Clinical trial NCT00086866: Vaccine Therapy in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed With Surgery
Official title: Randomized, Open Phase II Study of Immunization With the Recombinant MAGE-3 Protein Combined With Adjuvant AS02B or AS15 in Patients With Unresectable and Progressive Metastatic Cutaneous Melanoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Melanoma (Skin)
Keywords: stage III melanoma
stage IV melanoma
recurrent melanoma
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2004-07-12
Enrollment: 165
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Vaccines may make the body build an immune response to kill tumor cells.

PURPOSE: This randomized phase II trial is studying two different regimens of vaccine therapy and comparing them to see how well they work in treating patients with stage III or stage IV melanoma that cannot be removed with surgery.

Detailed description: OBJECTIVES:

Primary

* Compare the objective response rate (complete and partial response) in patients with unresectable stage III or stage IV M1a cutaneous melanoma immunized with vaccine comprising D1/3-MAGE-3-His fusion protein and SB-AS02B adjuvant vs SB-AS15 adjuvant.
* Compare the activity of SB-AS02B adjuvant vs SB-AS15 adjuvant, in terms of maximizing the antigenicity of MAGE-3, in patients treated with these regimens.
* Compare the rate of grade 3/4 vaccine-related toxicity in patients treated with these regimens.

Secondary

* Compare progression-free survival in patients treated with these regimens.

OUTLINE: This is a randomized, open label, parallell-group, multicenter study. Patients are stratified according to disease stage (III in transit vs other stage III vs IV), presence of lesion ≥ 20 mm (yes vs no), and participating center. Patients are randomized to 1 of 2 treatment arms.

* Induction therapy

  * Arm I: Patients receive immunization comprising D1/3-MAGE-3-His fusion protein and SB-AS02B adjuvant intramuscularly (IM) once weekly on weeks 1, 3, 5, 7, 9, and 11.
  * Arm II: Patients receive immunization comprising D1/3-MAGE-3-His fusion protein SB-AS15 adjuvant IM once weekly on weeks 1, 3, 5, 7, 9, and 11.

Patients achieving a clinical complete response (CR), partial response (PR), stable disease (SD), or slow progressive disease (SPD) proceed to maintenance therapy.

* Maintenance therapy: Patients in both arms receive immunization (according to their randomized arm) once weekly on weeks 15, 18, 21, 24, 27, 30, 34, 40, 46, and 52.

Patients maintaining a CR, PR, or SD proceed to long-term treatment.

* Long-term treatment: Beginning 3 months after completion of maintenance therapy, patients in both arms receive immunization (according to their randomized arm) once every 3 months for 4 courses and then once every 6 months for 4 courses.

Treatment continues in both arms in the absence of disease progression that does not correspond to SPD status, unacceptable toxicity, or the diagnosis of an autoimmune disease.

Patients are followed every 12 weeks.

PROJECTED ACCRUAL: A total of 68 patients (34 patients per treatment arm) will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed cutaneous melanoma

  * Unresectable stage III OR stage IV M1a disease
* Documented progressive disease within the past 12 weeks
* Measurable disease
* Skin, soft tissue, or lymph node metastasis allowed provided the disease is not amenable to curative treatment with surgery
* Tumor must express the MAGE-3 gene by reverse transcription polymerase chain reaction analysis (more than 1% of the positive MAGE-3 control included in the assay)
* No visceral metastases within the past 56 days by imaging

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* ECOG 0-1

Life expectancy

* Not specified

Hematopoietic

* Hemoglobin ≥ lower limit of normal (LLN)
* WBC ≥ LLN
* Lymphocyte count ≥ LLN
* Platelet count ≥ LLN
* No bleeding disorders

Hepatic

* Bilirubin ≤ upper limit of normal (ULN)
* Lactic dehydrogenase ≤ ULN
* AST and ALT ≤ 2 times ULN
* PT and aPTT normal
* Hepatitis B surface antigen negative (antibody test may be positive)
* Hepatitis C antibody negative

Renal

* Creatinine ≤ ULN

Cardiovascular

* No clinically significant heart disease (CTC grade III or IV)

Immunologic

* No autoimmune disease (vitiligo allowed)
* No anti-nuclear antibody titer ≥ 1/320 OR equal to 1/160 AND auto-antibodies directed against specific auto-antigens
* No immunodeficiency
* No active infection requiring antibiotic therapy
* HIV negative

