Description:
Background:
The 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
patient s 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 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.
CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer
Title
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
Clinical Trial IDs
NCT ID: NCT01583686
ORG ID: 120111
NCI ID: 12-C-0111
Trial Conditions
Cervical Cancer
Pancreatic Cancer
Ovarian Cancer
Ovarian
Lung Cancer
Trial Interventions
| Drug |
Synonyms |
Arms |
| Fludarabine |
|
Single Arm |
| Cycolphosphamide |
|
Single Arm |
| Aldesleukin |
|
Single Arm |
Trial Purpose
Background:
The 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 patient s 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 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 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.
Secondary Objective:
-Determine the in vivo survival of CAR gene-engineered cells.
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:
- 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 IV aldesleukin
- Patients will undergo complete evaluation of tumor with physical examination, CT of the
chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after
treatment. If the patient has 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 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.
Trial Arms
| Name |
Type |
Description |
Interventions |
| Single Arm |
Experimental |
Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by IV infusion of anti-mesothelin CAR engineered PBL plus low dose IV aldesleukin. |
Fludarabine, Cycolphosphamide, Aldesleukin |
Eligibility Criteria
- INCLUSION CRITERIA:
1. Metastatic or unresectable measurable cancers that express mesothelin. As in
other protocols conducted by Dr. Hassan in the NCI, epitheial 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 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 ECOG 0 or 1.
7. Life expectancy of greater than three months.
8. 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.
9. Serology:
1. Seronegative for HIV antibody. (The experimental treatment being evaluated
in this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immunecompetence 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 HCV RNA negative.
10. Women of child-bearing potential must have a negative pregnancy test because of
the potentially dangerous effects of the treatment on the fetus.
11. Hematology:
1. Absolute neutrophil count greater than 1000/mm(3) without the support of
filgrastim.
2. WBC (> 3000/mm(3)).
3. Platelet count greater than 100,000/mm(3).
4. Hemoglobin greater than 8.0 g/dl.
12. Chemistry:
1. Serum 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.
13. 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).
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.
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, coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune system, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease.
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 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
- Age greater than or equal to 60 years old
Minimum Eligible Age: 18 Years
Maximum Eligible Age: 70 Years
Eligible Gender: Both
Primary Outcome Measures
Determine a safe dose of administration and determine if this approach will result in an objective tumor regression.
Secondary Outcome Measures
Determine the in vivo survival of CAR gene-engineered cells.
Trial Keywords
Metastatic Cancer
Immunotherapy
Gene Therapy
Mesothelioma
Pancreatic Cancer
