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Phase I/II Study of Metastatic Cancer That Expresses Her-2 Using Lymphodepleting Conditioning Followed by Infusion of Anti-Her-2 Gene Engineered Lymphocytes

Phase 1/Phase 2
18 Years
Not Enrolling
Metastatic Cancer

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Trial Information

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).


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

- 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.


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).

Inclusion Criteria


1. Metastatic cancer that expresses Her-2 at greater than or equal to 2+ and
assessed by immunohistochemistry (IHC) in the clinical laboratory improvement
amendment (CLIA) approved test in the Laboratory of Pathology, Center for Cancer
Research (CCR), National Cancer Institute (NCI), National Institutes of Health

2. Patients must have previously received 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. Subjects with estrogen receptor-positive or progesterone
receptor-positive breast cancer must have progressed on or not be a candidate
for anti-estrogens or aromatase inhibitors and all breast cancer patients must
have progressed on or not be a candidate for an anthracycline-containing regimen
and a taxane-containing regimen.

3. Patients with breast cancer must have previously received trastuzumab. Patients
will not continue to receive trastuzumab during the trial period.

4. Greater than or equal to 18 years of age.

5. Willing to sign a durable power of attorney

6. Able to understand and sign the Informed Consent Document

7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

8. Life expectancy of greater than three months.

9. 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.

10. Serology:

1. Seronegative for human immunodeficiency virus (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 reverse transcriptase polymerase
chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA)

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.

11. Hematology:

1. Absolute neutrophil count greater than 1000/mm^3 without the support of

2. White blood cell (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 alanine aminotransferase (ALT)/aspartate aminotransferase (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. Left ventricular ejection fraction (LVEF) greater than or equal to 50%.

14. 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

15. Patients who have previously received anti-cytotoxic T-lymphocyte antigen 4
(CTLA4) antibody therapy must have a normal colonoscopy with normal colonic


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. 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.

3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency

4. 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).

5. Concurrent Systemic steroid therapy

6. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

7. History of coronary revascularization or ischemic symptoms

8. Documented forced expiratory volume in 1 second (FEV1) less than or equal to 60%
predicted tested in patients with:

1. A prolonged history of cigarette smoking (20 pack/year of smoking within the
past 2 years).

2. Symptoms of respiratory dysfunction

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Participants With an Objective Clinical Tumor Regression Response

Outcome Description:

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.

Outcome Time Frame:

12 days

Safety Issue:


Principal Investigator

Steven A Rosenberg, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

November 2008

Completion Date:

December 2010

Related Keywords:

  • Metastatic Cancer
  • Metastatic Cancer
  • Tumor Regression
  • Immunotherapy
  • Safety
  • Cancer
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892