Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Melanoma

Carcinoma, Renal Cell

Melanoma, Cutaneous Malignant

Kidney Neoplasms

Carcinoma

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

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Renal Cell Carcinoma

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Melanoma (skin cancer). Cyclophosphamide 60 mg/kg/day intravenous on days -8 and -7. Fludarabine 25 mg/m\^2 day intravenous on days -6 through -2. IL-2 720,000 IU/kg/intravenous every 8 hours for up to 5 days. Thirty minutes infusion of natural killer (NK) cells 2 days after last dose of chemotherapy.

Renal cell (kidney cancer). Cyclophosphamide 60 mg/kg/day intravenous on days -8 and -7. Fludarabine 25 mg/m\^2 day intravenous on days -6 through -2. IL-2 720,000 IU/kg/intravenous every 8 hours for up to 5 days. Thirty minutes infusion of natural killer (NK) cells 2 days after last dose of chemotherapy.

Thirty minutes infusion of natural killer (NK) cells 2 days after last dose of chemotherapy.

Natural Killer (NK) Lymphocytes

IL-2 720,000 IU/kg/intravenous every 8 hours for up to 5 days.

IL-2

Cyclophosphamide 60 mg/kg/day intravenous on days -8 and -7.

Fludarabine 25 mg/m\^2 day intravenous on days -6 through -2.

Background:

* Natural killer (NK) cells are large lymphocytes (a type of white blood cell) that are important in the immune response to cancer.
* IL-2 (Aldesleukin) is a substance the body makes that controls the growth and function of many types of cells. The Food and Drug Administration has approved IL-3 for treating metastatic melanoma and kidney cancer. (Metastatic disease is cancer that has spread beyond the primary site.)

Objectives: To determine the safety and effectiveness of treating metastatic melanoma and kidney cancer with laboratory-treated NK cells and IL-2.

Eligibility: Patients 18 years of age or older with metastatic melanoma or kidney cancer who have previously been treated with high-dose IL-2.

Design:

* Leukapheresis. Patients under leukapheresis to obtain NK cells for the treatment regimen. Blood is collected through a needle in an arm vein and directed through a cell separator machine where white blood cells are extracted. The rest of the blood is returned to the patient through a needle in the other arm. NK cells are removed from the white blood cells and treated for re-infusion into the patient.
* Chemotherapy. Starting 8 days before infusion of the treated NK cells, patients receive intravenous (IV, through a vein) infusions of cyclophosphamide and fludarabine to suppress the immune system.
* NK cell infusion. Patients receive a 30-minute IV infusion of NK cells 2 days after the last dose of chemotherapy.
* IL-2 therapy. Within 24 hours of the NK cell infusion, patients receive high-dose IL-2 as a 15-minute IV infusion every 8 hours for up to 5 days. A second cycle of IL-2 is given about 14 days after the first.
* Blood tests and biopsy. Patients have frequent blood tests during the treatment period and may be asked to undergo a biopsy (surgical removal of a small piece of tumor or lymph node) at the end of treatment to look at the effects of the treatment on the tumor immune cells.
* Follow-up evaluation. Patients are evaluated 4-6 weeks after completing treatment. They have a physical examination, scans of tumor sites, blood tests and blood sampling (or leukapheresis) to examine the response to treatment. Patients who improve with treatment return for evaluations every month. Those whose tumor grows again after originally shrinking may receive one additional treatment course.

Background:

* Natural killer (NK) cells are large granular lymphocytes that are critical effector cells in the early innate immune response to pathogens and cancer.
* Previous and current clinical investigations have clearly demonstrated that T lymphocytes can mediate the regression of metastatic melanoma. However, not all patients with cancer are eligible for this type of immunotherapy either because resectable tumor is not available, the TIL do not expand sufficiently, or the tumor infiltrating lymphocytes (TIL) that do proliferate do not exhibit sufficient tumor specific reactivity.
* We have recently developed techniques for the in vitro isolation and expansion of anti-tumor NK cells to levels suitable for the treatment of cancer patients and are proposing in this protocol to evaluate therapy using these NK cells.
* In Surgery Branch pre-clinical experiments, we evaluated lysis of fresh melanoma cell digests, melanoma cell lines, renal cell carcinoma (RCC) lines, and normal peripheral blood mononuclear cells (PBMCs) by NK cells from several patients and demonstrated that NK cells could lyse some fresh melanoma digests, as well as melanoma cell lines and renal cell cancer (RCC) lines, while sparing normal allogeneic and autologous PBMCs.

