A Phase II Open-Label, Multicenter Study of Denileukin Diftitox in Patients With Stage IIIC and Stage IV Melanoma

Inclusion Criteria

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

1. Male or female patients ≥18 years of age;

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

3. Naïve 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 ≥3 months;

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

7. Serum albumin ≥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) ≥1.5 x 109/L;

- Platelet count ≥100 x 109/L;

- Hemoglobin ≥9 g/dL;

- Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance ≥50
mL/min;

- Total serum bilirubin ≤1.5 x ULN;

- Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT)
≤2.5 x ULN, and ≤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 <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 ≥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 <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
≤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 ≤1, except for alopecia;

10. Significant cardiovascular impairment (history of congestive heart failure New York
Heart Association [NYHA] Grade >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.