Natural Killer Cells and Bortezomib to Treat Cancer - Full Text View

Sponsor:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00720785

Purpose

Natural killer (NK) cells are white blood cells that have a limited ability to kill cancer cells. This ability might be enhanced if they are given 24 hours after an injection of the drug bortezomib. This study will determine the following:

What dose of NK cells can be given safely to subjects with metastatic solid tumors or leukemia.
The effectiveness and side effects of NK cell therapy
How the body handles NK cells.

People between 18 and 70 years of age who have a solid tumor or leukemia, and for whom standard treatments are not effective, may be eligible for this study. Participants undergo the following procedures:

Apheresis to collect NK cells. For this procedure, a catheter (plastic tube) is placed in a vein in the subject's arm. Blood flows from the vein into a cell separator machine, which separates the white cells from the other blood components. The white cells are extracted and the rest of the blood is returned to the body through a second tube placed in a vein in the other arm.

Chemotherapy with the drug pentostatin to suppress the immune system and prevent it from attacking the NK cells that will be infused.

Chemotherapy with bortezomib to increase NK cell function.

Infusion of the NK cells. In this dose-escalating study, successive groups of patients entering the study receive increasingly higher numbers of cells to determine the highest safe dose level. Up to four dose levels may be studied.

Interleukin-2 drug therapy to maintain NK cell activity.

Evaluations during therapy including:

Clinical assessment, history and review of medications
Blood draws for routine and research tests.
Pharmacokinetics study after the NK infusion to see how the body handles the cells. For this test, the number of NK cells in the blood are measured over time. This requires drawing about 1 teaspoon of blood at 15 minutes, 30 minutes, 1, 2, 4, 8, 12, and 24 hours after the infusion (day 1); then every 24 hours on days 2 through 7, then once on days 10, 14, and 21.
Bone marrow biopsy (subjects with leukemia only).
Chest x-ray.
CT scan, bone scan and PET scan, if indicated, for disease evaluation.

Patients who respond well after one treatment cycle may be eligible to continue NK cell therapy.

Condition	Intervention	Phase
Lung or Prostatic Neoplasms Colorectal or Kidney Neoplasms Pancreatic Neoplasms Leukemia, Myelogenous, Chronic, BCR-ABL Positive Melanoma	Drug: NK cells +CliniMACs CD3 and CD56 systems	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Safety and the Anti- Tumor Effects of Escalating Doses of Adoptively Infused Ex Vivo Expanded Autologous Natural Killer (NK) Cells Against Metastatic Cancers or Hematological Malignancies Sensitized to NK-TRAIL Cytotoxicity With Bortezomib

Resource links provided by NLM:

MedlinePlus related topics: Cancer Kidney Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Melanoma Pancreatic Cancer Prostate Cancer

Drug Information available for: Bortezomib

U.S. FDA Resources

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

Primary Outcome Measures:

Safety of escalating NK cell doses

Secondary Outcome Measures:

The anti-neoplastic effects of this treatment regimen (assessed using standard disease specific response criteria) and the toxicity profile associated with extended cycles of protocol therapy.

Estimated Enrollment:	32
Study Start Date:	July 2008
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Intervention Details:

N/A

Detailed Description:

Natural killer (NK) cells are innate immune lymphocytes that are identified by the expression of the CD56 surface antigen and the lack of CD3. Unlike antigen specific T cells, NK cells do not require the presence of a specific tumor antigen for the recognition and killing of cancer cells. Our in vitro studies have demonstrated that pretreatment of malignant cells with bortezomib significantly enhances NK-mediated tumor cytotoxicity by sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL). TRAIL is a member of tumor necrosis factor family of cytokines that promotes apoptosis. Importantly, in our laboratory, in vitro expanded NK cells isolated from patients with metastatic cancers or hematological malignancies exhibited significantly more cytotoxicity against their tumor cells when tumors were pre-treated with bortezomib compared with untreated tumor controls. These findings suggest that drug-induced sensitization to TRAIL could be used as a novel strategy to potentiate anticancer effects of autologous adoptively infused NK cells in patients with cancer.

Murine studies conducted in our laboratory have also established that bortezomib treatment sensitizes tumors in vivo to killing by adoptively infused syngeneic NK cells; murine renal cell carcinoma line (RENCA) tumors in BALB/c mice grew significantly slower and survival was prolonged when syngeneic NK cell infusions were given following bortezomib treatment compared to mice receiving NK cell infusions alone or bortezomib alone. This anti-tumor effect was further potentiated by eradicating T-regulatory cells prior to adoptive NK cell infusion and by administering interleukin-2 after adoptive NK cell infusion.

Recently, our laboratory has developed techniques for the in vitro isolation and expansion of NK cells to levels suitable for the treatment of cancer patients. Furthermore, we have also established good viability and sterility of these expanded NK cells which, compared to fresh NK cells, have increased surface expression of TRAIL and have enhanced cytotoxicity against tumor cells.

We therefore propose this non-randomized, Phase I, dose escalating study designed to evaluate the safety and the anti- tumor effects of escalating doses of adoptively infused ex vivo expanded autologous natural killer (NK) cells against metastatic cancers or hematological malignancies sensitized to NK -TRAIL cytotoxicity with Bortezomib.

The primary study objective is to determine the safety (maximum tolerated dose) of escalating NK cell doses of adoptively infused ex vivo expanded autologous NK cells in patients with treatment refractory metastatic tumors or hematological malignancies that are sensitized to NK cell cytotoxicity using bortezomib. Secondary objectives will include the anti-neoplastic effects of this treatment regimen (assessed using standard disease specific response criteria) and the toxicity profile associated with extended cycles of protocol therapy.