Objectives:

* Determine the ability of the administration of autologous natural killer (NK) cells plus aldesleukin (IL-2) following a non-myeloablative lymphodepleting preparative regimen to mediate tumor regression in patients with metastatic melanoma or kidney cancer.
* Determine the rate of repopulation of the natural killer cells in treated patients.
* Determine the toxicity of this treatment regimen.

Eligibility:

* Patients, 18 years of age or older with metastatic melanoma or metastatic kidney cancer who have previously received high dose IL-2, with an Eastern Cooperative Oncology Group (ECOG) of 0 or 1.
* Patients may not have any active systemic infections, coagulations disorders, major medical illnesses of the cardiovascular, respiratory or immune systems or any form of autoimmune disease or immunodeficiency.

Patients must be eligible to receive high-dose IL-2.

Design:

* Patients will undergo apheresis on 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols) to obtain cells for generation of autologous natural killer cells.
* All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -8 and -7 and fludarabine (25 mg/m\^2/day IV) on days -6 through -2.
* On day 0 patients will receive the infusion of autologous natural killer lymphocytes and then begin the first cycle of high-dose IL-2 (720,000 IU/kg IV every 8 hours for up to 15 doses). A second cycle of IL-2 will be administered approximately 14 days later.
* Clinical and Immunologic response will be evaluated about 4 to 6 weeks

after the second cycle of IL-2.

-Using a small optimal Phase II design, two cohorts of patients, initially 16 in each cohort, will be enrolled, and if at least one of the first 16 patients has a clinical response (partial response (PR) or complete response (CR)), accrual will continue to 29 patients, targeting a 15% goal for objective response.

Natural Killer Cells Plus IL-2 Following Chemotherapy to Treat Advanced Melanoma or Kidney Cancer

Phase II Study in Metastatic Melanoma or Kidney Cancer Using Autologous Natural Killer Cells Plus Aldesleukin (IL-2) Following a Lymphodepleting Chemotherapy

Objective response (complete response (CR) or partial response (PR)) is measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

National Cancer Institute (NCI)

Steven A. Rosenberg, M.D./National Cancer Institute

NK Cells + IL-2: Melanoma

NK Cells + IL-2: Renal Cell

Total

Age, Categorical

Age Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Steven A. Rosenberg, M.D.

Complete Response

Partial Response

Objective Response

Safety

Overall Study

Symptoms and General Pathology

Neoplasm Metastasis

Neoplastic Processes

Analgesics

Lenograstim

Interleukin-2

Mesna

Antimetabolites

Adjuvants, Immunologic

Analgesics, Non-Narcotic

Melanoma is a serious form of skin cancer that develops in the skin cells that make our skin color (melanocytes).

Peripheral blood lymphocytes are harvested by lymphapheresis and engineered to express a T cell receptor that binds to P53.

anti-protein 53 or tumor protein 53 (p53) T-cell receptor transduced peripheral blood lymphocytes

720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 5 days

aldesleukin

Beginning on day 1 or 2, administered subcutaneously at a dose of 5 mcg/kg/day (not to exceed 300 mcg/day); continue daily until neutrophil count \> 1.0 x 10\^9/L x 3 days or \> 5.0 x 10\^9/L.

filgrastim

60 mg/kg/day x 2 days intravenously in 250ml dextrose 5% in water (D5W) with mesna 15 mg/kg/day x 2 days over 1 hour.

cyclophosphamide

25 mg/m2/day intravenously piggyback (IVPB) daily over 30 minutes for 5 days.

fludarabine phosphate

Steven A Rosenberg, M.D., Ph.D

Background:

The p53 gene normally suppresses tumor growth, but when it is mutated, or damaged, tumors can grow unchecked.

In cancers where the p53 gene has mutated, an increased level of p53(overexpression of p53) can be measured in the tumor.

