High-dose Interleukin-2 (HDIL-2), Combined With recMAGE-A3 + AS15 ASCI

The goal of this clinical research study is to learn if high-dose interleukin-2 (HDIL-2), when given in combination with recMAGE-A3 + AS15 (Antigen-Specific Cancer Immunotherapeutic, ASCI), can help to control unresectable or metastatic melanoma in patients expressing MAGE-A3 antigen in tumor cells. The safety of this drug combination will also be studied.

The Study Drugs:

HDIL-2 is similar to a hormone naturally found in the body that boosts the immune system by helping "natural killer" (NK) cells live longer and work better. NK cells are a type of white blood cell that kill other cells, and they may kill cancer cells.

recMAGE-A3 + AS15 ASCI is a vaccine designed to teach your immune system to recognize molecules expressed on the tumor cells and to kill those tumor cells. This may increase the effectiveness of IL-2 by slowing the growth of the cancer cells, which may cause them to die.

Study Drug Administration:

Eligible participants will begin the study within 14 days of signing the consent form. All participants will be seen in clinic on Day 1 of weeks 1,3,5,7 while receiving cycles 1 and 2 of HDIL-2, Day 1 of weeks 9,11,15 while receiving cycles 3 and 4, Day 1 on weeks 18,21,24 while receiving cycles 5 and 6, and Day 1 of weeks 27,30 while receiving cycles 7 and 8 (Figure 1 and 2). Patients will receive recMAGE-A3 + AS15 in clinic on the same days stated above. After the injection on Day 1 of weeks 1, 3, 9, 11, 18, 21, 27, 30, participants will be admitted to the hospital to receive HDIL-2. Treatment of HDIL-2 will start on Day 2 and within 24 hours of receiving recMAGE + AS15.

Participant may continue to receive the study drug combination for up to 8 cycles (33 weeks) and ASCI alone for up to 76 more weeks. Participants continuing on the study beyond completing 8 cycles of HDIL-2 will receive the ASCI injection (recMAGE-A3 + AS15) on Day 1 every 6 weeks for 4 doses (weeks 34,40,46,52) then on Day 1 every 12 weeks (weeks 64, 76, 98, 110) for 4 doses. Participants who had their HDIL-2 discontinued before completing 8 cycles because of HDIL-2 related toxicities without showing signs of progression of disease or those who had their HDIL-2 discontinued before completing 8 cycles because of achieving complete response will be allowed to continue on the ASCI injection alone. Participant will be taken off the study therapy early if the disease gets worse, they experience intolerable side effects, or the study doctor thinks it is in the participant's best interest.

This is an investigational study. IL-2 is commercially available and FDA approved for the treatment of metastatic melanoma. HDIL-2 is a higher dose than the standard approved dose of IL-2. RecMAGE-A3 + AS15 is not FDA approved or commercially available yet. It is currently being used for research purposes only.

• Drug: HDIL-2
  720,000 IU/kg by vein over an approximate 15 minute period every eight hours, for a maximum of 14 doses per cycle.
  Other Names:

  • Interleukin-2
  • IL-2
  • Aldesleukin
  • Proleukin
• Biological: recMAGE-A3 + AS15
  300 μg plus 420 μg of CpG7909 (a part of the Adjuvant System AS15) by intermuscular injection within 24 hours from first dose of HDIL-2.
  Other Names:

  • Recombinant MAGE-A3 Protein
  • recMAGE-A3 + AS15 ASCI
  • MAGE-A3
  • MAGE-A3 ASCI

Inclusion Criteria:

1. Written informed consent has been obtained from the patient before the performance of any protocol-specific procedure.
2. Male or female patient with histologically proven, measurable unresectable or metastatic cutaneous melanoma
3. Patient is >/= 18 years of age.
4. Patients must have at least one biopsiable cutaneous, subcutaneous, lymph node lesion, lung or liver lesion and willing to undergo a punch or a CT or US guided biopsy of this lesion. Cutaneous lesions must measure >/= 4mm and lymph nodes, subcutaneous, lung or liver lesions must measure >/= 1cm.
5. ANA (antinuclear antibody) titer < 1:80
6. The patient's tumor shows expression of MAGE-A3 gene.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. White Blood Count (WBC) >/= 3000/mm^3 and Hemoglobin >/= 9 g/dl
9. Platelet count >/= 100,000/mm^3.
10. Normal aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) except for patients with liver metastases, in which serum ALT and AST </= 2.5 X upper limit of normal (ULN) will be permitted.
11. Creatinine </= 1.5 mg/dL
12. Normal total bilirubin except for patients with liver metastases, in which total bilirubin </= 1.5 X ULN will be permitted (patients with Gilbert's syndrome must have a total bilirubin less that 3.0 mg/dL).
13. Lactate dehydrogenase (LDH or LD) </= 2 X ULN
14. Stress cardiac test (stress thallium, stress MUGA (Multi Gated Acquisition Scan), dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) with estimated ejection fraction >50% within 6 months of signing consent form
15. Pulmonary function tests showing FEV1 > 65% or FVC > 65% of predicted within 6 months of signing consent form
16. Women of childbearing potential (WOCBP) must be using an adequate method of contraception prior to treatment, throughout the study, and for up to 8 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. In general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as: Amenorrhea for 12 consecutive months without another cause, or For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level 35 mIU/mL.
17. (Continued #16) Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 days before the start of treatment.
18. Men must also agree to use an adequate method of contraception.

Exclusion Criteria:

1. The patient has at any time received systemic chemotherapy, immunotherapy or targeted therapy (except for isolated limb perfusion, interferon, or radiation in the adjuvant setting, as long as this was performed at least 4 weeks before first study treatment administration).
2. Brain metastasis or history of brain metastasis.
3. Any types of melanoma other than cutaneous, i.e. ocular or mucosal .
4. The patient received any cancer immunotherapeutic containing a MAGE-A3 antigen.
5. Patients with a history of second malignancies are eligible provided that they have been free of recurrence from secondary malignancy for at least 3 years, does not include squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ.
6. The patient has a history of an autoimmune disease such as, but not limited to, multiple sclerosis, lupus, rheumatoid arthritis, and inflammatory bowel disease or an antinuclear antibody (ANA) titer > 1:80.
7. The patient has a history of allergic disease or reactions likely to be exacerbated by any component of the study investigational compound.
8. The patient has a family history of congenital or hereditary immunodeficiency.
9. Known to be positive for viral hepatitis B or C (HBsAg or Anti HCV) or HIV (HIV antibodies).
10. Systemic steroid therapy, steroid-containing compounds or any other immunosuppressive agents or to be used for more than 7 consecutive days (at a dose of prednisone or equivalent of >/= 0.125 mg/kg/day).
11. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent, or to comply with the trial procedures. Each patient will be evaluated by the principal investigator or his designee.
12. The patient has concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk. Each patient will be evaluated by the principal investigator or his designee.
13. Initiation of another anti-cancer therapy.
14. For female patients: the patient is pregnant or lactating.
15. WOCBP who are unwilling or unable to use an acceptable contraceptive method to avoid pregnancy.