The primary endpoint will be assessed at day 21 (3 weeks after NK cell infusion).

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:
1. Diagnosed with histologically confirmed metastatic solid tumor - cancer of the lung (small cell or non small cell), prostate (adenocarcinoma), colorectum, kidney (renal cell carcinoma), pancreas (adenocarcinoma), or malignant melanoma, and disease confirmed to be metastatic and unresectable for which standard curative or beneficial treatments are no longer effective.
  
  OR
  
  Diagnosed with a hematological malignancy (chronic myelogenous leukemia [CML] or chronic lymphocytic leukemia [CLL] or small lymphocytic lymphoma [SLL]) and disease resistant or refractory to standard therapy and CLL/SLL patients are required to have failed prior treatment with at least one nucleoside analogue.
2. least 4 weeks since any prior systemic therapy (excluding corticosteroid therapy) to treat the underlying malignancy (standard or investigational).
3. At least 2 weeks since prior palliative radiotherapy.
4. Ages greater than or equal to 18 years and less than or equal to 70 years.
5. Evidence of progressive disease over a 3-month interval.
6. Hbg greater than 9.0 and RBC transfusion independent (solid tumor patients only).

EXCLUSION CRITERIA:

Disease not evaluable radiographically (applies to solid tumor patients only).
Disease involving greater than 25% of the liver radiographically (estimated based on review of liver lesions seen on CT scan ).
History of an allogeneic hematopoietic stem cell transplant.
Brain metastases (with the exception of patients with a single brain metastasis less than 1cm treated with either sterotactic or gamma knife radiotherapy) due to poor prognosis and potential for neurological dysfunction that would confound evaluation of neurological and other adverse events).
Peripheral neuropathy of grade greater than 1, which would require reduction of bortezomib dose.
Acute diffuse infiltrative pulmonary disease.
Acute pericardial disease.
Life expectancy less than 3 months.
ECOG performance status 2, 3 or 4.
Uncontrolled concurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, life threatening cardiac arrhythmia. Patients with symptoms of coronary artery disease, cardiac arrhythmias or an abnormal thallium stress test must be evaluated and cleared by cardiology prior to enrollment.
Ongoing or active infection.
Contraindication for administration of pentostatin, bortezomib, and/or interleukin-2.
Allergy or hypersensitivity to bortezomib, boron or mannitol by history.
Concurrent use of corticosteroids.
Organ and marrow function characterized by
- Leukocytes less than 2,500/mcL
- Absolute neutrophil count less than 1,500/mcL (must be present off growth factors)
- Platelets less than 100,000/mcL
- Total bilirubin greater than 3 times upper limit of normal
- AST (SGOT)/ALT (SGPT) greater than 4 times upper limit of normal
- Creatinine clearance less than 50 cc/min based on a 24 hour urine collection
- Left ventricular ejection fraction less than 40% by echocardiogram (ECHO)
- Hypercalcemia greater than 2.5 mmol/L
HIV-positive patients
Hepatitis C positive patients
Active Hepatitis B infection (Hep B surface antigen positive)
Pregnant or nursing
Psychiatric illness/social situations that would limit compliance with study requirements and ability to comprehend the investigational nature of the study and provide informed consent.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00720785

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

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

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

More Information

Additional Information:

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

Publications:

Farag SS, Fehniger TA, Becknell B, Blaser BW, Caligiuri MA. New directions in natural killer cell-based immunotherapy of human cancer. Expert Opin Biol Ther. 2003 Apr;3(2):237-50. Review.

Farag SS, Caligiuri MA. Human natural killer cell development and biology. Blood Rev. 2006 May;20(3):123-37. Epub 2005 Dec 20. Review.

Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L, Dang NH, Samaniego F, Wang M, Broglio K, Samuels B, Gilles F, Sarris AH, Hart S, Trehu E, Schenkein D, Cabanillas F, Rodriguez AM. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2005 Feb 1;23(4):667-75. Epub 2004 Dec 21.

Study ID Numbers:	080186, 08-H-0186
Study First Received:	July 22, 2008
Last Updated:	August 24, 2009
ClinicalTrials.gov Identifier:	NCT00720785 History of Changes
Health Authority:	United States: Federal Government

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

Metastatic Solid Tumor
Chronic Myelogenous Leukemia (CML)
Small Lymphocytic Lymphoma (SLL)
Tumor Cytotoxicity
Chronic Lymphocytic Leukemia (CLL)
Metastatic Solid Tumor
Lung Cancer
Prostate Cancer
Colon Cancer

Kidney Cancer
Pancreatic Cancer
Leukemia
Chronic Myelogenous Leukemia
CML
Small Lymphocytic Lymphoma
SLL
Chronic Lymphocytic Leukemia
CLL

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Prostatic Diseases
Genital Neoplasms, Male
Antineoplastic Agents
Pancreatic Neoplasms
Neoplasms, Nerve Tissue
Urogenital Neoplasms
Urologic Neoplasms
Melanoma
Leukemia
Neoplasms by Site
Urologic Diseases
Kidney Neoplasms
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal

Nevi and Melanomas
Kidney Diseases
Endocrine Gland Neoplasms
Neoplasms by Histologic Type
Digestive System Neoplasms
Hematologic Diseases
Bortezomib
Myeloproliferative Disorders
Endocrine System Diseases
Enzyme Inhibitors
Leukemia, Myeloid
Genital Diseases, Male
Pharmacologic Actions
Protease Inhibitors
Neuroendocrine Tumors

ClinicalTrials.gov processed this record on November 27, 2009