Study of Denileukin Diftitox in Patients With Stage IIIC and Stage IV Melanoma

This is a multicenter, open-label, dose/schedule and clinical efficacy study in patients with
Stage IIIC and Stage IV melanoma.

Dose-Schedules: This is a schedule, dose, and pharmacodynamic study of Denileukin diftitox in
in patients with Stage IIIC and Stage IV melanoma. Two arms of 40 patients each were
originally planned (see below) for a total of 80 patients. Patients were randomly assigned to
1 of 2 arms: 1. 12 mcg/kg/day on Days 1 through 4 of each 21-day treatment cycle, for a total
of 4 cycles (12 weeks); 2. 12 mcg/kg/day on Days 1, 8, and 15 of each 21-day treatment cycle,
for a total of 4 cycles (12 weeks). Patients will be evaluated for (clinical response, safety
and tolerability, and pharmacodynamic measures of ONTAK activity. An optional substudy will
be conducted that will involve collection of serial tumor biopsies at study entry and Day 84
in order to assess tissue pharmacodynamic markers of ONTAK activity (Treg depletion in tumor,
appearance of melanoma antigen-specific CD8+lymphocytes, and other markers of mucosal
immunity and inflammatory response).

Following an amendment, patients will be enrolled in Arm 1 only (expanded to a total of 55
patients) and Arm 2 was closed. According to the original design, if two responses or less
were observed among 22 patients on either arm, that arm would be discontinued.

Patients experiencing clinical benefit (immune-related stable disease [irSD], immune-related
partial response [irPR], or immune-related complete response [irCR] per irRC) after 4 cycles
of treatment, may continue their denileukin diftitox treatment for up to 8 cycles

Inclusion Criteria Patients may be entered in the study only if they meet all of the
following criteria.

1. Male or female patients greater than or equal to18 years of age;

2. Patients with histologically confirmed melanoma (Stage IIIC or Stage IV, American
Joint Commission on Cancer);

3. Naive to prior systemic chemotherapy, targeted therapy (eg, BRAF), or immunotherapy
(eg, interleukin-2 [IL-2] or interferon) for the treatment of melanoma, including any
cytotoxic agents or IL-2 used for adjuvant therapy (adjuvant interferon is allowed).
Prior granulocyte macrophage colony-stimulating factor (GM-CSF) is allowed;

4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2;

5. Life expectancy greater than or equal to 3 months;

6. At least 1 site of radiographically measurable disease by immune-related response
criteria (irRC);

7. Serum albumin greater than or equal to 3 g/dL;

8. Adequate hematologic, renal, and liver function as defined by laboratory values
performed within 21 days prior to initiation of dosing:

- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L;

- Platelet count greater than or equal to 100 x 10^9/L;

- Hemoglobin greater than or equal to 9 g/dL;

- Serum creatinine less than or equal 1.5 x upper limit of normal (ULN) or
creatinine clearance greater than or equal to 50 mL/min;

- Total serum bilirubin less than or equal to 1.5 x ULN;

- Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT)
less than or equal to 2.5 x ULN, and less than or equal to 5 x ULN if liver
metastases are present.

9. Fertile males should use an effective method of contraception during treatment and for
at least 3 months after completion of treatment, as directed by their physician;

10. Pre-menopausal females and females less than 2 years after the onset of menopause
should have a negative pregnancy test at Screening. Pre-menopausal females must agree
to use an acceptable method of birth control from the time of the negative pregnancy
test up to 90 days after the last dose of study drug. Females of non-childbearing
potential may be included if they are either surgically sterile or have been
postmenopausal for greater than or equal to 1 year; Before study entry, written
informed consent must be obtained from the patient prior to performing any
study-related procedures.

Exclusion Criteria

Patients will not be entered in the study for any of the following:

1. Known central nervous system (CNS) lesions, except for asymptomatic non-progressing,
treated brain metastases.

Treated brain metastases are defined as having no evidence of progression or
hemorrhage for 2 months, as ascertained by clinical examination and brain imaging
(magnetic resonance imaging [MRI] or computerized tomography [CT]) during the
Screening period (using the pretreatment brain image as Baseline). Treatment for brain
metastases must have been completed at least 2 months prior to Day 1 of the first
treatment cycle and may include whole brain radiotherapy, radiosurgery (Gamma Knife,
LINAC, or equivalent), or a combination as deemed appropriate by the treating
physician. Dexamethasone must be discontinued at least 4 weeks prior to Day 1.
Patients with CNS metastases treated by neurosurgical resection or brain biopsy
performed within 2 months prior to Day 1 will be excluded;

2. Carcinomatous meningitis;

3. Prior treatment with denileukin diftitox;

4. Known hypersensitivity to denileukin diftitox or any of its components: diphtheria
toxin, IL-2, or excipients;

5. Prior surgery for melanoma less than 4 weeks before enrollment;

6. Other malignancy within 3 years of randomization, with the exception of adequately
treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no
subsequent evidence of recurrence and/or malignancies diagnosed at a stage where
definitive therapy results in near certain cures. The Medical Monitor must be
consulted in such cases;

7. Currently receiving any other anticancer treatment for melanoma (including palliative
radiotherapy);

8. Received treatment in another clinical study within the 4 weeks prior to commencing
study treatment or patients who have not recovered from side effects of an
investigational drug to Common Terminology Criteria for Adverse Events (CTCAE) Grade
less than or equal to 1, except for alopecia;

9. Received radiotherapy for non-CNS disease within the 2 weeks prior to commencing study
treatment or have not recovered from side effects of all radiation-related toxicities
to Grade less than or equal to 1, except for alopecia;

10. Significant cardiovascular impairment (history of congestive heart failure New York
Heart Association [NYHA] Grade greater than 2 [see Appendix 5], unstable angina, or
myocardial infarction within the past 6 months, or serious cardiac arrhythmia);

11. Use of chronic systemic steroids (>5 days) within 2 weeks of Day 1 of the first
treatment cycle (replacement therapy for adrenal insufficiency is allowed);

12. Patients with an allograft requiring immunosuppression;

13. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen,
or hepatitis C positive;

14. Pregnant, breast-feeding, or refusing double barrier contraception, oral
contraceptives, or avoidance of pregnancy measures; Have any other uncontrolled
infection or medical condition that could interfere with the conduct of the study.