Cyclophosphamide and Fludarabine Followed By Vaccine Therapy, Autologous Gene-Modified Lymphocytes, and High-Dose Aldesleukin in Treating Patients With Metastatic Melanoma - Full Text View

Sponsored by:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00612222

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. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. 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. Giving cyclophosphamide and fludarabine together with vaccine therapy, autologous gene-modified lymphocytes, and aldesleukin may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine followed by vaccine therapy, autologous gene-modified lymphocytes, and high-dose aldesleukin works in treating patients with metastatic melanoma.

Condition	Intervention	Phase
Melanoma (Skin)	Drug: ALVAC-MART-1 vaccine Drug: aldesleukin Drug: autologous anti-MART-1 F5 T-cell receptor gene-engineered peripheral blood lymphocytes Drug: cyclophosphamide Drug: fludarabine phosphate	Phase II

MedlinePlus related topics: Cancer Melanoma

Drug Information available for: Cyclophosphamide Fludarabine Fludarabine monophosphate Aldesleukin

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes and ALVAC Virus Immunization

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

Primary Outcome Measures:

Clinical tumor regression [ Designated as safety issue: No ]

Secondary Outcome Measures:

In vivo survival of T-cell receptor (TCR) gene-engineered cells [ Designated as safety issue: No ]
Toxicity profile [ Designated as safety issue: Yes ]

Estimated Enrollment:	41
Study Start Date:	January 2008
Estimated Primary Completion Date:	January 2010 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

Determine if the administration of ALVAC-MART-1 vaccine, autologous anti-MART-1 F5 T-cell receptor (TCR) gene-engineered peripheral blood lymphocytes, and high-dose aldesleukin after a nonmyeloablative, but lymphodepleting, preparative regimen results in clinical tumor regression in patients with metastatic melanoma.

Secondary

Determine the in vivo survival of TCR gene-engineered cells.
Determine the toxicity profile of this treatment regimen.

OUTLINE:

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-MART-1 F5 T-cell receptor (TCR) genes and expanded in culture.
Nonmyeloablative, lymphodepleting 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.
Vaccine therapy: Patients receive ALVAC-MART-1 vaccine subcutaneously on days 0 (prior to peripheral blood lymphocyte infusion) and 14.
Autologous gene-engineered peripheral blood lymphocyte therapy: Patients receive autologous anti-MART-1 F5 TCR gene-engineered peripheral blood lymphocytes IV over 20-30 minutes on day 0.
High-dose aldesleukin: Patients receive high-dose aldesleukin IV over 15 minutes 3 times daily on days 0-4 (maximum of 15 doses).

Patients with a partial response or stable disease that subsequently progresses may receive one re-treatment course (as above) beginning 6-8 weeks after the last dose of aldesleukin.

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:

Diagnosis of metastatic melanoma
Measurable disease
HLA-A*0201 positive
MART-1 positive tumor by immunohistochemistry
Progressive or recurrent disease after prior treatment with high-dose aldesleukin
Tumor-infiltrating lymphocytes not available as treatment on other Surgery Branch protocols

PATIENT CHARACTERISTICS:

ECOG performance status 0-1
Life expectancy > 3 months
ANC > 1,000/mm³ (without filgrastim [G-CSF] support)
WBC > 3,000/mm³
Platelet count > 100,000/mm³
Hemoglobin > 8.0 g/dL
ALT/AST ≤ 2.5 times upper limit of normal (ULN)
Total bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL for patients with Gilbert's syndrome)
Serum creatinine ≤ 1.6 mg/dL
HIV antibody-negative
Hepatitis B antigen-negative
Hepatitis C antibody-negative
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 4 months after completion of the preparative regimen
Normal colonoscopy with normal colonoscopic biopsies required for patients previously treated with MDX-010 or ticilimumab
No active systemic infections
No ongoing opportunistic infections
No primary immunodeficiency (e.g., severe combined immunodeficiency disease)
No history of severe immediate hypersensitivity reaction to study drugs
No coagulation disorders
No myocardial infarction
No cardiac arrhythmias
No history of coronary revascularization or ischemic symptoms
LVEF > 45%
- Patients with clinically significant atrial and/or ventricular arrhythmias (including, but not limited to, atrial fibrillation, ventricular tachycardia, or second- or third-degree heart block) or ≥ 60 years of age must have documented LVEF > 45%
No obstructive or restrictive pulmonary disease
FEV_1 > 60% of predicted in patients with a prolonged history of smoking (20 pack years) or symptoms of respiratory dysfunction
No other major medical illnesses of the cardiovascular, respiratory, or immune system

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior therapy (alopecia or vitiligo allowed)
More than 4 weeks since prior systemic therapy
More than 6 weeks since prior ipilimumab (MDX-010)
No concurrent systemic steroid therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00612222

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:	CDR0000586107, NCI-08-C-0056, NCI-P07193
Study First Received:	February 8, 2008
Last Updated:	December 11, 2008
ClinicalTrials.gov Identifier:	NCT00612222
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

stage IV melanoma
recurrent melanoma

Study placed in the following topic categories:

Cyclophosphamide
Fludarabine monophosphate
Recurrence
Melanoma
Neuroendocrine Tumors
Virus Diseases
Neuroectodermal Tumors

Aldesleukin
Neoplasms, Germ Cell and Embryonal
Nevus, Pigmented
Neuroepithelioma
Nevus
Fludarabine

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Anti-HIV Agents
Antimetabolites, Antineoplastic
Neoplasms by Histologic Type
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Neoplasms, Nerve Tissue
Physiological Effects of Drugs
Antiviral Agents

Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Anti-Retroviral Agents
Therapeutic Uses
Myeloablative Agonists
Nevi and Melanomas
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Alkylating Agents

ClinicalTrials.gov processed this record on January 13, 2009