Other

* Not pregnant
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 3 months after study participation
* No other malignancy within the past 5 years except surgically cured basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
* No other serious acute or chronic illness requiring concurrent medications
* No psychological, familial, sociological, or geographical condition that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

* More than 8 weeks since prior adjuvant vaccine therapy
* No prior vaccine therapy containing a MAGE-3 antigen
* No prior vaccine therapy for metastatic melanoma
* No concurrent immunomodulating agents (e.g., BCG)

Chemotherapy

* No prior systemic chemotherapy
* No concurrent chemotherapy

Endocrine therapy

* No concurrent corticosteroids

  * Concurrent prednisone or equivalent allowed provided the dose is ≤ 40 mg/day and treatment duration is for no more than 3 weeks
  * Concurrent inhaled and topical steroids are allowed

Radiotherapy

* No prior radiotherapy to the spleen
* No concurrent radiotherapy to \> 20% of all existing lesions (i.e., target lesions, non-target lesions, and nonmeasurable lesions)

  * Concurrent local low-dose (≤ 20 Grays) radiotherapy allowed

Surgery

* Recovered from prior surgery or biopsy
* No prior organ allograft
* No prior splenectomy
* Concurrent surgery to a limited number of lesions allowed for patients with a complete response, partial response, or stable disease after at least 3 courses of study therapy

Other

* No prior systemic anticancer therapy
* More than 4 weeks since prior isolated limb perfusion therapy
* No other concurrent anticancer therapy
* No other concurrent immunosuppressive agents

Primary outcomes:
measure: Response rate (complete response and partial response) as assessed by RECIST criteria
measure: Vaccine-related toxicity as assessed by CTCAE v3
Secondary outcomes:
measure: Rate of stabilization as assessed by RECIST criteria
measure: Rate of mixed response as assessed by RECIST criteria
measure: Rate of immune response
measure: Progression-free survival
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Hyeres
country: France
facility: Clinique Sainte-Marguerite
city: Lille
country: France
facility: Centre Hospitalier Regional et Universitaire de Lille
city: Montpellier
country: France
facility: Hopital St. Eloi
city: Nantes
country: France
facility: CHR Hotel Dieu
city: Paris
country: France
facility: Institut Curie Hopital
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
city: Mannheim
country: Germany
facility: Klinikum der Stadt Mannheim
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico - Aviano
city: Naples
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Siena
country: Italy
facility: Universita di Siena
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Daniel Den Hoed Cancer Center at Erasmus Medical Center
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Trust
state: England
Study officials:
affiliation: Daniel Den Hoed Cancer Center at Erasmus Medical Center
name: Willem H. J. Kruit, MD, PhD
role: STUDY_CHAIR
affiliation: Universitair Medisch Centrum St. Radboud - Nijmegen
name: Cornelis J. A. Punt, MD, PhD
role: STUDY_CHAIR
References:
citation: Kruit WH, Suciu S, Dreno B, et al.: Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: A randomized open-label phase II study of the EORTC Melanoma Group (16032- 18031). [Abstract] J Clin Oncol 26 (Suppl 15): A-9065, 2008.
citation: Louahed J, Gruselle O, Gaulis S, et al.: Expression of defined genes identified by pretreatment tumor profiling: association with clinical responses to the GSK MAGE- A3 immunotherapeutic in metastatic melanoma patients (EORTC 16032-18031). [Abstract] J Clin Oncol 26 (Suppl 15): A-9045, 2008.
citation: Kruit WH, Suciu S, Dreno B, Mortier L, Robert C, Chiarion-Sileni V, Maio M, Testori A, Dorval T, Grob JJ, Becker JC, Spatz A, Eggermont AM, Louahed J, Lehmann FF, Brichard VG, Keilholz U. Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer Melanoma Group in Metastatic Melanoma. J Clin Oncol. 2013 Jul 1;31(19):2413-20. doi: 10.1200/JCO.2012.43.7111. Epub 2013 May 28.
citation: Ulloa-Montoya F, Louahed J, Dizier B, Gruselle O, Spiessens B, Lehmann FF, Suciu S, Kruit WH, Eggermont AM, Vansteenkiste J, Brichard VG. Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol. 2013 Jul 1;31(19):2388-95. doi: 10.1200/JCO.2012.44.3762. Epub 2013 May 28.