Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Melanoma

Neoplasm Metastasis

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunomodulating Agents

Vemurafenib

Mesna

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Protein Kinase Inhibitors

Enzyme Inhibitors

Two weeks prior to the start of the preparative regimen, patients will begin taking vemurafenib. Patients will then receive lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine, followed by young TIL and high dose aldesleukin

Vemurafenib will administered orally twice a day at a dose of 960 mg from day -21 (+/- 7 days)until disease progression or patients are taken off protocol.

Young TIL will be administered intravenously on day 0(1x10e9 to 2x10e11) in the Patient Care Unit over 20-30 minutes via non-filtered tubing, gently agitating the bag during infusion to prevent cell clumping.

Young TIL

Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.

Aldeskeukin 720,000 IU/kg IV (based on total body weight)over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses)

Steven A Rosenberg, M.D.

Background:

- One possible treatment for advanced melanoma involves collecting white blood cells from the person with cancer and growing them in a laboratory. The cells can then be given back to the donor. This study will use this white blood cell treatment with the cancer treatment drug vemurafenib. Vemurafenib targets melanoma cells that have a mutation in the B-raf gene, and may be able to make them shrink.

Objectives:

- To see if vemurafenib and white blood cell therapy is a safe and effective treatment for advanced melanoma.

Eligibility:

- Individuals at least 18 years and less than or equal to 66 years of age who have advanced melanoma that contains the B-raf genetic mutation.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
* White blood cells will be collected from tumor cells. These cells will be collected during surgery or a tumor biopsy.
* Participants will have leukapheresis to collect additional white blood cells for the procedure.
* Participants will take vemurafenib twice a day, starting 3 weeks before receiving the white blood cells.
* Participants will have 1 week of chemotherapy to prepare their immune system to accept the white blood cells.
* Participants will receive an infusion of their collected white blood cells. They will also receive aldesleukin for up to 5 days to boost the immune system s response to the white blood cells. They will remain in the hospital until they have recovered from the treatment.
* Participants will have frequent follow-up visits to monitor the outcome of the treatment.

Background:

Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can mediate the regression of bulky metastatic melanoma when administered to the autologous patient along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.

Vemurafenib (VEM) administration has been shown to mediate objective responses in 50-60 percent of patients with metastatic melanoma bearing a BRAF mutation though many of these responses are transient.

There are several reasons to suggest that the combination of ACT with VEM will synergize in the destruction of melanoma including 1) rapid tumor destruction by VEM may provide a vaccine-like stimulus to the transferred TIL; 2) VEM has been shown to upregulate the expression of melanoma antigens; 3)VEM may make residual melanoma cells more sensitive to immune damage.

Objectives:

The primary objective is to determine the safety of the administration of vemurafenib in conjunction with ACT consisting of autologous TIL infused along with high dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen.

The secondary objectives are:

* To gain preliminary information concerning the ability of the combination therapy to mediate clinical tumor regression in patients with metastatic melanoma.
* To study the immunologic impact of VEM administration on the lymphoid infiltrate in melanoma deposits.

Eligibility:

Patients greater than or equal to 18 years old with pathologically confirmed diagnosis of

metastatic melanoma that expresses the VtoE BRAF mutation and VtoK BRAF mutation.

Patients with measurable disease, absolute neutrophil count greater than 1000/mm(3) and platelet count greater than 100,000/mm(3).

No serious comorbid conditions such as active systemic infections, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory or immune systems.

Design:

Patients will undergo biopsy or resection to obtain tumor for generation of autologous TIL cultures.

When cryopreserved TIL are available patients will begin the administration of VEM 960 mg (day 1) twice daily until disease progression or patients are taken off protocol.

On day -7, patients will begin a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day IV) on days -5 through -1.

On day 0, patients will receive between 1x109 to 2x1011 young TIL and then begin high dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).

Clinical and immunologic responses will be evaluated about 4-6 weeks after the last dose of aldesleukin.

This pilot trial will accrue 25 patients.

Vemurafenib and White Blood Cell Therapy for Advanced Melanoma

A Pilot Trial of the Combination of Vemurafenib With Adoptive Cell Therapy in Patients With Metastatic Melanoma

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for b raf inhibitor