Anti-gp100 Cells Plus ALVAC gp100 Vaccine to Treat Advanced Melanoma

Phase 2

Terminated

• Conditions: Metastatic Melanoma; Skin Cancer
• Interventions: Drug: cyclophosphamide; Drug: fludarabine phosphate; Biological: Aldesleukin; Biological: ALVAC gp100 Vaccine

• Registration Number: NCT00610311
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

Background:

* gp100 is a protein that is often found in melanoma tumors.

* An experimental procedure developed for treating patients with melanoma uses anti-gp100 cells designed to destroy their tumors. The anti-gp100 cells are created in the laboratory using the patient's own tumor cells or blood cells.

* The treatment procedure also uses a vaccine called plaque purified canarypox vector (ALVAC) gp100, made from a virus that ordinarily infects canaries and is modified to carry a copy of the gp100 gene. The virus cannot reproduce in mammals, so it cannot cause disease in humans. When the vaccine is injected into a patient, it stimulates cells in the immune system that may increase the efficiency of the anti gp 100 cells.

Objectives:

-To evaluate the safety and effectiveness of anti-gp100 cells and the ALVAC gp100 vaccine in treating patients with advanced melanoma.

Eligibility:

-Patients with metastatic melanoma for whom standard treatments have not been effective.

Design:

* Patients undergo scans, x-rays and other tests and leukapheresis to obtain white cells for laboratory treatment.

* Patients have 7 days of chemotherapy to prepare the immune system for receiving the gp100 cells.

* Patients receive the ALVAC vaccine, anti-gp100 cells and interleukin-2 (IL-2) (an approved treatment for advanced melanoma). The anti gp100 cells are given as an infusion through a vein. The vaccine is given as injections just before the infusion of gp100 cells and again 2 weeks later. IL-2 is given as a 15-minute infusion every 8 hours for up to 5 days after the cell infusion for a maximum of 15 doses.

* After hospital discharge, patients return to the clinic for periodic follow-up with a physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.

Detailed Description

Background:

* We have engineered human peripheral blood lymphocytes (PBLs) to express a T-cell receptor that recognizes an human leukocyte antigens (HLAA) 0201 restricted epitope derived from the gp100 protein.

* We constructed a single retroviral vector that contains both alpha and infinity chains and can mediate genetic transfer of this T cell receptor (TCR) with high efficiency (greater than 30 percent) without the need to perform any selection.

* In co-cultures with HLA-A 0201 positive melanoma gp100:154-162 TCR transduced T cells secreted significant amount of interferon (IFN)-(but no significant secretion was observed in control co-cultures with cell lines.

gp100:154-162 TCR transduced PBL could efficiently kill -HLA-A 0201 positive tumors. There was little or no recognition of normal fibroblasts cells.

* This TCR is over 10 times more reactive with melanoma cells than the melanoma antigen recognized by T-cells (MART)-1 TCR that mediated tumor regression in two patients with metastatic melanoma.

* In this trial we would like to test our hypothesis that the addition of an anti-tumor ALVAC vaccine will result in clinical tumor regression, and persistence of the transferred cells (as is the case in murine models).

Objectives:

Primary objectives:

-Determine if the administration of anti-gp100:154-162 TCR-engineered peripheral blood lymphocytes, ALVAC anti-tumor immunization, and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic melanoma.

Secondary objectives:

* Determine the in vivo survival of TCR gene-engineered cells.

* Determine the toxicity profile of this treatment regimen.

* Determine whether treated patients develop anti-mouse TCR antibody.

Eligibility:

Patients who are HLA-A 0201 positive and 18 years of age or older must have:

* metastatic melanoma;

* previously received and have been a non-responder to or recurred after aldesleukin;

* normal values for basic laboratory values.

Patients may not have:

* concurrent major medical illnesses;

* any form of primary or secondary immunodeficiency;

* severe hypersensitivity to any of the agents used in this study;

* contraindications for high dose aldesleukin administration.

Design:

* Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5 times 10\^9 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth.

* Transduction is initiated by exposure of approximately 10\^8 to 5 times 10\^8 cells to supernatant containing the anti-gp100:154-162 TCR retroviral vector. These transduced cells will be expanded and tested for their anti-tumor activity.

* Once engineered PBMC are demonstrated to be biologically active according to the strict criteria outlined in the Certificate of Analysis, patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor reactive, TCR gene-transduced PBMC plus intravenous (IV) aldesleukin (720,000 IU/kg q8h for a maximum of 15 doses). Approximately 2 hours prior to cell infusion, patients will be immunized with ALVAC virus expressing the tumor antigen. ALVAC immunization will be repeated at 2 weeks.