Objectives To determine whether advanced cancers that overexpress p53 can be treated effectively with lymphocytes (white blood cells) that have been genetically engineered to contain an anti-p53 protein.

Eligibility Patients 18 years of age and older with metastatic cancer (cancer that has spread beyond the original site) Patient's tumor overexpresses p53 Patient's leukocyte antigen type is HLA-A 0201 Design

Patients undergo the following procedures:

Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the anti-p53 protein is inserted into the cells using an inactivated (harmless)virus in a process called transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.

Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) for 1 week to suppress the immune system so that the patients immune cells do not interfere with the treatment.

Treatment with anti-p53 cells. Patients receive an IV infusion of the transduced cells containing anti-p53 protein, followed by infusions of a drug called IL-2, which helps boost the effectiveness of the transduced white cells.

Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue). Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans 4 to 6 weeks after treatment and then once a month 3 to 4 months to determine the response to treatment.

Patients have blood tests at 1, 3, 6 and 12 months and then annually for the next 10 years.

Background:

Human peripheral blood lymphocytes (PBL's) can be engineered to express alpha T-cell receptor that recognizes an human leukocyte antigen serotype witin HLA-A A serotype group) HLA-A2. 1 restricted epitope derived from the p53 protein.

We constructed a single retroviral vector that contains both alpha and existent chains and can mediate genetic transfer of this TCR with high efficacy (less than 30%) without the need to perform any selection.

In co-cultures with HLA-A2 and p53 double positive tumors including melanoma, hepatoma, sarcoma, small-cell lung cancer, esophageal and breast tumors, p53-TCR transduced T cells secreted significant amount of IFN-(but no significant secretion was observed in control co-cultures with either HLA-A2+/p53- or HLA-A2-p53+cell lines.

Additional secretion of cytokines (IL-2, IL-4, IL-10,granulocyte macrophage stimulating factor (GM-CSF),tumor necrosis factor alpha (TNFalpha)) and chemokines (regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha (MIP-1 alpha)) was also observed in co-cultures with HLA-A2+/p53+tumor lines.

p53-TCR transduced PBL could efficiently kill HLA-A2, 1/p53 expressing tumors (H2087, MDA-MB 231, Saos2/143, BE-3).

In addition, we also tested for specific lysis of normal tissues by p53-TCR transduced cells and there was little or no lysis of the normal fibroblasts, renal epithelia cells, resting or activated normal PBLs compared to control HLA_A2+/p53+H2087 tumor.

Objectives:

Primary objective:

Determine of the administration of anti-p53 TCR-engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer overexpressing p53.

Secondary objectives:

Determine the in vivo survival of TCR gene-engineered cells. Determine the toxicity profile of this treatment regimen.

Eligibility:

Patients who are HLA A0201 and 18 years of age or older must have metastatic cancer whose tumors overexpress p53; previously received and have been a non-responder or recurred to standard care for metastatic disease; biopsy available to evaluate p53 expression; 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:

PBMC, obtained by leukapheresis (approximately 5 x 10\^9 cells) will be cultured in the presence of anti-CD3 Muromonab-CD3( OKT3) and IL-2 in order to stimulate T-cell growth.

Transduction is initiated by exposure of approximately 10\^8 to 5 x 10\^8 cells to supernatant containing the anti-p53 TCR retroviral vector. These transduced cells will be expanded and tested for their anti-tumor activity.

Patients will receive a nonmyeloablative but lymphocyte depleting preparative regiment consisting of cyclophosphamide and fludarabine followed by intravenous infusion of in vitro tumor reactive, TCR gene-transduced PBL plus IV aldesleukin (720,000IU/kg q8h for a maximum of 15 doses).

Patients will undergo complete evaluation of tumor with physical examination, 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.

Patients will be entered into two cohorts based on histology: cohort 1 will include patients with metastatic melanoma or renal cell cancer, cohort 2 will include patients with other types of metastatic cancer.

For each of the 2 strata evaluated, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. For each of these two arms of the trial, 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 in that stratum.

For both strata, the objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-p53 TCR-gene engineered lymphocytes is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).

Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes

Phase II Study of Metastatic Cancer That Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-p53 T Cell Receptor (TCR)-Gene Engineered Lymphocytes

Response Evaluation Criteria In Solid Tumors (RECIST).

