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

Phase 2

Completed

• Conditions: Melanoma (Skin)
• Interventions: Biological: aldesleukin; Biological: filgrastim; Biological: therapeutic tumor infiltrating lymphocytes; Drug: cyclophosphamide; Drug: fludarabine phosphate; Radiation: radiation therapy

• Registration Number: NCT00096382
• Lead Sponsor: National Institutes of Health Clinical Center (CC)

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 Timeline

• Study Start: 2004-09
• Study First Submitted QC: 2004-11-08
• Study First Submitted: 2004-11-09
• Study First Posted: 2004-11-09
• Primary Completion: 2009-01
• Study Completion: 2009-01
• Results First Submitted: 2012-11-20
• Results First Submitted QC: 2013-03-25
• Results First Posted: 2013-03-27
• Status Verified: 2015-09
• Last Update Submitted: 2015-10-06
• Last Update Posted: 2015-10-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TBI 200cGy + TIL +HD IL-2, prior IL-2	filgrastim	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.
TBI 200cGy + TIL +HD IL-2, prior IL-2	therapeutic tumor infiltrating lymphocytes	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.
TBI 200cGy + TIL +HD IL-2, prior IL-2	radiation therapy	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.
TBI 200cGy + TIL +HD IL-2, prior IL-2	aldesleukin	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.
TBI 200cGy + TIL +HD IL-2, No prior IL-2	aldesleukin	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.
TBI 200cGy + TIL +HD IL-2, No prior IL-2	filgrastim	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.
TBI 200cGy + TIL +HD IL-2, No prior IL-2	therapeutic tumor infiltrating lymphocytes	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.
TBI 200cGy + TIL +HD IL-2, No prior IL-2	cyclophosphamide	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.
TBI 200cGy + TIL +HD IL-2, No prior IL-2	fludarabine phosphate	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.
TBI 200cGy + TIL +HD IL-2, No prior IL-2	radiation therapy	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.
TBI 200cGy + TIL +HD IL-2, prior IL-2	cyclophosphamide	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.
TBI 200cGy + TIL +HD IL-2, prior IL-2	fludarabine phosphate	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.

Primary Outcome Measures

Name	Time	Method
Clinical Tumor Regression	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	4 years	Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Trial Locations

Locations (2)

NCI - Surgery Branch; 🇺🇸 Bethesda, Maryland, United States

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office; 🇺🇸 Bethesda, Maryland, United States