Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-VEGFR2 Gene Engineered CD8+ Lymphocytes
18 Years
66 Years
Both
Metastatic Cancer, Metastatic Melanoma, Renal Cancer
Trial Information
Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-VEGFR2 Gene Engineered CD8+ Lymphocytes
Background:
- We have constructed a single retroviral vector that contains a chimeric T cell receptor
(CAR) that recognizes the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), which
can be used to mediate genetic transfer of this CAR with high efficiency (> 50%)
without the need to perform any selection. Administration of VEGFR2 CAR transduced
cells inhibited tumor growth in several different models in different mouse strains.
- In co-cultures with VEGFR2 expressing cells, anti-VEGFR2 transduced T cells secreted
significant amounts of IFN gamma with high specificity.
Objectives:
Primary objectives:
- To evaluate the safety of the administration of anti-VEGFR2 -CAR engineered CD8+
peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning
regimen, and aldesleukin.
- Determine if the administration of anti-VEGFR2 -CAR engineered CD8+ 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 cancer;
- previously received and have been a non-responder to or recurred after standard care
for metastatic disease;
Patients may not have:
-contraindications for high dose aldesleukin administration.
Design:
- PBMC obtained by leukapheresis (approximately 5 times 10(9) cells) will be cultured in
the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.
- Transduction is initiated by exposure of approximately 10(8) to 5 times 10(8) cells to
retroviral vector supernatant containing the VEGFR2 genes.
- 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 CD8+ PBMC plus IV aldesleukin. With approval of amendment C,
aldesleukin (based on total body weight) will be administered at a dose of 72,000 IU/kg
as an intravenous bolus over a 15 minute period every eight hours (+/- 1 hour)
beginning within 24 hours of the cell infusion and continuing for up to 5 days (maximum
15 doses
- 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. Initially, the protocol will enroll 1
patient in each dose cohort unless that patient experiences a dose limiting toxicity
(DLT). Should a single patient experience a dose limiting toxicity due to the cell
transfer at a particular dose level, additional patients would be treated at that dose
to confirm that no greater than 1/6 patients have a DLT prior to proceeding to the
next higher level. If a level with 2 or more DLTs in 3-6 patients has been identified,
three additional patients will be accrued at the next-lowest dose, for a total of 6,
in order to further characterize the safety of the maximum tolerated dose prior to
starting the phase II portion. If a dose limiting toxicity occurs in the first cohort,
that cohort will be expanded to 6 patients. If 2 DLTs are encountered in this cohort,
the study will be terminated. If IFN-gamma levels increase substantially (as defined
in the protocol) in the patient in a cohort compared to the prior patient, the cohort
would be expanded to an n=3 to obtain more data on this phenomenon. If one of these 3
patients experience a DLT, the cohort will be expanded to six patients. Following
amendment C, patients will be enrolled in cohorts 8-11, with the non-myeloablative
chemotherapy regimen, cells and low dose aldesleukin following a conventional 3+3
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 metastatic melanoma and renal cancer, and cohort 2 will include
patients with other types of metastatic cancer.
- 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.
- The objective will be to determine if the combination of aldesleukin, lymphocyte
depleting chemotherapy, and anti-VEGFR2 CAR-gene engineered CD8+ lymphocytes is able to
be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of
a modest 20% PR + CR rate (p1=0.20).
Inclusion Criteria
- INCLUSION CRITERIA:
1. Metastatic cancer with evaluable disease.
2. Patients must have previously received at least one 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.
3. Between the ages of 18 and 66.
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 receiving the
preparative regimen.
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 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 HCV RNA negative.
3. Women of child-bearing potential must have a negative pregnancy test
because of the potentially dangerous effects of the preparative
chemotherapy on the fetus.
10. 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.
11. 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.
12. 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).
13. More than 4 weeks must have elapsed since an surgical procedure at the time the
patient receives the preparative regimen due to the inhibition of wound healing
observed with VEGFR targeting angiogenesis inhibitors.
EXCLUSION CRITERIA:
1. Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
2. Patients with known brain metastases.
3. Patients receiving full dose anticoagulative therapy.
4. 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.
5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
6. 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).
7. Patients with diabetic retinopathy.
8. Concurrent Systemic steroid therapy.
9. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
10. History of coronary revascularization or ischemic symptoms.
11. Documented FEV1 less than or equal to 60% predicted tested in patients with:
1. A prolonged history of cigarette smoking (20 pk/year of smoking within the past
2 years).
2. Symptoms of respiratory dysfunction
j. In patients over 60 years of age, LVEF of less than 45%
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
To evaluate the safety of the administration of anti-VegFR2-CAR engineered peripheral blood lymphocytes in patients receiving a non-myeloablative conditioning regimen, and aldesleukin.
Outcome Time Frame:
6 years
Safety Issue:
Yes
Principal Investigator
Steven A Rosenberg, M.D.
Investigator Role:
Principal Investigator
Investigator Affiliation:
National Cancer Institute (NCI)
Authority:
United States: Federal Government
Study ID:
110013
NCT ID:
NCT01218867
Start Date:
October 2010
Completion Date:
October 2016
Related Keywords:
- Metastatic Cancer
- Metastatic Melanoma
- Renal Cancer
- Clinical Response
- Metastatic Cancer
- Immunotherapy
- Adoptive Cell Therapy
- Metastatic Melanoma
- Carcinoma, Renal Cell
- Kidney Neoplasms
- Melanoma
- Neoplasm Metastasis
- Neoplasms
- Neoplasms, Second Primary
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
