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

Phase 2
18 Years
Open (Enrolling)
Stage IIIC Melanoma, Stage IV Melanoma

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Trial Information

A Phase II Open-Label, Multicenter 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

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

- 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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety Parameter

Outcome Description:

Safety parameters: adverse events (AEs); vital signs; clinical laboratory evaluations; and physical examinations

Outcome Time Frame:

AEs and conmeds - until study termination; lab tests Day 1 and every 21 days until study termination

Safety Issue:


Principal Investigator

Harish Dave, MD

Investigator Role:

Study Director

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

June 2010

Completion Date:

June 2013

Related Keywords:

  • Stage IIIC Melanoma
  • Stage IV Melanoma
  • Neoplasms
  • Melanoma



University of Louisville Hospital Louisville, Kentucky  40202
University of Chicago Chicago, Illinois  60637
Kaiser Permanente Northwest Portland, Oregon  97227
The Angeles Clinic and Research Institute Los Angeles, California  90025
Henry Ford Medical Center Dearborn, Michigan  48126
Don and Sybil Harrington Cancer Center Amarillo, Texas  79106
San Diego Pacific Oncology and Hematology Associates, Inc. Encinitas, California  92008
MedStar Clinical Research Ctr at Washington Hospital Center Washington, District of Columbia  20010
Weinberg Cancer Institution at Franklin Square Baltimore, Maryland  21237
Southeast Nebraska Hematology & Oncology Consultants, Lincol Lincoln, Nebraska  68510