Phase I/II Study of Metastatic Cancer That Expresses Her-2 Using Lymphodepleting Conditioning Followed by Infusion of Anti-Her-2 Gene Engineered Lymphocytes
- We have constructed a single retroviral vector that contains a chimeric T cell receptor
(CAR) that recognizes the Her-2 tumor antigen, which can be used to mediate genetic
transfer of this CAR with high efficiency (greater than 30%) without the need to
perform any selection.
- In co-cultures with Her-2 positive tumors, anti-Her-2 CAR transduced T cells secreted
significant amount of interferon-gamma (IFN-gamma) (Her-2 high specificity).
- To evaluate the safety of the administration of anti-Her-2 -CAR engineered peripheral
blood lymphocytes in patients receiving the non-myeloablative conditioning regimen and
- Determine if the administration of anti-Her-2 -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 that expresses the Her-2 antigen.
- Determine the in vivo survival of CAR gene-engineered cells.
Patients who are 18 years of age or older must have
- metastatic cancer whose tumors express the Her-2 antigen;
- 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.
- Peripheral blood mononuclear cell (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 anti-Her-2 CAR genes .
- Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of
ex vivo tumor reactive, CAR genetransduced PBMC plus IV aldesleukin (720,000 IU/kg q8h
for a maximum of 15 doses).
- 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, with three cohorts. Should a single
patient experience a dose limiting toxicity (DLT) at a particular dose level, three
more 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.
- 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 metastatic breast cancer, and cohort 2 will include
patients with other types of metastatic cancer that express Her-2.
- 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 high dose aldesleukin,
lymphocyte depleting chemotherapy, and anti-Her-2 CAR-gene engineered 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% partial response (PR) + complete response (CR) rate (p1=0.20).
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With an Objective Clinical Tumor Regression Response
Response Evaluation Criteria in Solid Tumors (RECIST) are used to determine objective clinical response. Complete Rresponse (CR) is the disappearance of all target lesions, partial response (PR) is at least a 30% decrease in the target lesions, progressive disease (PD) is at least a 20% increase in the target lesions or appearance of one or more new lesions, and stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Steven A Rosenberg, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
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