Gene Therapy Using Anti-Her-2 Cells to Treat Metastatic Cancer

Phase 1

Terminated

Conditions: Metastatic Cancer

Interventions: Drug: in vitro tumor reactive, chimeric T cell receptor (CAR ) gene-transduced PBL plus IV aldesleukin
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Mesna

Registration Number: NCT00924287

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

* Human epidermal growth factor receptor-2 (Her-2) is a gene found in both normal cells and cancer cells. Extra copies of the gene (overexpression) can cause too many Her-2 proteins (receptors) to appear on the cell surface and cause tumors to grow.

* An experimental procedure developed for treating patients with cancer uses blood cells found in their tumors or bloodstream. The cells are genetically modified using the anti-Her-2 gene and a type of virus. The modified cells (anti-Her-2 cells) are grown in the laboratory and then given back to the patient to try to decrease the size of the tumors. This is called gene therapy.

Objectives:

* To determine whether advanced cancers that overexpress Her-2 can be treated effectively with lymphocytes (white blood cells) that have been genetically engineered to contain an anti-Her-2 protein.

Eligibility:

* Patients 18 years of age and older with metastatic cancer (cancer that has spread beyond the original site) and for whom standard treatments are not effective.

* Patient's tumor overexpresses Her-2.

Design:

* Workup with scans, x-rays and other tests.

* Leukapheresis to obtain cells for preparing the anti-Her-2 cells for later infusion.

* 1 week of chemotherapy to prepare the immune system for receiving the anti-Her-2 cells.

* Infusion of anti-Her-2 cells, followed by interleukin-2 (IL-2) treatment. The cells are given as an infusion through a vein. IL-2 is given as a 15-minute infusion through a vein every 8 hours for a maximum of 15 doses.

* Periodic follow-up clinic visits after hospital discharge for physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.

Detailed Description: Background:

* 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).

Objectives:

Primary objectives:

* 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 aldesleukin.

* 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.

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 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.

Design:

* 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).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Metastatic Cancer	in vitro tumor reactive, chimeric T cell receptor (CAR ) gene-transduced PBL plus IV aldesleukin	Cancer that has invaded other parts of the body
Metastatic Cancer	Cyclophosphamide	Cancer that has invaded other parts of the body
Metastatic Cancer	Fludarabine	Cancer that has invaded other parts of the body
Metastatic Cancer	Mesna	Cancer that has invaded other parts of the body

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	12 days	Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Number of Participants With an Objective Clinical Tumor Regression Response	12 days	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With In Vivo Survival of Transfused Cells	12 days	In-vivo survival of infused cells is determined by analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS).