Chemotherapy Followed by gp100 Lymphocytes and Aldesleukin to Treat Melanoma - Full Text View

Sponsor:	National Cancer Institute (NCI)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00665470

Purpose

Background:

This study uses a new experimental procedure for treating melanoma that uses the patient's own lymphocytes (type of white blood cell), which are specially selected to target and destroy their tumor.

Objectives:

To determine whether this experimental treatment can cause the patient's tumor to shrink.

To test the safety of the treatment and its effects on the immune system.

Eligibility:

Patients with metastatic melamona 18years of age and older for whom standard treatments are not effective or who cannot take high-dose interleukin-2 (IL-2).

Patients must have the tissue type HLA-A0201.

Design:

Workup: Patients have scans, x-rays, laboratory tests, and other tests as needed.

Patients have leukapheresis (a procedure for collecting lymphocytes that is similar to collecting whole blood) to collect cells for laboratory treatment and later reinfusion.

Chemotherapy: Patients have low-dose chemotherapy for 1 week to prepare the immune system to receive the cultured lymphocytes.

Cell infusion and IL-2 treatment: Patients receive the lymphocytes by infusion through a vein and then either high-dose IL-2 infused through a vein or low-dose IL-2 injected under the skin. High-dose IL-2 is given as infusions through a vein every 8 hours for up to 15 doses. Low-dose IL-2 is given as injections under the skin daily for 5 days, followed by a 2-day rest, with this regimen repeated for a total of 5 weeks.

Recovery: Patients rest for 1 to 2 weeks to recover from the effects of chemotherapy and IL-2.

Tumor biopsy: Patients may be asked to have a biopsy (removal of a small piece of tumor) after receiving treatment to look at the effects of treatment in the tumor.

Follow-up: After treatment is completed, patients return to the clinic for physical examinations, review of side effects, laboratory tests and scans every 1 to 6 months until the disease worsens.

Retreatment: Patients whose tumor did not grow after treatment or showed evidence of shrinking may be able to be retreated if their tumor begins to grow. They receive the same regimen of chemotherapy, lymphocyte infusion and IL-2 treatment....

Condition	Intervention	Phase
Skin Cancer Metastatic Melanoma	Drug: Aldesleukin	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase II Study in Patients With Metastatic Melanoma Using a Non-Myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of gp100 Reactive Peripheral Blood Lymphocytes (PBL) and High or Low Dose Aldesleukin

Resource links provided by NLM:

MedlinePlus related topics: Cancer Melanoma Skin Cancer

Drug Information available for: Aldesleukin

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Response
Toxicity as assessed by NCI CTCAE V3.0 [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Survival of infused cells [ Designated as safety issue: No ]

Enrollment:	10
Study Start Date:	April 2008
Study Completion Date:	April 2012
Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Cohort I Patients receive high-dose aldesleukin IV over 15 minutes every 8 hours beginning within 24 hours after PBL infusion and continuing for up to 5 days (maximum of 15 doses).	Drug: Aldesleukin Given IV
Experimental: Cohort II Beginning within 24 hours after PBL infusion, patients receive low-dose aldesleukin SC once daily 5 days a week for up to 6 weeks.	Drug: Aldesleukin Given IV

Detailed Description:

Background:

TIL transfer studies in patients with metastatic melanoma following lymphodepletion have resulted in 50% objective response rates with a 10-15% rate of complete responses.
Pre-clinical and clinical studies of adoptive immunotherapy have suggested that effective lymphocytes for transfer have high avidity for the target antigen, undergo limited in vitro antigen and IL-2 stimulation, and have high expression of CD27+.
We have developed a novel in vitro strategy using high throughput PCR screening to rapidly isolate low frequency antigen specific CD8+ T cells from the peripheral blood repertoire that have these characteristics, and that recognize the gp100:154-162 epitope, an abundantly expressed melanoma antigen, presented by HLAA2 on the tumor surface.
The current proposed transfer of gp100:154-162 reactive lymphocytes administered in conjunction with a lymphodepleting preparative regimen and aldesleukin would represent a significantly novel approach to adoptive immunotherapy.

Objectives:

To determine whether gp100:154-162 reactive CD4+ T cell depleted lymphocytes infused in conjunction with the administration of high-dose aldesleukin or low-dose aldesleukin may result in clinical tumor regression in patients with metastatic melanoma receiving a non-myeloablative lymphoid depleting preparative regimen.
To evaluate the safety of the treatment in patients receiving the non-myeloablative conditioning regimen, cell transfer, and high-dose or low-dose aldesleukin.
To determine the survival in patients, of infused cells following the administration of the non-myeloablative regimen, using analysis of the sequence of the variable region of the T cell receptor or flow cytometry (FACS).

Eligibility:

-Patients with refractory metastatic melanoma who are greater than or equal to 18 years of age, are HLA-A2+, who have gp100:154-162 reactive peripheral blood lymphocytes available and are physically able to tolerate non-myeloablative chemotherapy. Patients must be refractory to prior high dose aldesleukin treatment if they are medically eligible to receive it. Patients who can tolerate high-dose aldesleukin will receive it with cell infusion; those who cannot tolerate high-dose will receive low-dose aldesleukin.

Design:

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide (60 mg/kg/day X 2 days IV), fludarabine (25 mg/m2/day IV X 5 days).
Patients will receive intravenous adoptive transfer of gp100:154-162 reactive peripheral blood lymphocytes (minimum 1 X 10(9) and up to a maximum of 3 X 10(11) lymphocytes) followed by high-dose intravenous (IV) aldesleukin (720,000 IU/kg/dose every 8 hours for up to 15 doses) or low-dose subcutaneous (SQ) aldesleukin (125,000 IU IL-2/kg/dose for 5 days for 6 weeks with 2 days rest per week).
A complete evaluation of evaluable lesions will be conducted 4-6 weeks after the last dose of aldesleukin in the high dose arm and 2-4 weeks after the last dose of aldesleukin in the low dose arm. Patients will be enrolled into two cohorts. The cohort receiving high dose aldesleukin will be conducted using a small optimal two-stage Phase II design, initially 21 patients will be enrolled, and if two or more of the first 21 patients has a clinical response (PR or CR), accrual will continue to 41 patients, targeting a 20% goal for objective response. For the cohort who will receive low dose aldesleukin, the study will be conducted as a Minimax two-stage phase II trial. Initially 12 evaluable patients will be enrolled to this cohort, and if 1 or more the first 12 have a response, then accrual would continue until a total of 21 patients, targeting a 20% goal for objective response.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

-INCLUSION CRITERIA:

Measurable metastatic melanoma. The diagnosis of metastatic melanoma and positivity for gp100 will be confirmed by the Laboratory of Pathology of the NCI.
Patients must be refractory to high dose aldesleukin treatment if they are medically eligible to receive it. Patients with noncutaneous melanoma are not required to be refractory to high dose aldesleukin.
gp100:154-162 reactive peripheral blood lymphocytes derived from a

leukapheresis.
HLA-A*0201 positive.
Greater than or equal to 18 years of age.
Willing to practice birth control during treatment and for four months after receiving the preparative regimen.
Life expectancy of greater than three months.
Willing to sign a durable power of attorney.
Able to understand and sign the Informed Consent Document.
Clinical performance status of ECOG 0 or 1 for the high dose aldesleukin cohort or ECOG 0, 1 or 2 for the low dose aldesleukin cohort.
Hematology:
- Absolute neutrophil count greater than 1000/mm3 without support of filgrastim
- Normal WBC (greater than 3000/mm(3)).
- Hemoglobin greater than 8.0 g/dl
- Platelet count greater than 100,000/mm(3).
Serology:
- Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
- Seronegative for hepatitis B or hepatitis C.
Chemistry:
- Serum ALT/AST less than less or equal to 2.5 times the upper limit of normal.
- Serum creatinine less than or equal to 1.6 mg/dl.
- Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3 mg/dl.
Negative pregnancy test in women of child bearing potential because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria in Section 2.1.1.
Six weeks must have elapsed since prior anti-CTLA4 antibody therapy to allow antibody levels to decline.
Patients who have previously received anti-CTLA4 antibody and experienced treatment must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
Systemic steroid therapy required.
For patients receiving high dose IL-2 only: Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
History of severe immediate hypersensitivity reaction to any of the agents used in this study.
The following patients will be excluded from the high-dose IL-2 arm (but will be eligible for the low-dose arm):
1. History of coronary revascularization or ischemic symptoms
2. Any patient known to have an LVEF less than or equal to 45%.
3. Documented LVEF of less than or equal to 45% tested in patients with:
  - Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
  - Age greater than or equal to 60 years old
4. Documented FEV1 less than or equal to 60% predicted tested in patients with:
  - A prolonged history of cigarette smoking (20 pk/yrs of smoking)
  - Symptoms of respiratory dysfunction

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00665470

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Udai S Kammula, M.D.

National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4.

Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. 2007 Feb 1;109(3):455-64. Review.

Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001 May 17;411(6835):380-4. Review.

Responsible Party:	Udai S. Kammula, M.D./National Cancer Institute, National Institutes of Health
ClinicalTrials.gov Identifier:	NCT00665470 History of Changes
Other Study ID Numbers:	080104, 08-C-0104
Study First Received:	April 23, 2008
Last Updated:	April 14, 2012
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Malignant Melanoma
HLA-A2
Immunotherapy
Clinical Response
Skin Cancer

Additional relevant MeSH terms:

Skin Neoplasms
Melanoma
Neoplasms by Site
Neoplasms
Skin Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Aldesleukin
Interleukin-2

Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on May 24, 2012