* Patients will undergo complete evaluation of tumor with physical examination, computed tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met.

* The study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. If 0 or 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled.

* The objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, ALVAC immunization and anti-gp100:154-162 TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5 percent (p0=0.05) in favor of a modest 20 percent partial response (PR) plus complete response (CR) rate (p1=0.20).

Study Timeline

• Study Start: 2008-01
• Study First Submitted: 2008-02-06
• Study First Submitted QC: 2008-02-06
• Study First Posted: 2008-02-07
• Primary Completion: 2011-02
• Study Completion: 2011-02
• Results First Submitted: 2012-03-14
• Results First Submitted QC: 2012-03-14
• Results First Posted: 2012-04-10
• Status Verified: 2015-09
• Last Update Submitted: 2015-10-06
• Last Update Posted: 2015-10-28

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 3

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ALVAC plus anti-gp100:154-162 TCR PBL + HD IL-2	Aldesleukin	ALVAC plus anti-gp100:154-162 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin-2 (IL-2): ALVAC vaccine two hours prior to cell infusion patients will receive 0.5 ml containing a target dose of 10\^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10\^6.4 to 107.9/mL of the gp100 ALVAC virus subcutaneously in each extremity (total of 4 x 10\^7 CCID50/2mL. This will be repeated on day 14. Aldesleukin (IL2, Proleukin, Recombinant human interleukin 2)- 720,000 IU/kg intravenous over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses)
ALVAC plus anti-gp100:154-162 TCR PBL + HD IL-2	cyclophosphamide	ALVAC plus anti-gp100:154-162 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin-2 (IL-2): ALVAC vaccine two hours prior to cell infusion patients will receive 0.5 ml containing a target dose of 10\^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10\^6.4 to 107.9/mL of the gp100 ALVAC virus subcutaneously in each extremity (total of 4 x 10\^7 CCID50/2mL. This will be repeated on day 14. Aldesleukin (IL2, Proleukin, Recombinant human interleukin 2)- 720,000 IU/kg intravenous over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses)
ALVAC plus anti-gp100:154-162 TCR PBL + HD IL-2	ALVAC gp100 Vaccine	ALVAC plus anti-gp100:154-162 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin-2 (IL-2): ALVAC vaccine two hours prior to cell infusion patients will receive 0.5 ml containing a target dose of 10\^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10\^6.4 to 107.9/mL of the gp100 ALVAC virus subcutaneously in each extremity (total of 4 x 10\^7 CCID50/2mL. This will be repeated on day 14. Aldesleukin (IL2, Proleukin, Recombinant human interleukin 2)- 720,000 IU/kg intravenous over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses)
ALVAC plus anti-gp100:154-162 TCR PBL + HD IL-2	fludarabine phosphate	ALVAC plus anti-gp100:154-162 T cell receptor (TCR) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin-2 (IL-2): ALVAC vaccine two hours prior to cell infusion patients will receive 0.5 ml containing a target dose of 10\^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10\^6.4 to 107.9/mL of the gp100 ALVAC virus subcutaneously in each extremity (total of 4 x 10\^7 CCID50/2mL. This will be repeated on day 14. Aldesleukin (IL2, Proleukin, Recombinant human interleukin 2)- 720,000 IU/kg intravenous over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Metastatic Melanoma Who Develop Clinical Tumor Regression (CR or PR)	4-6 weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met	Clinical tumor response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 criteria. Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is a 30% decrease in lesions taking as reference the baseline sum longest diameter (LD). For details about the RECIST criteria see the protocol link module.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	18.5 months	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Number of Participants Who Develop Anti-mouse T Cell Receptor (TCR) Antibodies	1 month	Blood samples are collected from the patient and an immunological test is conducted in the laboratory to determine if the patient has generated antibodies against the mouse T-cell receptor which is part of the anti-gp100 cells.
Number of Participants With in Vivo Survival of T-cell Receptor (TCR) Gene-engineered Cells.	1 month	T cell receptor (TCR) and vector presence will be quantitated in peripheral blood mononuclear cells (PBMC) samples using established polymerase chain reaction (PCR) techniques. This will provide data to estimate the in vivo survival of lymphocytes derived from the infused cells.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike; 🇺🇸 Bethesda, Maryland, United States