Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma

NCT00096382 | Completed Phase 2 Results

• 5 other identifiers: 04028804-C-0288NCI-7025NCI-PRMC-P6273CDR0000393480
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 2

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. Radiation therapy uses high-energy x-rays to damage tumor cells. Biological therapies, such as cellular adoptive immunotherapy, work in different ways to stimulate the immune system and stop tumor cells from growing. Autologous stem cell transplant may be able to replace immune cells that were destroyed by chemotherapy and radiation therapy. Interleukin-2 may stimulate a person's lymphocytes to kill tumor cells. Combining chemotherapy, radiation therapy, and biological therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine together with radiation therapy followed by cellular adoptive immunotherapy, autologous stem cell transplant, and interleukin-2 works in treating patients with metastatic melanoma.

Conditions

Melanoma (Skin)

Keywords

stage IV melanoma; recurrent melanoma

Outcome Measures

Primary Outcomes (2)

• Clinical Tumor Regression

  Tumor regression is defined as a complete response (CR) or partial response (PR) and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

  Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years.

• Safety

  Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

  4 years

Study Arms (2)

TBI 200cGy + TIL +HD IL-2, prior IL-2

OTHER

Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.

Biological: aldesleukin; Biological: filgrastim; Biological: therapeutic tumor infiltrating lymphocytes; Drug: cyclophosphamide; Drug: fludarabine phosphate; Radiation: radiation therapy

TBI 200cGy + TIL +HD IL-2, No prior IL-2

OTHER

Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator. Lymphocytes that that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.

Biological: aldesleukin; Biological: filgrastim; Biological: therapeutic tumor infiltrating lymphocytes; Drug: cyclophosphamide; Drug: fludarabine phosphate; Radiation: radiation therapy

Interventions

aldesleukin BIOLOGICAL

high dose: 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days (maximum 5 doses) or low dose: 250,000 IU/kg subcutaneously daily for 5 days, after a two day rest, 125,000 IU/kg subcutaneously daily for 5 days for five weeks (2 days rest per week)

Also known as: IL-2, Interleukin-2

TBI 200cGy + TIL +HD IL-2, No prior IL-2; TBI 200cGy + TIL +HD IL-2, prior IL-2

filgrastim BIOLOGICAL

10 mcg/kg/day daily subcutaneously until neutrophil count \>1x10\^9/1.

Also known as: GCSF

TBI 200cGy + TIL +HD IL-2, No prior IL-2; TBI 200cGy + TIL +HD IL-2, prior IL-2

therapeutic tumor infiltrating lymphocytes BIOLOGICAL

Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.

TBI 200cGy + TIL +HD IL-2, No prior IL-2; TBI 200cGy + TIL +HD IL-2, prior IL-2

cyclophosphamide DRUG

60 mg/kg/day x 2 days intravenously over 1 hour

Also known as: Cytoxan

TBI 200cGy + TIL +HD IL-2, No prior IL-2; TBI 200cGy + TIL +HD IL-2, prior IL-2

fludarabine phosphate DRUG

25 mg/m\^2/day intravenous piggyback daily over 15-20 minutes for 5 days

Also known as: Fludara

TBI 200cGy + TIL +HD IL-2, No prior IL-2; TBI 200cGy + TIL +HD IL-2, prior IL-2

radiation therapy RADIATION

Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.

Also known as: total body irradiation

TBI 200cGy + TIL +HD IL-2, No prior IL-2; TBI 200cGy + TIL +HD IL-2, prior IL-2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Diagnosis of metastatic melanoma * Measurable disease * Resected or stable brain metastases are allowed PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Eastern Cooperative Oncology Group (ECOG) 0-1 Life expectancy * At least 3 months Hematopoietic * See Immunologic * Absolute neutrophil count \> 1,000/mm\^3 (without support of filgrastim \[G-CSF\]) * Platelet count \> 100,000/mm\^3 * Hemoglobin ≥ 8 g/dL (transfusion allowed) * No coagulation disorders Hepatic * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 times upper limit of normal * Bilirubin ≤ 2 mg/dL (\< 3 mg/dL in patients with Gilbert's syndrome) * No hepatitis B or C Renal * Creatinine ≤ 1.6 mg/dL Cardiovascular * Left ventricular ejection fraction (LVEF) ≥ 45% by cardiac stress test\* * No active major cardiovascular illness as evidenced by stress thallium or other comparable test * No myocardial infarction * No cardiac arrhythmias NOTE: \*For patients ≥ 50 years of age receiving high-dose interleukin-2 (IL-2) OR patients with a history of electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia, or arrhythmias Pulmonary * Forced expiratory volume 1 (FEV\_1) ≥ 60% of predicted by pulmonary function test in patients with prolonged history of cigarette smoking or symptoms of respiratory dysfunction\* * No active major respiratory illness * No obstructive or restrictive pulmonary disease NOTE: \*For patients receiving high-dose IL-2 only Immunologic * No active major immunologic illness * No active systemic infections * No primary or secondary immunodeficiency * Fully recovered immune competence after prior chemotherapy or radiotherapy as evidenced by both of the following: * Absolute neutrophil count \> 1,000/mm\^3 * No opportunistic infections * Human Immunodeficiency virus (HIV) negative * Epstein-Barr virus positive Other * Not pregnant or nursing * Fertile patients must use effective contraception during and for 4 months after study treatment PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics Chemotherapy * At least 6 weeks since prior nitrosourea therapy * No prior cyclophosphamide and fludarabine as part of a preparative regimen on National Cancer Institute (NCI) Surgery Branch adoptive cell therapy studies unless sufficient numbers of CD34+ stem cells (more than 2 x10\^6/kg patient weight) have been obtained prior to the administration of chemotherapy Endocrine therapy * No concurrent systemic steroid therapy Radiotherapy * Not specified Surgery * See Disease Characteristics * Prior minor surgery within the past 3 weeks allowed if recovered Other * Recovered from all prior therapy * At least 30 days since prior systemic therapy * No other concurrent experimental agents

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office

Bethesda, Maryland, 20892-1182, United States

Location

NCI - Surgery Branch

Bethesda, Maryland, 20892-1201, United States

Location

Related Publications (1)

• Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012 Jun 14;119(24):5688-96. doi: 10.1182/blood-2011-10-386482. Epub 2012 May 3.

  PMID: 22555974 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

aldesleukin; Interleukin-2; Filgrastim; Cyclophosphamide; fludarabine phosphate; Radiotherapy; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Therapeutics; Investigative Techniques

Results Point of Contact

• Title: Steven A. Rosenberg, M.D.
• Organization: National Cancer Institute, National Institutes of Health

sar@mail.nih.gov

301-496-4164

Study Officials

• Steven A. Rosenberg, MD, PhD

  NCI - Surgery Branch

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: November 9, 2004
• First Posted: November 9, 2004
• Study Start: September 1, 2004
• Primary Completion: January 1, 2009
• Study Completion: January 1, 2009
• Last Updated: October 28, 2015
• Results First Posted: March 27, 2013

Record last verified: 2015-09

Locations

US (2)