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

The purpose of this study is to determine whether Patients with Stage IIIC and Stage IV Melanoma experience benefit when treated with Denileukin diftitox in two different dosing schedules.

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

• Stage IIIC Melanoma
• Stage IV Melanoma

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.