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

• ClinicalTrials.gov Identifier: NCT00096382
• Recruitment Status: Completed
• First Posted: November 9, 2004
• Results First Posted: March 27, 2013
• Last Update Posted: October 28, 2015
• Sponsor: National Institutes of Health Clinical Center (CC)
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Steven Rosenberg, M.D., National Institutes of Health Clinical Center (CC)

Tracking Information

• First Submitted Date: November 9, 2004
• First Posted Date: November 9, 2004
• Results First Submitted Date: November 20, 2012
• Results First Posted Date: March 27, 2013
• Last Update Posted Date: October 28, 2015
• Study Start Date: September 2004
• Actual Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 25, 2013)

• Clinical Tumor Regression [ Time Frame: Every 4-6 weeks for up to 1 year, and then every 6 months for up to 5 years. ]
  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.
• Safety [ Time Frame: 4 years ]
  Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

• Original Primary Outcome Measures: Not Provided
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma
• Official Title: Treatment of Patients With Metastatic Melanoma Using a Transplant of Autologous Lymphocytes Reactive With Tumor Following a Myeloablative Lymphocyte Depleting Regimen of Chemotherapy, Total Body Irradiation and Reconstitution With CD34+ Cells

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.

Detailed Description

OBJECTIVES:

Primary

• Determine complete clinical tumor regression in patients with metastatic melanoma treated with a myeloablative lymphoid-depleting preparative regimen comprising cyclophosphamide, fludarabine, and total body irradiation followed by autologous tumor-reactive tumor-infiltrating lymphocyte infusion, autologous CD34+ stem cell transplantation, and low-dose or high-dose interleukin-2.
• Evaluate the safety of this regimen in these patients.

Secondary

• Determine the survival of the infused lymphocytes by analyzing the sequence of the variable region of the T-cell receptor or flow cytometry in patients treated with this regimen.

OUTLINE:

• Autologous stem cell collection: Patients receive filgrastim (G-CSF) subcutaneously (SC) twice daily for 8 days. Beginning on day 5 of G-CSF, patients undergo apheresis daily for up to 3 days. Patients may receive 1 additional course of G-CSF and apheresis or use stem cells stored from a prior stem cell harvest in order to obtain an adequate number of cells.
• Lymphocyte-depleting myeloablative preparative regimen: Patients receive cyclophosphamide intravenous (IV) over 1 hour on days -5 and -6 and fludarabine IV over 15-30 minutes on days -6 to -2. Patients also undergo total body irradiation on day -1.
• Autologous lymphocyte infusion: Patients receive autologous tumor-reactive tumor-infiltrating lymphocytes IV over 20-30 minutes on day 0* followed by G-CSF SC once daily until blood counts recover.
• Autologous stem cell transplantation: Patients receive autologous CD34+ stem cells IV on day 2.

• Interleukin therapy: Patients are assigned to 1 of 2 cohorts, depending on whether they have received prior high-dose interleukin-2 (IL-2).

  • Cohort 1 (patients who received prior high-dose IL-2): Beginning on day 0*, patients receive high-dose IL-2 IV over 15 minutes 3 times daily for up to 5 days (maximum of 15 doses).
  • Cohort 3 (patients who have not received prior high-dose IL-2): Patients receive treatment as in cohort 1.

NOTE: *Day 0 is 1-4 days after the last dose of fludarabine.

Patients are evaluated at 4-6 weeks.

PROJECTED ACCRUAL: A total of 116 patients will be accrued for this study.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma (Skin)

Intervention

• Biological: aldesleukin
  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)
  Other Names:

  • IL-2
  • Interleukin-2
• Biological: filgrastim
  10 mcg/kg/day daily subcutaneously until neutrophil count >1x10^9/1.
  Other Name: GCSF
• Biological: therapeutic tumor infiltrating lymphocytes
  Lymphocytes that are isolated from the tumor, grown in the laboratory to high amounts and then infused into the patient.
• Drug: cyclophosphamide
  60 mg/kg/day x 2 days intravenously over 1 hour
  Other Name: Cytoxan
• Drug: fludarabine phosphate
  25 mg/m^2/day intravenous piggyback daily over 15-20 minutes for 5 days
  Other Name: Fludara
• Radiation: radiation therapy
  Patients will receive 2Gy of total body irradiation (TBI) at a rate of 0.07 Gy/minute using a linear accelerator.
  Other Name: total body irradiation

Study Arms

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

  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.

  Interventions:

  • 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

  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.

  Interventions:

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

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 25, 2013): 34
• Original Enrollment: Not Provided
• Actual Study Completion Date: January 2009
• Actual Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00096382
• Other Study ID Numbers: 040288; 04-C-0288; NCI-7025; NCI-PRMC-P6273; CDR0000393480
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Steven Rosenberg, M.D., National Institutes of Health Clinical Center (CC)
• Study Sponsor: National Institutes of Health Clinical Center (CC)
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Steven A. Rosenberg, MD, PhD; NCI - Surgery Branch

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: September 2015