Metastatic Cancer Clinical Trial
Official title:
Phase I/II Study of Metastatic Cancer That Expresses NY-ESO-1 Using Lymphodepleting Conditioning Followed by Infusion of Gene Engineered Lymphocytes Cotransduced With Genes Encoding IL-12 and Anti-NY ESO-1 TCR
Background:
- A new cancer treatment involves collecting white blood cells from an individual, modifying
them to secrete IL-2 and target the ESO-1 protein expressed on some cancers, and returning
them to the body. The cells may then be able to seek out the cancer cells and destroy them.
Some kinds of cancer contain a protein called ESO-1, which is found on the surface of the
cells. Doctors want to modify white blood cells to have an anti-ESO-1 effect, and use them to
treat the cancer that has the ESO-1. In addition to adding genes that target the ESO-1
protein to the cells, the genes for IL-12 are added to the cells. IL-12 is a protein that
stimulates the immune system. This type of therapy is called gene transfer.
Objectives:
- To test the safety and effectiveness of anti-ESO-1/IL-12 white blood cells against
metastatic cancer.
Eligibility:
- Individuals at least 18 years of age who have metastatic cancer that expresses ESO-1 and
has not responded to standard treatments.
Design:
- Participants will be screened with a medical history and physical exam. They will also
have blood tests and imaging studies.
- Participants will have leukapheresis about a month before the treatment to collect white
blood cells.
- They will have chemotherapy 5 days before the treatment to suppress the immune system,
and prepare the body for the anti-ESO-1/IL-12 cells.
- The anti-ESO-1/IL-12 cells will be given as an infusion.
- Participants will be monitored in the hospital during their recovery from the treatment.
- Participants will have regular followup exams every 1 to 6 months. The exams will
include blood tests, imaging studies, and other studies.
Due to toxicities seen with the regimen, it was decided not to pursue the phase 2 portion of
the study.
Background:
- In prior trials we have shown that adoptive transfer of lymphocytes, transduced with a T
cell receptor (TCR) that recognizes the NY-ESO-1 antigen, can mediate regression of
metastatic cancer, though responses are often transient, and complete responses are
rare.
- Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed a
retroviral vector that contains an inducible single chain IL-12 driven by an NFAT
responsive promoter which can be used to mediate transfer of this gene into anti-tumor
lymphocytes. This construct enables the secretion of IL-12 following stimulation of the
TCR.
- Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound
increase in the ability of these lymphocytes to mediate tumor regression following
administration to tumor bearing mice. These cells have a profound advantage in inducing
anti-tumor responses because very few cells are needed and there is no requirement for
the concomitant administration of interleukin-2 (IL-2) as is the case for conventional
cell transfer immunotherapies.
- Based on these studies we have now used a retrovirus that encodes an inducible human
single chain IL-12 driven by an NFAT responsive promoter and a retrovirus that encodes
an anti-NY-ESO-1 TCR to cotransduce autologous lymphocytes for the treatment of patients
with metastatic cancer that expresses the NY-ESO-1 antigen.
Objectives:
Primary objectives:
- To evaluate the safety of the administration of IL-12 and anti-NY-ESO-1 engineered
lymphocytes in patients receiving a non-myeloablative conditioning regimen.
- To determine if the administration of the transduced lymphocytes to patients following a
nonmyeloablative but lymphoid depleting preparative regimen will result in clinical
tumor regression in patients with metastatic cancer.
Secondary objective:
- To determine the in vivo survival of cotransduced gene-engineered cells.
Eligibility:
Patients who are 18 years of age or older must have
- Metastatic cancer whose tumors express the ESO antigen;
- ECOG performance status 0 or 1;
Design:
- Autlogous lymphocytes will be cotransduced with retroviral vectors, encoding IL-12 and
anti- NY-ESO-1 TCR.
- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous infusion of
IL-12/anti-ESO TCR gene-transduced lymphocytes.
- 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 of the first 3 dose cohorts unless that patient experiences a dose limiting
toxicity (DLT). Following cohort 3, all subsequent cohorts will proceed in a phase 1
dose escalation design, with 5 cohorts of n=3. Should a single patient experience a DLT
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
(MTD) prior to starting the phase II portion. If a DLT 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.
- Once the MTD has been determined, the study then will proceed to the phase II portion
using a phase II optimal design where initially 21 evaluable patients will be enrolled
in each of 2 cohorts. 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.
- The objective will be to determine if the combination of lymphocyte depleting
chemotherapy, and IL-12/ESO TCR gene engineered lymphocytes is associated with a
complete response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR
rate (p1=0.20).
;
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