See the protocol Link module for full criteria if desired.

Here are the total number of participants with adverse events. Adverse events were described using the Common Terminology Criteria for Adverse Events (CTCAE) version 3. For the detailed list of adverse events see the adverse event module.

Survival of TCR gene-engineered cells is defined as \>10% murine TCR positive cells.

Steven A. Rosenberg, M.D., Ph.D.

Metastatic Melanoma

Other Metastatic Cancers

Steven Rosenberg, M.D., Ph.D.

Melanoma is a serious form of skin cancer that develops in the skin cells that make our skin color (melanocytes).

There are no statistical differences between the arms, therefore, they can be combined for this outcome measure.

Metastatic Melanoma & Other Metastatic Cancers

Clinical Tumor Regression

The Number of Participants With Adverse Events

In Vivo Survival of T-cell Receptor (TCR) Gene-engineered Cells in Participants

Blood and Lymph Conditions

Leukemia

Leukemia, Promyelocytic, Acute

Hematologic Diseases

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Acute Graft Versus Host Disease

Acute Promyelocytic Leukemia

Arsenic Trioxide

Duration of maintenance therapy with single agent ATO of 12 months

Duration of maintenance therapy with single agent ATO for 6 months

duration of maintenance therapy, 6 months versus 12 months

Single agent arsenic trioxide

Vikram Mathews, MD

Mammen Chandy, MD

P P Bapsy, MD

Cecil Ross, MD

Geetha Narayanan, MD

Krishnan Nair, MD

Tapan Saikia, MD

Farah Jijina, MD

Farrah Jijina, MD

Reena Nair, MD

Purvish Parikh, MD

Shashi Apte, MD

Ashis Mukherjee, MD

Ashish Mukherjee, MD

Atul Sharma, MD

Vinod Kochupillai, MD

There is very limited data on the use of arsenic trioxide in newly diagnosed patients with acute promyelocytic leukemia. The use of arsenic trioxide was limited to relapsed patients mainly because of the superior efficacy of ATRA as primary therapy for newly diagnosed APML. Though the early study by Niu et al showed 72% remission rates in 11 newly diagnosed patients, the role of arsenic trioxide as primary therapy was limited by the hepatic toxicity seen in this study. Studies from our centre have shown remission rates of 70-75% in newly diagnosed patients with acute promyelocytic leukemia. There was no major toxicity seen related to the administration of arsenic trioxide. Follow up data on these patients continue to show long term remission rates above 70%. These remission rates are similar to the data available in patients with acute promyelocytic leukemia treated with ATRA. Lu et al studied 19 patients treated with oral arsenic (Tetra-arsenic tetra-sulfide) wherein 84% achieved hematological remission with disease free survival of 76% at 3 years. Studies from other groups using arsenic trioxide alone or in combination with ATRA have shown similar remission rates. Arsenic trioxide as primary therapy for patients with newly diagnosed acute promyelocytic leukemia is a very attractive treatment option for developing countries mainly because of the low cost involved along with the favorable toxicity profile. However long term remission data is still not available and the ideal course and duration of treatment still needs to be defined. This multi-center study aims to further clarify the efficacy of this agent in the treatment of newly diagnosed cases of acute promyelocytic leukemia and to study the optimal maintenance regimen.

This multicenter trial will study the clinical and molecular response among patients with newly diagnosed acute promyelocytic leukemia (APL) who fulfill the inclusion and exclusion criteria.

Patients included in this trial should have been diagnosed to have Acute Promyelocytic Leukemia morphologically on FAB criteria. This is sufficient to initiate therapy with arsenic trioxide (ATO) but this diagnosis has to be confirmed using either Fluorescent in situ hybridization (FISH) for t(15;17) or reverse transcriptase polymerase chain reaction assay (RT-PCR) for PML-RARalpha transcripts within 7 days of inclusion into the study.

All these patients would have in the absence of this study received only palliative therapy due to the lack of resources to support standard chemotherapy.

Women who are pregnant will not be considered for this study.

