, or ischemic heart disease
- Age greater than or equal to 65 years old
13. Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted
tested in patients with:
- A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2
years).
- Symptoms of respiratory dysfunction
14. Patients who are receiving any other investigational agents.
Gender
All
Ages
18 Years - 70 Years
Accepts Healthy Volunteers
No
Contacts
Steven A Rosenberg, M.D., ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01583686
Organization ID
120111
Secondary IDs
12-C-0111
Responsible Party
Principal Investigator
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Steven A Rosenberg, M.D., Principal Investigator, National Cancer Institute (NCI)
Verification Date
October 2019