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

Melanoma (Skin) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00324623
• Other study ID #: CDR0000468827
• Secondary ID: CHUV-CEPO-ITA-02
• Status: Completed
• Phase: Phase 1
• First received: May 10, 2006
• Last updated: November 19, 2012
• Start date: September 2005

Study information

• Verified date: November 2012
• Source: Centre Hospitalier Universitaire Vaudois
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: Swissmedic
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Melanoma
• Melanoma (Skin)

Intervention

Biological:
• Melan-A VLP vaccine, IMP321 adjuvant

• adoptive immunotherapy

• therapeutic autologous lymphocytes

Drug:
• cyclophosphamide

• fludarabine phosphate

Locations

Country	Name	City	State
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne

Sponsors (1)

Lead Sponsor	Collaborator
Prof. Serge Leyvraz

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phenotype, function, and T-cell receptor repertoire		Anti-tumor immune response evaluated at each vaccine and until the last administered vaccine	No
Primary	Tumor response		Tumor response evaluated 4 weeks after last vaccine	No
Primary	Toxicity		Within 30 days after completion of the last vaccine	Yes