Cyclophosphamide, Fludarabine, and High-Dose Interleukin-2 in Treating Patients With Metastatic Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00085423
Recruitment Status : Completed
First Posted : June 11, 2004
Results First Posted : April 10, 2013
Last Update Posted : April 10, 2013
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Dartmouth-Hitchcock Medical Center

Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Interleukin-2 may stimulate a person's white blood cells to kill tumor cells and may help a person's immune system recover from the side effects of chemotherapy.

PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with high-dose interleukin-2 works in treating patients with metastatic melanoma.

Condition or disease Intervention/treatment Phase
Melanoma (Skin) Biological: aldesleukin Biological: sargramostim Drug: cyclophosphamide Drug: fludarabine phosphate Phase 2

Detailed Description:



  • Determine the objective response rate in lymphodepleted patients with metastatic melanoma treated with cyclophosphamide, fludarabine, and high-dose interleukin-2.
  • Determine the feasibility of this regimen in these patients.


  • Determine the quality and quantity of lymphocyte recovery in these patients during and after treatment with this regimen.
  • Determine time to disease progression and survival in patients treated with this regimen.

OUTLINE: This is an open-label, multicenter study.

Patients receive lymphodepleting therapy comprising cyclophosphamide IV over 1 hour on days 1 and 2 and fludarabine IV over 30 minutes on days 3-7. Patients then receive high-dose interleukin-2 IV every 8 hours (14 doses) on days 8-12 and 22-26. Patients also receive sargramostim (GM-CSF) subcutaneously beginning on day 8 and continuing until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 18-33 patients will be accrued for this study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Dose Interleukin-2 (IL-2) Therapy In "Lymphodepleted Primed" Patients With Metastatic Melanoma
Study Start Date : February 2004
Actual Primary Completion Date : December 2008
Actual Study Completion Date : February 2010

Arm Intervention/treatment
Experimental: IL-2, CTX, fludarabine, GM-CSF
Aldesleukin (IL-2), cyclophosphamide, fludarabine phosphate, sargramostim
Biological: aldesleukin
‡Interleukin-2 (aldesleukin) IV (600,000 U/kg; Chiron, Emeryville, CA): two 5-day courses on days 8 and 22. Interleukin-2 was given over 15 minutes every 8 hours. Goal is 14 doses/5-day course
Other Name: Aldesleukin; IL-2; HD IL-2; Interleukin-2

Biological: sargramostim
GM-CSF was given subcutaneously daily from day 8 until absolute granulocyte count exceeds 5,000 cells/mL for 2 consecutive days.
Other Name: GM-CSF; granulocyte-macrophage colony-stimulating factor

Drug: cyclophosphamide
Cyclophosphamide (60 mg/kg/d; Baxter, Deerfield, IL) intravenously (IV) for 2 days with sodium 2- mercaptoethanesulfonate (Mesna; Sicor, Irvine, CA) at 20% of cyclophosphamide dose IV 15 minutes before and 40% of the cyclophosphamide dose orally at 2 and 6 hours after the initiation of chemotherapy.
Other Name: cyclophosphamide,Cytoxan

Drug: fludarabine phosphate
Fludarabine IV (25 mg/M2/day)-five daily doses from Day 3
Other Name: Fludara

Primary Outcome Measures :
  1. Number of partiCIPANTS WITH OBJECTIVE RESPONSE AS MEASURED BY RECIST [ Time Frame: Response at 12 weeks ]
    Objective response as measured by radiological and physical examination using RECIST criteria.

Secondary Outcome Measures :
  1. Number of Participants With Lymphocyte Recovery as Measured by Blood Count [ Time Frame: on days 1-15, weekly for 2 weeks, and then every 2-3 months ]
    Lymphocyte recovery to a greater than 1000 cells/mcL was determined by differential peripheral blood cell counts on sequential days as noted in time frame.

  2. Time to Progression as Measured by RECIST [ Time Frame: From date of randomization until the first date of documented progression or date of death from any cause, which ever came first, assessed up till 100 months ]
    Clinical outcome used the National Cancer Institute's Response Evaluation Criteria in Solid Tumors (RECIST)1.0.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed melanoma
  • Metastatic disease
  • Measurable disease
  • No history of brain metastases
  • Over 18
  • Karnofsky 60-100%
  • Life expectancy At least 12 weeks
  • Hematopoietic
  • Absolute neutrophil count ≥ 1,000/mm^3
  • Platelet count ≥ 75,000/mm^3
  • Hemoglobin ≥ 8.5 g/dL
  • aspartate aminotransferase ≤ 2 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
  • Bilirubin ≤ 2 times ULN (except for patients with Gilbert's syndrome)
  • Hepatitis B and C negative
  • Creatinine ≤ 2.0 times ULN
  • Creatinine clearance ≥ 50 mL/min
  • Cardiovascular
  • Ejection fraction ≥ 50%
  • No evidence of congestive heart failure
  • No symptoms of coronary artery disease
  • No serious cardiac arrhythmias
  • No myocardial infarction within the past 6 months
  • Cardiac stress test negative or of low probability for patients > 40 years of age OR who have had prior myocardial infarction > 6 months ago
  • Pulmonary Forced expiratory volume 1 ≥ 2.0 liters OR at least 75% of predicted for height and age
  • Diffusing capacity of lung for carbon monoxide ≥ 60%
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative

Exclusion Criteria:

  • No uncontrolled diabetes
  • No history of autoimmune disease
  • No active infection
  • No other concurrent significant illness that would preclude study participation
  • No other malignancy within the past 5 years except nonmelanoma skin cancer or non-invasive cancer (e.g., carcinoma in situ of the cervix, superficial bladder cancer without local recurrence, or carcinoma in situ of the breast)
  • At least 4 weeks since prior immunotherapy and recovered
  • No other concurrent anticancer biologic agents
  • At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered
  • No concurrent chemotherapy
  • At least 4 weeks since prior steroid therapy
  • No concurrent corticosteroids
  • At least 4 weeks since prior radiotherapy and recovered
  • No concurrent radiotherapy
  • At least 4 weeks since prior surgery and recovered
  • No concurrent immunosuppressive therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00085423

United States, New Hampshire
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756-0002
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
National Cancer Institute (NCI)
Study Chair: Marc S. Ernstoff, MD Norris Cotton Cancer Center

Publications of Results:
Responsible Party: Dartmouth-Hitchcock Medical Center Identifier: NCT00085423     History of Changes
Obsolete Identifiers: NCT00225771
Other Study ID Numbers: CDR0000370788
P30CA023108 ( U.S. NIH Grant/Contract )
DMS-0320 ( Other Identifier: Dartmouth-Hitchcock )
DMS-16531 ( Other Identifier: Dartmouth-Hitchcock )
First Posted: June 11, 2004    Key Record Dates
Results First Posted: April 10, 2013
Last Update Posted: April 10, 2013
Last Verified: April 2013

Keywords provided by Dartmouth-Hitchcock Medical Center:
recurrent melanoma
stage IV melanoma

Additional relevant MeSH terms:
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic
Sensory System Agents