Cyclophosphamide and Fludarabine Followed By Gene-Modified Lymphocytes and Aldesleukin in Treating Patients With Metastatic Cancer - Full Text View

Sponsored by:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00805987

Purpose

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Gene-modified lymphocytes may stimulate the immune system in different ways and stop tumor cells from growing. Aldesleukin may stimulate lymphocytes to kill tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of gene-modified lymphocytes when given together with cyclophosphamide, fludarabine, and aldesleukin and to see how well they work in treating patients with metastatic cancer.

Condition	Intervention	Phase
Breast Cancer Unspecified Adult Solid Tumor, Protocol Specific	Drug: aldesleukin Drug: anti-Her-2-CAR-engineered autologous peripheral blood lymphocytes Drug: cyclophosphamide Drug: filgrastim Drug: fludarabine phosphate Procedure: fluorescence activated cell sorting Procedure: immunologic technique Procedure: laboratory biomarker analysis Procedure: reverse transcriptase-polymerase chain reaction	Phase I Phase II

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Cyclophosphamide Filgrastim Fludarabine Fludarabine monophosphate Aldesleukin

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled
Official Title:	Phase I/II Study of Metastatic Cancer That Expresses Her-2 Using Lymphodepleting Conditioning Followed by Infusion of Anti-Her-2 Gene Engineered Lymphocytes

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose of anti-HER-2 chimeric antigen receptor (CAR)-engineered autologous peripheral blood lymphocytes [ Designated as safety issue: Yes ]
Safety [ Designated as safety issue: Yes ]
Clinical tumor response [ Designated as safety issue: No ]
Duration of response [ Designated as safety issue: No ]

Secondary Outcome Measures:

In vivo survival of CAR-engineered autologous peripheral blood lymphocytes [ Designated as safety issue: No ]

Estimated Enrollment:	100
Study Start Date:	December 2008
Estimated Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

To evaluate the safety of anti-HER-2 chimeric antigen receptor (CAR)-engineered autologous peripheral blood lymphocytes when given with high-dose aldesleukin following a nonmyeloablative lymphodepleting preparative regimen in patients with metastatic cancer that expresses HER-2.
To determine if the administration of anti-HER-2 CAR-engineered autologous peripheral blood lymphocytes and high-dose aldesleukin following a nonmyeloablative lymphodepleting preparative regimen results in clinical tumor regression in these patients.

Secondary

To determine the in vivo survival of CAR-engineered autologous peripheral blood lymphocytes.

OUTLINE: This is a phase I dose-escalation study of anti-HER-2 chimeric antigen receptor (CAR)-engineered autologous peripheral blood lymphocytes followed by a phase II study. Patients enrolled in the phase II portion are stratified according to cancer type (breast cancer vs all other cancer types).

Leukapheresis and cell preparation: Patients undergo leukapheresis to obtain peripheral blood mononuclear cells that are subsequently cultured in the presence of anti-CD3 (OKT3) and aldesleukin. The cells are then transduced by exposure to anti-HER-2 CAR retroviral vector and expanded in culture.
Nonmyeloablative, lymphocyte-depleting preparative regimen: Patients receive cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30 minutes on days -5 to -1.
Anti-HER-2 CAR-engineered autologous peripheral blood lymphocyte infusion: Patients receive anti-HER-2 CAR-engineered autologous peripheral blood lymphocytes IV over 20-30 minutes on day 0. Patients also receive filgrastim (G-CSF) subcutaneously beginning on day 1 or 2 and continuing until blood counts recover.
High-dose aldesleukin: Patients receive high-dose aldesleukin IV over 15 minutes every 8 hours on days 0-4 (maximum of 15 doses).

Patients are evaluated 4-6 weeks after completion of aldesleukin. Patients achieving partial response or stable disease (for at least 2 months) that subsequently progresses may receive another course of treatment (as above) beginning 6-8 weeks after completion of aldesleukin.

Blood samples are collected periodically for immunological monitoring of cell function by FACS analysis using tetramer staining, immunological assays, and RT-PCR.

After completion of study treatment, patients are followed periodically for up to 15 years.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed metastatic cancer
- Tumor expresses HER-2 at ≥ 2+ as assessed by IHC
Progressive or recurrent disease after prior systemic standard therapy (or effective salvage chemotherapy regimens) for metastatic disease
- Patients with breast cancer must have progressed on OR not be a candidate for anthracycline-containing and taxane-containing regimens
- Patients 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
- Patients with breast cancer must have received trastuzumab (Herceptin®)

PATIENT CHARACTERISTICS:

Menopausal status not specified
ECOG performance status 0-1
Life expectancy > 3 months
Absolute neutrophil count > 1,000/mm³ (without filgrastim [G-CSF] support)
WBC > 3,000/mm³
Platelet count > 100,000/mm³
Hemoglobin > 8.0 g/dL
ALT and AST ≤ 2.5 times upper limit of normal
Total bilirubin ≤ 1.5 mg/dL (< 3.0 mg/dL in patients with Gilbert's syndrome)
Serum creatinine ≤ 1.6 mg/dL
LVEF ≥ 50%
FEV_1 > 60% predicted in patients with a prolonged history of cigarette smoking (i.e., 20 pk/year of smoking within the past 2 years) or symptoms of respiratory dysfunction
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 4 months after receiving the preparative regimen
HIV antibody negative
Hepatitis B antigen negative
Hepatitis C antibody negative
- If hepatitis C antibody positive, patient must be tested for the presence of antigen by RT-PCR AND be hepatitis C RNA negative
Patients who have previously received anti-CTLA4 antibody therapy must have a normal colonoscopy with normal colonic biopsies
No myocardial infarction or cardiac arrhythmias
No history of coronary revascularization or ischemic symptoms
No obstructive or restrictive pulmonary disease
No active systemic infections or coagulation disorders
No primary immunodeficiency (e.g., severe combined immunodeficiency disease)
No concurrent opportunistic infections
No history of severe immediate hypersensitivity reaction to any of the agents used in this study
No other major medical illness of the cardiovascular, respiratory, or immune system

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
More than 4 weeks since prior systemic therapy and recovered (alopecia or vitiligo allowed)
No concurrent systemic steroid therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00805987

Locations

United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Recruiting
Bethesda, Maryland, United States, 20892-1182
Contact: Clinical Trials Office - Warren Grant Magnusen Clinical Center 888-NCI-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Steven A. Rosenberg, MD, PhD

NCI - Surgery Branch

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000629279, NCI-09-C-0041, NCI-P07334
Study First Received:	December 9, 2008
Last Updated:	December 11, 2008
ClinicalTrials.gov Identifier:	NCT00805987
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

recurrent breast cancer
stage IV breast cancer
unspecified adult solid tumor, protocol specific

Study placed in the following topic categories:

Aldesleukin
Skin Diseases
Neoplasm Metastasis
Breast Neoplasms
Fludarabine

Fludarabine monophosphate
Cyclophosphamide
Breast Diseases
Recurrence

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Anti-HIV Agents
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Antiviral Agents
Immunosuppressive Agents
Pharmacologic Actions

Neoplasms
Neoplastic Processes
Neoplasms by Site
Pathologic Processes
Anti-Retroviral Agents
Therapeutic Uses
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Alkylating Agents

ClinicalTrials.gov processed this record on January 16, 2009