Cyclophosphamide and Fludarabine Followed by Cellular Adoptive Immunotherapy and Vaccine Therapy in Patients With Metastatic Melanoma

November 19, 2012 updated by: Prof. Serge Leyvraz

Phase I Study of In Vivo Expansion of Melan-A/MART-1 Antigen-Specific CD8 T Lymphocytes Following Transient Immunosuppression in Patients With Advanced Melanoma

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, may be used to prepare the body for other treatments, such as cellular adoptive immunotherapy. Biological therapies, such as cellular adoptive immunotherapy, may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines may help the body build an effective immune response to kill tumor cells. Giving cyclophosphamide together with fludarabine followed by biological therapy may be an effective treatment for metastatic melanoma.

PURPOSE: This phase I trial is studying the side effects of giving cyclophosphamide together with fludarabine followed by cellular adoptive immunotherapy, and vaccine therapy in treating patients with metastatic melanoma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES:

  • Determine the magnitude and duration of the expansion of antigen-specific T-cells present in post-vaccination peripheral blood mononuclear cells and reinfused after immunosuppression in patients with metastatic melanoma.
  • Characterize the T-cell subsets (phenotype, function, T-cell receptor repertoire) in these patients.
  • Determine the tumor response in patients treated with this regimen.
  • Determine the toxicity of this regimen in these patients.

OUTLINE: This is an open-label dose-finding study. Patients undergo leukapheresis to collect whole peripheral blood mononuclear cells (PBMC). Patients are then assigned to 1 of 3 treatment groups.

  • Group 1 (closed to accrual as of 5/8/2007): Patients receive cyclophosphamide IV on days -7 and -6 and fludarabine IV on days -5 to -3. Patients undergo autologous PBMC infusion on day 0. Patients also receive vaccination comprising Melan-A vaccine emulsified in incomplete Freund's adjuvant (IFA) subcutaneously (SC) once every 3 weeks beginning on day 0.
  • Group 2 (closed to accrual as of 8/15/2007): Patients receive cyclophosphamide IV at a higher dose than in group 1 on days -7 and -6 and fludarabine IV on days -5 to -3. Patients also receive an autologous PBMC infusion and Melan-A vaccine emulsified in IFA as in group 1.
  • Group 3: Patients receive cyclophosphamide IV at 30 mg/kg on days -7 and -6. Patients also receive fludarabine 30 mg/m2 IV on days -5 to -3, autologous PBMC infusion on day 0,and Melan-A vaccine emulsified in IFA and IMP321. The first 3 patients receive 25 micrograms of IMP321, in the absence of severe 3 or 4 toxicity, the dose will be escalated to IMP321 250 micrograms.

PROJECTED ACCRUAL: A total of 9 patients will be accrued for this study.

Study Type

Interventional

Enrollment (Actual)

8

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Lausanne, Switzerland, CH-1011
        • Centre Hospitalier Universitaire Vaudois

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Diagnosis of metastatic melanoma
  • Progressive disease after receiving prior Melan-A peptide vaccine on an immunotherapy protocol of the Ludwig Institute AND achieved a detectable immune response (increase of specific CD8^+ TET^+ Melan-A)
  • Tumor must express MART-1/Melan-A antigen
  • HLA-A2 positive
  • Not eligible for other protocols due to progressive disease OR maximum number of vaccine injections with stable disease has been attained

PATIENT CHARACTERISTICS:

  • Performance status 0-2
  • Whole blood counts normal
  • Pulmonary status normal
  • Transaminases < 1.5 times upper limit of normal (ULN)
  • Gamma-glutamyl-transferase < 1.5 times ULN
  • Bilirubin normal
  • Creatinine clearance > 70 mL/min
  • No major uncontrolled heart disease
  • No arterial hypertension

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Prior chemotherapy, biologic therapy, radiotherapy, and/or surgery allowed

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Lymphodepletion, vaccine, IMP321 adjuvant
Drug: cyclophosphamide
Drug: fludarabine phosphate
Biological: therapeutic autologous lymphocytes
Biological: adoptive immunotherapy
Biological: Melan-A VLP vaccine, IMP321 adjuvant

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Phenotype, function, and T-cell receptor repertoire
Time Frame: Anti-tumor immune response evaluated at each vaccine and until the last administered vaccine
Anti-tumor immune response evaluated at each vaccine and until the last administered vaccine
Tumor response
Time Frame: Tumor response evaluated 4 weeks after last vaccine
Tumor response evaluated 4 weeks after last vaccine
Toxicity
Time Frame: Within 30 days after completion of the last vaccine
Within 30 days after completion of the last vaccine

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Prof. Serge Leyvraz

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2005

Primary Completion (Actual)

November 1, 2011

Study Registration Dates

First Submitted

May 10, 2006

First Submitted That Met QC Criteria

May 10, 2006

First Posted (Estimate)

May 11, 2006

Study Record Updates

Last Update Posted (Estimate)

November 20, 2012

Last Update Submitted That Met QC Criteria

November 19, 2012

Last Verified

November 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000468827
  • CHUV-CEPO-ITA-02
  • EU-20607

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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