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

NCT ID: NCT00085423

Last Updated: 2013-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-02-29
• Study Completion Date: 2010-02-28

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.

Detailed Description

OBJECTIVES:

Primary

• 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.

Secondary

• 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.

Conditions

Melanoma (Skin)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

IL-2, CTX, fludarabine, GM-CSF

Aldesleukin (IL-2), cyclophosphamide, fludarabine phosphate, sargramostim

Group Type: EXPERIMENTAL

aldesleukin

Intervention Type: BIOLOGICAL

‡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

sargramostim

Intervention Type: BIOLOGICAL

GM-CSF was given subcutaneously daily from day 8 until absolute granulocyte count exceeds 5,000 cells/mL for 2 consecutive days.

cyclophosphamide

Intervention Type: DRUG

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.

fludarabine phosphate

Intervention Type: DRUG

Fludarabine IV (25 mg/M2/day)-five daily doses from Day 3

Interventions

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

Intervention Type: BIOLOGICAL

sargramostim

GM-CSF was given subcutaneously daily from day 8 until absolute granulocyte count exceeds 5,000 cells/mL for 2 consecutive days.

Intervention Type: BIOLOGICAL

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.

Intervention Type: DRUG

fludarabine phosphate

Fludarabine IV (25 mg/M2/day)-five daily doses from Day 3

Intervention Type: DRUG

Other Intervention Names

Aldesleukin; IL-2; HD IL-2; Interleukin-2; GM-CSF; granulocyte-macrophage colony-stimulating factor; cyclophosphamide,Cytoxan; Fludara

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marc S. Ernstoff, MD

Role: STUDY_CHAIR

Norris Cotton Cancer Center

Locations

Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 20124177 (View on PubMed)

Other Identifiers

P30CA023108

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DMS-0320

Identifier Type: OTHER

Identifier Source: secondary_id

DMS-16531

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000370788

Identifier Type: -

Identifier Source: org_study_id

NCT00225771

Identifier Type: -

Identifier Source: nct_alias