Treatment Protocol: All patients who are included in this study will be initiated on treatment with ATO. Arsenic tri-oxide (10 mg/10ml) will be diluted in 500 ml of Dextrose Saline (only glass bottles to be used) and infused intravenously over 3 - 4 hours once a day.

No premedication is required prior to administration of the drug. The dosage schedule for administration will be as follows:

Adults: 10 mg once a day Children or adults \<45kg: 0.15 mg/kg/day (maximum dose = 10mg) once a day

The total courses of therapy will be as follows:

Induction therapy: Induction therapy will be continued till ANC\> 1.5 x 10e9/L and Platelet count \> 100 x 10e9/L along with the absence of abnormal promyelocytes in peripheral smear on 2 consecutive occasions. Once this is achieved, bone marrow studies will be done to assess remission. If the bone marrow shows \< 5% of myeloblasts and promyelocytes along with a normocellular to mildly hypocellular marrow, arsenic can be stopped. If not in CR, arsenic is continued for an additional 2 weeks and a repeat bone marrow is done to confirm CR. Arsenic tri-oxide will be given for a maximum of 60 days following which the patient would be considered a non-responder/partial responder and excluded from further treatment. If bone marrow shows \<5% blasts and promyelocytes at 60 days but peripheral blood count criteria for CR are not fulfilled, patient can be still be continued on the study regimen.

Consolidation therapy: All patients who achieve CR will receive consolidation therapy for a period of 28 days after an interval of 4 weeks from achieving hematological CR. The dosage and mode of administration will be similar to the schedule followed in induction.

Maintenance therapy: All patients who are in molecular CR at the end of consolidation therapy will be randomized into 2 groups:

Group A: This group will receive 12 months of maintenance therapy. ATO will be administered for 10 days every month for a period of 12 months.

Group B: This group will receive 6 months of maintenance therapy. ATO will be administered for 10 days every month for a period of 6 months.

All patients who continue to be RT-PCR positive at the end of consolidation will not be randomized and will continue to receive all the courses of maintenance treatment. Subsequent therapy will be individualized based on the molecular monitoring results.

A total of 400 patients will be recruited at the time of initiation into this study. We expect a loss to follow up/treatment failure/death of approximately 10% of the study population and hence 360 patients will be randomized into the final 2 arms of the study ie maintenance therapy for 12 months versus 6 months after completing the consolidation therapy.

Patients with CNS disease will be treated with therapeutic Radiotherapy and intrathecal chemotherapy using Cytosine, Hydrocortisone and Methotrexate.

Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia

Molecular Remission With Arsenic Trioxide in Acute Promyelocytic Leukemia: Indian APL Study Group - IAPLSG

Ministry of Science and Technology, India

Christian Medical College, Vellore, India

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Natural Killer Cells Plus IL-2 Following Chemotherapy to Treat Advanced Melanoma or Kidney Cancer	NCT00328861	Metastatic Mela... Metastatic Kidn...	Natural Killer ... IL-2 Cyclophosphamid... Fludarabine	18 Years -	National Institutes of Health Clinical Center (CC)
Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes	NCT00393029	Anti-p53 TCR-Ge...	anti-protein 53... aldesleukin filgrastim cyclophosphamid... fludarabine pho...	18 Years -	National Institutes of Health Clinical Center (CC)
Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia	NCT00517712	Acute Promyeloc...	Single agent ar...	-	Christian Medical College, Vellore, India
Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes	NCT00393029	Anti-p53 TCR-Ge...	anti-protein 53... aldesleukin filgrastim cyclophosphamid... fludarabine pho...	18 Years -	National Institutes of Health Clinical Center (CC)
Phase II Study of Metastatic Cancer That Overexpresses P53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-P53 TCR-Gene Engineered Lymphocytes	NCT00393029	Anti-p53 TCR-Ge...	anti-protein 53... aldesleukin filgrastim cyclophosphamid... fludarabine pho...	18 Years -	National Institutes of Health Clinical Center (CC)
Natural Killer Cells Plus IL-2 Following Chemotherapy to Treat Advanced Melanoma or Kidney Cancer	NCT00328861	Metastatic Mela... Metastatic Kidn...	Natural Killer ... IL-2 Cyclophosphamid... Fludarabine	18 Years -	National Institutes of Health Clinical Center (CC)

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