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

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ClinicalTrials.gov 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

June 10, 2004
June 11, 2004
January 26, 2012
April 10, 2013
April 10, 2013
February 2004
December 2008   (Final data collection date for primary outcome measure)
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.
Not Provided
Complete list of historical versions of study NCT00085423 on ClinicalTrials.gov Archive Site
  • 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.
  • 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.
Not Provided
Not Provided
Not Provided
Cyclophosphamide, Fludarabine, and High-Dose Interleukin-2 in Treating Patients With Metastatic Melanoma
High Dose Interleukin-2 (IL-2) Therapy In "Lymphodepleted Primed" Patients With Metastatic Melanoma

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.



  • 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.

Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Melanoma (Skin)
  • 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
Experimental: IL-2, CTX, fludarabine, GM-CSF
Aldesleukin (IL-2), cyclophosphamide, fludarabine phosphate, sargramostim
  • Biological: aldesleukin
  • Biological: sargramostim
  • Drug: cyclophosphamide
  • Drug: fludarabine phosphate
Gunturu KS, Meehan KR, Mackenzie TA, Crocenzi TS, McDermott D, Usherwood EJ, Margolin KA, Crosby NA, Atkins MB, Turk MJ, Ahonen C, Fuse S, Clark JI, Fisher JL, Noelle RJ, Ernstoff MS. Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. J Clin Oncol. 2010 Mar 1;28(7):1196-202. doi: 10.1200/JCO.2009.24.8153. Epub 2010 Feb 1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
February 2010
December 2008   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
United States
P30CA023108 ( U.S. NIH Grant/Contract )
DMS-0320 ( Other Identifier: Dartmouth-Hitchcock )
DMS-16531 ( Other Identifier: Dartmouth-Hitchcock )
Not Provided
Not Provided
Dartmouth-Hitchcock Medical Center
Dartmouth-Hitchcock Medical Center
National Cancer Institute (NCI)
Study Chair: Marc S. Ernstoff, MD Norris Cotton Cancer Center
Dartmouth-Hitchcock Medical Center
April 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP